Perioperative chemotherapy for resectable colorectal liver metastases: Where now?

doi:10.1016/j.ejso.2013.04.002

European Journal of Surgical Oncology (EJSO)

Volume 39, Issue 8, August 2013, Pages 807-811

https://doi.org/10.1016/j.ejso.2013.04.002 Get rights and content

Abstract

Following the publication of the EORTC trial (40983), perioperative chemotherapy has become the standard of care for all patients with resectable colorectal cancer liver metastases (CRLM). However recently presented data suggest that the earlier advantage seen in progression free survival (PFS) may not translate over into a meaningful overall survival (OS) advantage. At the other end of the spectrum, patients with irresectable but liver limited CRLM continue to be offered treatment based on improving PFS, at the expense of regimens with greater response rates (but maybe poorer PFS rates) that could bring them to potentially curative liver resection. We therefore argue that patients with liver limited CRLM should be managed in three separate groups:

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Group One: those with easily resectable disease who should be offered immediate surgery, followed by adjuvant therapy if considered appropriate.
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Group Two: those with borderline resectable or high recurrence risk CRLM who could be offered appropriate systemic neoadjuvant therapy prior to planned liver surgery.
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Group Three: those with inoperable but liver limited CRLM who should be offered the most effective and appropriate systemic therapy with the primary purpose of achieving maximal disease response (and not PFS) with the intention of conversion to surgical resectability with curative intent.

Section snippets

Conflict of interest statement

GJP was a co-investigator of the EORTC 40983 trial.

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Cited by (32)

