Supporting Mini-Systematic Review and Meta-Analysis on the Establishment of
Selection Criteria for Patients Who are Suitable for a Simultaneous Resection
Today we know that multiple patients are suitable for simultaneous resection and
prognostic factors which significantly influence the short- and long-term outcomes
have been reported. However, generally accepted selection criteria have not been
established so far. Thus, the establishment of suitable selection criteria would be the
most interesting result of the present study.
On the basis of the included studies and other evidental documents, a mini-systematic
review was conducted, and a meta-analysis of the risk factors for postoperative
morbidity was performed on Reddy et al.’s and Luo et al.’s studies with a total of
1015 cases (due to the diverse forms of reporting, simply direct data-pooling
analytical method was not appropriate).27,49 Particularly, we also refer to current
published prognostic scoring systems for patients with colorectal liver metastasis.
These published prognostic scoring systems were not limited to synchronous
colorectal liver metastasis, let alone simultaneous resections. However, of note was
the observation that the results of the present meta-analysis regarding the
intraoperative blood loss, operation time, and complication rate might be influenced
by the fact that multiple surgeons prefer a simultaneous resection in patients with a
restricted metastatic disease, whereas extended and anatomical difficult resections are
rather performed as staged procedures. This could severely influence the perioperative
results in both groups and ignore the unrevealed prognostic factors in the groups of
simultaneous resections within the included studies. From another point of view,
when excluding other risk variables, simultaneous resection is associated with a
higher risk of mortality in patients with synchronous colorectal liver metastases
(Nordlinger et al. reported an operative mortality of 7% for simultaneous resections,
compared with 2% for staged resections based on 1568 patientss9), which is not
surprising as simultaneous resection is essentially a more invasive procedure to staged
resection. Thus, comprehensive and objective selection criteria would be the aim of
this mini-systematic review and meta-analysis.
Detailed assessments of the risk factors are listed below.
Prognostic Factors for Patients with Synchronous colorectal liver metastases
within included studies
Patient Demographic Information Patient demographics form the core of
epidemiological objective characteristics data of a population in any medical
institution. They allow for the identification of a patient and his or her categorization
into categories for the purpose of statistical analysis. In the included studies,
commonly examined demographics include age and gender, and both distributions
and trends of the two variables within Capussotti et al.’s and Thelen et al.’s studies
are of interest.38,42
Univariate analysis in Capussotti et al.’s found the sex to be one of the five
statistically significant prognostic factors in the synchronous resection group (P =
0.0233), which was further identified by multivariate analysis as independent
prognostic factor (P = 0.040).38 The finding that male patients had a statistically
significantly worse prognosis than female patients has never been clearly explained
up to now. Alternatively, female patients owned a better prognosis after hepatectomy
for colorectal liver metastases implied by previous Adson et al.’s and Hohenberger et
al.’s studies.s19,s20 It is hypothesized that sex hormonal may influence the prognostic
outcome, still, future studies are necessary to confirm and clarify this interesting
observation.
Thelen and colleagues have found that in patients with simultaneous major liver
resection, an age exceeding 70 years correlated significantly with postoperative
mortality in the univariate analysis (P = 0.029), whereas in younger patients, the
mortality rate was comparable between both groups after major hepatectomy.42 This
finding was also in line with Tanaka et al’s that patient age of 70 years or older (P <
.05) predicted decreased overall survival by univariate analysis.37
In summary, male sex and patient beyond the age of 70 years may be considered as
potential risk factors for simultaneous resection.
Extend of Liver Resection A majority of included studies have mentioned the term
major hepatectomy (more than three Couinaud segments) which was commonly used
to describe liver resections at risk for postoperative complications. As a matter of fact,
no standard definition of major hepatectomy exists until Reddy and his colleagues,
after reviewing the demographics, diagnoses, surgical treatments and outcomes from
1670 patients underwent a hepatic resection at two high-volume centres, found that
resection of four or more liver segments was independently associated with postoperative mortality and severe, overall, and hepatic-related morbidity (all P < 0.01) on
multivariable analysis. Thus, consistence with the included studies, a major
hepatectomy should be defined as resection of four or more liver segments.s21
In this mini-systematic review, meta-analysis on the risk factors of postoperative
morbidity for a total of 1015 cases has revealed that major hepatectomy was
associated with a higher risk for simultaneous resection than minor hepatectomy (P =
0.05). In Thelen et al.’s study, four patients (10%) died in the postoperative course.
These four patients all had undergone simultaneous major liver resections (two right
lobectomies, one extended right lobectomy, and one right trisectionectomy).42 In
parallel to our own results, major liver resection was the only independent risk factor
responsible for postoperative mortality in simultaneous liver resections in that study
(P = 0.041). While in the delayed resection group, none of the investigated parameters
revealed statistically significant influence on the postoperative mortality. Also, a 12%
postoperative mortality for simultaneous resections and a 24% mortality for
simultaneous resections involving major liver resections have been reported by Bolton
and Fuhrman.s22
In 2007, the largest multi-center retrospective study on this topic so far has reported
that for major hepatectomy, combined severe morbidity (which required operative or
nonoperative intervention or contributed to prolongation of hospital stay) after
delayed resections was lower compared to simultaneous resections (36.1% versus
17.6%, P = 0.05. Major hepatectomy independently predicted severe morbidity in the
group of simultaneous resection, HR = 3.4, P = 0.008), but it was similar for minor
hepatectomy (14.1% versus 10.5%, P > 0.05).27 Moreover, intraoperative blood loss,
frequency of microscopic positive hepatic resection margins (R1 resection), mortality,
overall morbidity, and length of hospital stay after hepatectomy were all greater after
simultaneous resections compared to after hepatectomy alone among patients who
underwent major hepatectomy.
In summary, major hepatectomy might be avoided in simultaneous liver resections for
safety consideration from a conservative point of view, and minor liver resections are
equally safe as simultaneous and staged resections.
Liver Metastasis Half of patients with colorectal cancer have liver metastasis during
their illness. In the Western world, metastasis to the liver is more common than
primary liver cancer.
In Capussotti et al.’s series, for the first time, the presence of more than three
metastases was confirmed to be a prognostic factor in the synchronous group, and
patients with more than three metastases had a significantly worse survival in
synchronous group than in delayed group (3-year survival, 15.0% vs. 34.3%, P =
0.007).38 In multivariable analysis for the total study population by de Hass et al.,
three or more colorectal liver metastases at diagnosis (RR = 3.5, P = 0.001) was also
identified as an independent predictors for disease recurrence.47
Resection of structures infiltrated by liver metastases was associated in eight patients:
diaphragm in six patients (five in the delayed group), portal vein in one, and rib in one
(both in the synchronous group) (4.2% vs. 8.8%, P = .504) in Capussotti et al.’s study.
Univariate analysis found the associated resection of structures infiltrated by liver
metastases to be one of the five statistically significant prognostic factors in the
synchronous resection group (P < 0.001), which was further identified by multivariate
analysis as independent prognostic factor (P < 0.0001).38
In summary, these data suggest that patients with four or more liver metastases
synchronous with primary colorectal cancer and metastasis infiltration of neighboring
structures have to be carefully evaluated before resection, because they could have a
dismal prognosis due to rapidly progressing disease.
Primary Tumor Location Two strategies in the colon and rectal cancers have been
revealed in an attempt to review the literature initially: probably a majority of
simultaneous operations were done in patients with a colon primary tumor and
conversely more delayed hepatectomies were done in patients with a rectal primary.
As rectal surgical procedures have more morbidity than colonic surgery with more
bleeding dissection, it would be expected, according to this hypothesis, that blood loss
and hospital stay can have been increased in the rectal surgery and therefore in the
delayed strategy.
From our integrative analysis for the location of colorectal primary, Supporting figure
1, primary location section, has showed that right colon resection was 26% and 14%
respectively in simultaneous and delayed hepatectomies, almost was twice as large as
delayed group.
In Vassiliou et al.’s series, right colon resection was more performed in simultaneous
group than that in the delayed group (67% vs. 18%, P < 0.005).46 In Reddy et al.’s
multi-centre study, right colectomy was also more often performed in simultaneous
patients whereas more staged patients were treated with left colectomy and low
anterior resection.27 It is a common sense that bilateral subcostal incision could
provide excellent liver exposure and facilitate colon resection from the cecum up to
the descending colon. In contrast, malignancies located in the sigmoid colon
downward necessitate a midline incision and an extension to the right. Simultaneous
resection is an acceptable option in patients with resectable synchronous colorectal
metastasis by avoiding a second laparotomy, which could reduce the overall hospital
stay, and with no difference in morbidity and mortality rates, based on the distribution
that right hemicolectomy was more common in simultaneous group, whereas more
left hemicolectomies performed in staged group in Martin et al.’s study published in
2009 (Although a subset analysis of patients according to location of primary tumor
did not reveal a particular group of patients who are placed at unacceptably high risk
by the performance of simultaneous colon and liver resection in their previous 2003
study.23).41
Further, rectal cancer was significantly more frequent in the staged resection group in
Thelen et al.’s study, and in their own practice, major liver resections were considered
only in combination with right or left colectomy, whereas simultaneous resection of
rectal primaries were only performed with minor liver resections.42
In summary, simultaneous resection should be preferred for most of the right colon
lesions as well as small liver lesions that can be approached from a midline incision,
regardless of the colonic tumor location.