Neoadjuvant chemotherapy for borderline resectable colorectal cancer liver metastases: a single-institution retrospective study
2024, HPB
This study aimed to extract prognostic factors in patients undergoing neoadjuvant chemotherapy (NAC) for borderline resectable colorectal liver metastasis (BR-CRLM) (tumor size ≥5 cm, number of tumors ≥4, or resectable extrahepatic diseases) and assess validity of this strategy.
Since 2010, patients with BR-CRLM were treated with hepatectomy after six cycles of NAC. Prognostic factors of these patients were evaluated using clinicopathological data.
Of 650 patients who underwent initial hepatectomy for CRLM from 2010 to 2018, 246 BR-CRLM cases underwent hepatectomy after NAC (BR-NAC). The 5-year recurrence-free survival rate was 16.7% and the 5-year overall survival rate (5y-OS) was 52.9%. Number of tumors ≥6, carcinoembryonic antigen (CEA) level ≥25 ng/mL, tumor diameter ≥5 cm, and progressive disease (PD) after NAC were identified as independent poor prognostic factors for OS. Patients were divided into four groups according to the number of risk factors, and prognoses of the four groups were well stratified.
In patients with BR-NAC, number of tumors ≥6, CEA ≥25 ng/mL, tumor diameter ≥5 cm, and PD after NAC were independent poor prognostic factors. Patients with three or four risk factors showed poor prognosis and may need to switch chemotherapy.
PARAGON II – A single arm multicentre phase II study of neoadjuvant therapy using irinotecan bead in patients with resectable liver metastases from colorectal cancer
2016, European Journal of Surgical Oncology
Citation Excerpt :
These results compare favourably with reports describing alternative methods of liver directed therapy, such as hepatic arterial infusion pumps.20,21 Contemporary trials assessing irinotecan based therapies for systemic disease report dose-limiting side effects (diarrhea and neutropenia) in 10–15% of cases22 and the use of neoadjuvant systemic therapy for initially resectable disease remains controversial.5,6,24 Preliminary pharmacokinetic modelling from this study suggests that systemic exposure to irinotecan after DEBIRI is low25 and the absence of systemic toxicity reported in this trial suggest that DEBIRI would be a rational approach in such cases where the risk: benefit balance in favour of treatment may be marginal.
Perioperative chemotherapy confers a 3-year progression free survival advantage following resection of colorectal liver metastases (CRLM), but is associated with significant toxicity. Chemoembolisation using drug eluting PVA microspheres loaded with irinotecan (DEBIRI) allows sustained delivery of drug directly to tumour, maximising response whilst minimising systemic exposure. This phase II single arm study examined the safety and feasibility of DEBIRI before resection of CRLM.
Patients with resectable CRLM received lobar DEBIRI 1 month prior to surgery, with a radiological endpoint of near stasis. The trial had a primary end-point of tumour resectability (R0 resection). Secondary end-points included safety, pathologic tumour response and overall survival.
40 patients received DEBIRI, with a median dose of 103 mg irinotecan (range 64–175 mg). Morbidity was low (2.5%, CTCAE grade 2) with no evidence of systemic chemotoxicity. All patients proceeded to surgery, with 38 undergoing resection (95%, R0 resection rate 74%). 30-day post-operative mortality was 5% (n = 2), with neither death TACE related. 66 lesions were resected, with histologic major or complete pathologic response seen in 77.3% of targeted lesions. At median follow up of 40.6 months, 12 patients (34.3%) had died of recurrent disease with a median overall survival of 50.9 months. Nominal 1, 3 and 5-year OS was 93, 78 & 49% respectively.
Resection after neoadjuvant DEBIRI for CRLM is feasible and safe. Single treatment with DEBIRI resulted in tumour pathologic response and median overall survival comparable to that seen after systemic neoadjuvant chemotherapy.
Registered at clinicaltrials.gov (NCT00844233).
Management of disappearing colorectal liver metastases
2016, European Journal of Surgical Oncology
Citation Excerpt :
Three year overall survival (OS) rates up to 75% have been described when combining these treatment strategies in patients with extensive metastatic colorectal cancer.4 Neo-adjuvant systemic treatment can be considered in patients with initially resectable metastatic colorectal cancer, although it is doubtful whether this translates into a meaningful overall survival advantage.5,6 The EPOC trial showed no overall survival benefit for patients undergoing perioperative chemotherapy, although it was only powered to investigate progression free survival and included more than 50% of patients with a single liver metastasis.6,7
The development of new potent systemic treatment modalities has led to a significant increase in survival of patients with colorectal liver metastases. In the neo-adjuvant setting, these modalities can be used for patient selection, down staging, and conversion from non-resectable to resectable liver metastases. In addition, complete radiological disappearance of metastases can occur, the phenomenon of disappearing liver metastases.
Because only a small percentage of these patients (0–8%) have a complete radiological response of all liver metastases, most patients will undergo surgery. At laparotomy, local residual disease at the site of the disappeared metastasis is still found in 11–67%, which highlights the influence of the imaging modalities used at (re)staging. When the region of the disappeared liver metastasis was resected, microscopically residual disease was found in up to 80% of the specimens. Alternatively, conservative management of radiologically disappeared liver metastases resulted in 19–74% local recurrence, mostly within two years.
Obviously, these studies are highly dependent on the quality of the imaging modalities utilised. Most studies employed CT as the modality of choice, while MRI and PET was only used in selective series.
Overall, the phenomenon of disappearing liver metastases seems to be a radiological rather than an actual biological occurrence, because the rates of macroscopic and microscopic residual disease are high as well as the local recurrence rates. Therefore, the disappeared metastases still require an aggressive surgical approach and standard (re)staging imaging modalities should include at least CT and MRI.
Neoadjuvant chemotherapy for resectable colorectal liver metastases: What is the evidence? Results of a systematic review of comparative studies
2015, Surgeon
Citation Excerpt :
However, pre-operative chemotherapy can cause liver damage, which may increase the risk of post-operative complications. In addition, pre-operative chemotherapy may also lead to the disappearance of metastases on radiological imaging, which might result in more difficult curative surgery.8,26–29 Furthermore, some patients who undergo neoadjuvant chemotherapy progress to unresectable disease, and are excluded from potentially curative surgical treatment.30,31
The role of preoperative chemotherapy for resectable colorectal liver metastases is still highly controversial. The purpose of this systematic review is to summarize the current evidence on this topic.
A systematic literature search was performed to identify all studies published from January 2003 up to and including January 2014 regarding patients with initially resectable colorectal liver metastases. Data were examined for information about indications, operation, neoadjuvant and adjuvant therapies, perioperative results, and survival.
Fourteen retrospective studies published between 2003 and 2014 satisfied the inclusion criteria, including 1607 patients who underwent pre-operative chemotherapy and liver resection (NEO-CHT group), and 1785 patients submitted to hepatectomy with or without post-operative chemotherapy (SURG group). Postoperative mortality rates ranged from 0 to 5% in the NEO-CHT group and from 0 to 4% in SURG group. Complications ranged from 7 to 63% in both groups. Adopted pre-operative chemotherapy protocols were highly heterogeneous. The 5-year overall survival rates ranged from 38.9 to 74% in the NEO-CHT group and from 20.7 to 56% in the SURG group, with no significant difference in seven of eight studies.
This review shows that there is a lack of clear evidence on the role of neoadjuvant chemotherapy in the treatment of resectable colorectal metastases in the literature. The majority of studies were retrospective and there was high heterogeneity among them in the treatment protocols. The EORTC 40983 trial and the majority of retrospective studies did not find any overall survival advantage in patients treated with neoadjuvant therapy. Additional high-quality studies (randomized) are needed to shed light on this topic.
Optimal imaging sequence for staging in colorectal liver metastases: Analysis of three hypothetical imaging strategies
2014, European Journal of Cancer
Citation Excerpt :
The use of all three imaging modalities as a triple liver assessment is associated with low futile laparotomy rates, and is considered routinely in all patients being considered for hepatectomy at the study institution [4]. It has also been shown that management of these patients outside of a specialist multidisciplinary team (MDT), or tumour board is associated with lower resection rates, and patients being inappropriately denied curative treatment [5,6]. Consequently in the United Kingdom it is now seen as the standard of care that a specialist liver surgeon should assess all patients with liver limited metastases from colorectal cancer [7].
Computed tomography (CT), positron emission tomography CT (PET-CT) and magnetic resonance imaging (MRI) all play a role in the management of colorectal liver metastases (CRLM), but inappropriate over investigation can lead to delays in treatment and additional cost. This study aimed to determine the optimal sequence for pre-operative imaging pathway to minimise delays to treatment and healthcare costs.
All patients with colorectal liver metastases referred to a single tertiary liver specialist multidisciplinary team (MDT) between 2008 and 2011 were examined. Primary data of clinical and radiological outcomes of all patients were analysed. These data were used to construct and test 3 hypothetical imaging strategies – ‘Upfront’, ‘Sequential’ and ‘Hybrid’ models.
Six hundred and forty four consecutive patients were included. One hundred and sixty five patients were excluded for curative resection following the initial CT review. Subsequently 167/433 patients did not proceed to hepatectomies. Eighty (47.9%) of these patients had extra-hepatic disease identified on PET-CT, and 29 were due to the exclusion by MRI liver. A resectable pattern of liver disease on initial CT did not exclude patients with occult disease on PET-CT.
Based on cost analysis, assessment of initial CT, followed by MDT with subsequent PET-CT and MRI imaging thereafter (Hybrid model), was associated with the shortest time-to-decision and lowest cost.
Resectable pattern of liver metastases should not solely be used to determine the application of PET-CT for staging. Hybrid model is associated with the lowest cost and shortest time-to-treatment.
The role of hepatectomy in the management of metastatic gastric adenocarcinoma: A systematic review
2014, Surgical Oncology
Citation Excerpt :
This is not unexpected given the lack of consensus on the gold-standard chemotherapy regimen for the treatment of metastatic gastric cancer [37]. This is not dissimilar to the setting of colorectal liver metastasis where the role of perioperative chemotherapy in patients with resectable hepatic metastasis remains unclear [38]. The degree of variation in the chemotherapeutic agents, and patients treated made it difficult to draw firm conclusions as to the optimum role of chemotherapy in the setting of hepatectomy for gastric cancer metastases.
Gastric cancer has a high mortality, with many patients presenting with advanced disease. Many patients who undergo curative gastrectomy will subsequently develop metastatic disease. Hepatectomy has an established place in treating metastases from a variety of cancers but its role in gastric cancer is not clear. This review sought to systematically appraise the literature to establish the role of hepatectomy in treating gastric cancer metastases.
Medline and EMBASE were searched for all papers publishing data on survival of patients with metastatic gastric adenocarcinoma who underwent hepatectomy.
Seventeen studies with 438 patients were included. There were no randomised controlled trials. Perioperative mortality was 2%, with morbidity between 17 and 60%. Patients with solitary metastases appeared to have better survival. Other favourable survival characteristics included unilobar disease, and metachronous presentation. No advantage was demonstrated with either adjuvant or neoadjuvant chemotherapy.
Few patients with hepatic metastases from gastric cancer are suitable for hepatectomy, but for those suitable there appears to be survival benefit. Patients with synchronous, multiple or bilobar metastases have worse survival.
The evidence supporting the role of hepatectomy in the treatment of hepatic metastases from gastric cancer is weak. However in a selected group there appears to be a survival advantage; patients with solitary metastases had better survival outcomes than those with multiple metastases and metachronous presentation was associated with a better prognosis than synchronous presentation. Hepatectomy should be considered in these patients in the setting of a randomised trial.