Co-Morbidity Symptoms of colorectal cancer are numerous and nonspecific, usually
not obvious within several years of disease progression, and may be variously
presented according to where in the large intestine the tumor is located. Typically,
right-sided cancers cause iron deficiency anemia due to the slow loss of blood over a
long period of time, whereas cancers of the left colon are more likely to cause partial
or complete bowel obstruction.
In Thelen et al.’s series, simultaneous liver resections were generally not performed in
patients with complications of the colorectal tumor such as bowel obstruction or
colonic perforation.42 Further, for other co-existent conditions as severe coronary
heart disease, reduced general constitution or severe chronic obstructive pulmonary
disease, simultaneous resection was not the preference.
In clinical practice, a lack of concern for the impact of coexistent diseases might have
on the outcome of care is common, which is partly due to the lack of a validated,
practical method for measuring these co-morbidities. In the present systematic review,
a majority of included studies did not select patient preoperative co-morbidity as
potential prognostic factor neither in univariate nor multivariate analysis. Thus for
evaluating the effectiveness of timing selection for SCRLM, future clinical and health
services research and audit should take comorbidity into account. In addition, blood
transfusion was found to be significant on both univariate and logistic regression
(odds ratio 2.98, P = 0.001) as a predictor of complication by Martin et al.41
In summary, the measurement of co-existent or comorbid conditions preoperatively
should not be neglected.
TNM Stages The most common staging system used for an estimate of the amount of
penetration of colorectal cancer is the TNM (for tumors/nodes/metastases) system,
from the American Joint Committee on Cancer.
In simultaneous resection group, only the univariate analysis in Capussotti et al.’s had
found T4 stage of primary colorectal tumor to be one of the five statistically
significant prognostic factors in the synchronous resection group (P = 0.0216), which
was further identified by multivariate analysis as independent prognostic factor (P =
0.0035).38 Alternatively, although concomitant extrahepatic disease was identified as
one of the prognostic factors in the univariate analysis (P = 0.005) for both
simultaneous and delayed resections, it was not an independent one showed by the
multivariate analysis (P = 0.098) in de Haas et al.’s study.47 For the other studies,
none of the analyzed staging parameters showed significant influence on survival
after simultaneous hepatectomy.
In summary, due to the fact that multiple surgeons prefer a simultaneous resection in
patients with a less severe disease, the association between tumor staging and patient
prognosis on the statuses how far the cancer has grown into the wall of the intestine,
whether or not it has reached nearby structures, and whether or not it has spread to the
lymph nodes or distant organs may be covered in the included studies.
Neoadjuvant Chemotherapy Neoadjuvant chemotherapy prior to hepatectomy may
facilitate the resectability of the liver lesions and treat occult metastasis but may also
lead to hepatic parenchyma damage in patients with resectable colorectal liver
metastases.
Five studies reported the use of preoperative chemotherapy before resections. In de
Hass et al.’s, Luo et al.’s and Reddy et al.’s studies, simultaneous patients were less
often treated with chemotherapy before hepatic resection.27,47,49 This may explain the
higher recurrence rate with the simultaneous resection strategy found in de Haas et
al.’s study.47 However, of note was the observation that the drop-out in the delayed
hepatectomy group of patients with progressive intrahepatic and/or extrahepatic
disease after resection of the primary colorectal tumour may have selected a residual
group with a more favourable prognosis, which may be the reason why preoperative
chemotherapy was not an independent predictor of recurrence in de Haas et al.’s
study.
Generally, it is hypothesized that in delayed resection group, time-test strategy and
neoadjuvant chemotherapy probably led to avoid surgery in patients with rapidly
progressing disease and to perform hepatectomy in selected patients who could really
benefit from surgery. A recently published systematic review of randomized and
nonrandomized trials of the clinical response and outcomes of neoadjuvant systemic
chemotherapy for 3728 patients with resectable colorectal liver metastases has
demonstrated that, for objective radiological surveillance, a median of 4% (range 038%) and 52% (range 10-90%) of patients had complete and partial response
respectively after neoadjuvant chemotherapy. Pathologically, a median of 9% (range
2-24%) and 36% (range 20-60%) had complete and partial response, respectively.