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ReviewPerioperative chemotherapy for resectable colorectal liver metastases: Where now?

Abstract

Section snippets

Conflict of interest statement

Ann Oncol

Ann Oncol

Lancet

Clin Colorectal Cancer

Ann Oncol

J Gastrointest Surg

Ann Oncol

J Gastrointest Surg

J Am Coll Surg

Ann Oncol

Lancet Oncol

Resection of colorectal liver metastases

World J Surg

Analysis of predictive factors for recurrence after hepatectomy for colorectal liver metastases

World J Surg

Genetic markers of survival and liver recurrence after resection of liver metastases from colorectal cancer

World J Surg

Hepatic resection for colorectal metastases: can preoperative scoring predict patient outcome?

World J Surg

Trends in long-term survival following liver resection for hepatic colorectal metastases

Ann Surg

Survival benefit of repeat liver resections for recurrent colorectal metastases: 143 cases. Association Francaise de Chirurgie

J Clin Oncol

Resection rate and effect of postoperative chemotherapy on survival after surgery for colorectal liver metastases

Br J Surg

Evaluation of long-term survival after hepatic resection for metastatic colorectal cancer: a multifactorial model of 929 patients

Ann Surg

Resection of liver metastases from colorectal cancer: are there any truly significant clinical prognosticators?

Dis Colon Rectum

Patient selection for hepatic resection of colorectal metastases

Arch Surg

Hepatic resection for colorectal metastases: analysis of prognostic factors

Dis Colon Rectum

Indicators of prognosis after hepatic resection for colorectal secondaries

Surgery

Systematic review and meta-analysis of follow-up after hepatectomy for colorectal liver metastases

Br J Surg

J Clin Oncol

Review
Perioperative chemotherapy for resectable colorectal liver metastases: Where now?