Moreover, of patients, 41% (range 0-65%) had stable or progressive disease whilst on
neoadjuvant chemotherapy. Median disease-free survival was 21 (range 11-40)
months, and median overall survival was 46 (range 20-67) months.s23
In summary, there is argument over the oncologic benefit of neoadjuvant
chemotherapy in patients who would already be suitable for a curative hepatectomy.
Current evidence suggests that objective response to this practice may be achieved
with improvement in disease-free survival in patients with resectable colorectal liver
metastases, not overall survival.
Review of the published prognostic scoring systems for colorectal liver
metastases
Hepatic resection provides the best chance for cure in patients with colorectal liver
metastasis. Over the past decade, a variety of factors that might influence survival and
recurrence have been identified and multiple prognostic scoring systems have been
proposed. Relevant articles were reviewed from the published literature using the
Pubmed and Embase databases. As shown from Supporting Table 4, a total of 7916
patients from 18 studies were identified, published between 1996 and 2011.s1-s18
Seven of these originated from European institutions, seven from Asian and four from
North American centres. The number of patients per study ranged from 81 to 1568
with the median follow-up ranged from 16 to 54. Four were multi-centre studies, and
five were prospective. Cox proportional hazards regression was used for multivariate
analysis to identify the factors in all studies. Generally speaking, 25 independent
prognostic factors were identified (Supporting Table 5). Of these, 11 were identified
by two or more studies. Although there was a tendency towards the number and
maximum size of metastases, lymph nodes spread from colorectal cancer,
preoperative high CEA level and presence of extrahepatic disease as representing
independent risk factors, the existing predictive models are diverse and there has no
well-accepted ideal prognostic scoring system been established.
Selection Criteria Establishment for Simultaneous Resection
It is hypothesized that simultaneous resection should be associated with more
prognostic factors to be found as to the overall procedures, because the surgical
strategy is more drastic in simultaneous resection itself, whereas patients underwent
various kinds of interventions to treat the liver metastases regardless of strategies
applied when analysis is for the overall procedures. As shown by Supporting Figure
11, representative region for prognostic factors detected in overall resectable
colorectal liver metastases should be smaller than that restricted in simultaneous
group in SCRLM patients under the precondition of strictly balanced patient
characteristics (as indicated by the area). In our study, a majority of patients included
were in less severe diseases in simultaneous resection group compared to those in
delayed group, thus some potential factors may not be found if review patients
underwent simultaneous resection alone. Therefore, the real form of expression of
distribution for the prognostic factors in simultaneous group should be smaller, and
tilt to the less severe direction for risk assessment. Also, this hypothesis has been
confirmed by this mini-systematic review and meta-analysis (Supporting Table 3). In
addition, the Zone A without overlapping the representative region for overall
resectable colorectal liver metastases was exclusive to simultaneous resection group;
factors in it were viewed as the selection criteria for simultaneous patients directly
against delayed resection. While the overall prognostic factors in Zone A+B+C were
considered as the whole prognostic factors for CLM.
Finally, based on the included studies and current published prognostic models,
several factors were considered as the selection criteria for simultaneous resection
directed against delayed resection: liver resection no more than 3 segments, colon
resection (especially the right-sided colectomy), age less than 70 years old and coexistent severe conditions. These factors were exclusive to simultaneous resection
group. From Supporting Figure 12, future large and well desired randomized
controlled trials would be conducted under these selection criteria to conform the
conclusions.
Comment
As demonstrated by the main meta-analysis of timing of hepatectomy for patients
with synchronous liver metastases, long-term outcomes of overall survival and
recurrence-free survival were similar between simultaneous and delayed groups;
short-term outcome of postoperative morbidity was less in simultaneous group.
Therefore, the safety of simultaneous resection was more considered when
establishing the selection criteria. It was true that patients in simultaneous group had
less severe disease compared with those in delayed group because of the nature of the
included study types, but this was not the main concern in the present study. The most
interesting result of the current study would be the establishment of selection criteria
for patients who are really suitable for simultaneous resection, besides simply
compare the safety and effectiveness of the two resection strategies.
Limitation
In this mini-systematic review and meta-analysis only observational studies were
included, thus the main limitation was the selection bias for patients allocated to each
group. Initially, a scoring-system was planned for SCRLM patients, but the
applicability of the scoring system recommended by the current study for the
postoperative risk assessment after simultaneous hepatectomy could not be validated.
It is a common sense that the best method to establish the selection criteria should be
based on the individual patient data analysis (IPD meta-analysis), however this is not
always be available, and the diverse reporting forms from the included studies could
reduce the reliability of the conclusion.
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