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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_1209_Библиотеки_им_академика_М_И_Перельмана.pdf
149© Springer International Publishing Switzerland 2016
J.M. Millis, J.B. Matthews (eds.), Diffi cult Decisions in Hepatobiliary
and Pancreatic Surgery, Diffi cult Decisions in Surgery: An Evidence-Based
Approach, DOI 10.1007/978-3-319-27365-5_13
Chapter 13
When Should Patients with Liver Metastases
from Colorectal Cancer Receive
Chemotherapy?
Malini D. Sur and Eugene A. Choi
Abstract Advances in hepatic resection techniques and cytotoxic therapy over the
last 30 years have led to vast improvements in outcomes after hepatic resection in
patients with colorectal liver metastases (CLM). Nonetheless, the optimal sequence
of therapy for CLM remains a signifi cant clinical challenge. This chapter will summarize the evidence-based literature that pertains to the timing of chemotherapy in
relation to surgery for CLM in the absence of extra-hepatic metastases.
Keywords Colorectal liver metastases • Chemotherapy • Hepatectomy
Introduction
Hepatic metastases are the most common indication for liver resection in the United
States [ 1 ]. For many aggressive primary cancers, there is no strong evidence to sup-
port surgery for secondary tumors in the liver. However, long-term survival after
resection of colorectal liver metastases (CLM) in well-selected patients was observed
as early as 1976 [ 2 ]. Signifi cant advances in both hepatic resection techniques and
chemotherapeutic agents over the last 30 years have led to vast improvements in
outcomes after hepatic resection in patients with CLM, with a median survival currently estimated at 3.6 years [ 3 ]. Nevertheless, the management of CLM remains
challenging in part due to the debate about the optimal sequence of treatments. This
chapter will review the evidence-based literature about the timing of chemotherapy
in relation to surgery for CLM in the absence of extra-hepatic metastases.
M. D. Sur
Department of Surgery , University of Chicago Medicine , Chicago , IL , USA
E. A. Choi (
*)
Department of Surgery , Baylor College of Medicine ,
One Baylor Place MS: BCM390 , Houston , TX 77030 , USA
e-mail:
eugene.choi@bcm.edu
150
Overall Risks and Benefi ts of Treatment Sequence Options
Historically, patients with clearly resectable CLM were quickly taken to the operating room to avoid tumor progression spread and conversion to unresectable disease.
Adjuvant therapy was proposed as a way to reduce the rate of early recurrences [ 4 ],
but there were concerns that administering systemic chemotherapy prior to surgery
might increase the rate of post-operative complications. These concerns were
heightened as the hepatotoxic effects of standard chemotherapeutic agents used
against colorectal cancer , 5-fl uorouracil, oxaliplatin, and irinotecan, were increasingly recognized [ 5 ]. Another disadvantage of upfront chemotherapy is signifi cant
tumor response that would make planning liver surgery diffi cult. The desire to maximize the functional liver remnant must be balanced with the risk of leaving behind
radiographically undetectable but microscopic residual disease that may be present
within the tissue occupied by the original lesion [ 6 – 8 ].
By 2001, it became apparent that a proportion of patients with CLM initially
deemed unresectable would respond to chemotherapy to become surgical candidates [ 9 ]. The principle that neoadjuvant chemotherapy could reduce the extent of
necessary hepatic resection to remove all metastatic disease was applicable to
patients with resectable but bulky CLM. Prioritizing the administration of chemotherapy in the setting of metastatic disease refl ects the desire to treat all disease
(primary and metastatic) as quickly as possible. In addition, any occult or micrometastatic disease can be treated with chemotherapy. Although upfront chemotherapy delays surgery and might risk progression of disease, this approach may help
select patients with favorable tumor biology for surgery. Those responding to treatment can undergo hepatectomy , while those with unfavorable tumor biology avoid
high-risk surgery that is unlikely to be have signifi cant long-term benefi ts. Patients
who undergo resection after chemotherapy might also benefi t from an increased
likelihood of having margin negative resections [ 10 ]. Following surgery, an adju-
vant chemotherapy regimen could be tailored to individual patients based on the
pathologic response to the pre-operatively administered agent. Finally, neoadjuvant
therapy avoids the risk of delays in systemic treatment after surgery due to postoperative complications that are frequent after major liver resection s. The effect of
hepatotoxicity of neoadjuvant agents on post-operative complication rates has also
been raised, as the extent of liver resection and need for blood transfusion may be
more infl uential factors [ 11 ]. Table 13.1 summarizes the proposed advantages and
disadvantages of adjuvant versus neoadjuvant chemotherapy for CLM.
Search Strategy
A literature search of English language publications from 2004 to 2014 was conducted to identify published data addressing the timing of chemotherapy administration in relation to liver surgery for patients with potentially resectable liver
M.D. Sur and E.A. Choi
151
metastases from primary colorectal cancer . The PICO outline was used, as demonstrated in Table 13.2 . Databases searched were PubMed and Web of Science. Terms
used in the search were “timing,” “ surgery ,” “chemotherapy,” AND “liver metastatic
colorectal cancer ” OR “colorectal liver metastases.” References cited within the
resulting articles were carefully reviewed and included if they met inclusion and
exclusion criteria.
Articles were included only if they compared adjuvant chemotherapy to surgery
alone, perioperative chemotherapy to surgery alone, or adjuvant chemotherapy to
perioperative chemotherapy. Articles were excluded if they primarily addressed
chemotherapy for unresectable metastatic colorectal cancer , timing of colorectal
Table 13.1 Proposed advantages and disadvantages of adjuvant versus neoadjuvant chemotherapy
for colorectal liver metastases
Adjuvant chemotherapy Neoadjuvant chemotherapy
Proposed
advantages
Minimize risk of progression of
resectable disease into disease that
is unresectable or resectable with
greater morbidity
Prioritize treatment of systemic
disease, treating potentially occult
micrometastases
Avoid risk of increased surgical
morbidity due to hepatotoxic
effects of cytotoxic agents
Select patients with favorable tumor
biology to undergo hepatectomy
Optimize chances of resecting all
disease by avoiding inadequate
resection in areas of disappearing
metastases
Allow time for portal vein
embolization if needed
Increase rates of margin-negative
resection
Adjust adjuvant therapy regimen
based on response to neoadjuvant
agent
Proposed
disadvantages
Post-operative complications may
substantially delay administration
of systemic therapy
Risk progression of resectable
disease into disease that is
unresectable or resectable with
greater morbidity
Patients with unfavorable tumor
biology may undergo major liver
resection only to relapse very soon
after
Hepatotoxicity of cytotoxic agents
may increase morbidity of major
liver resections
Table 13.2 PICO table for timing of chemotherapy for resectable colorectal liver metastases
P (Patients) I (Intervention) C (Comparator) O (Outcomes)
Patients with
resectable
colorectal liver
metastases
(a) Adjuvant
chemotherapy
(a) Surgery
alone
Progression-free survival,
recurrence rate, recurrencefree survival, disease-free
survival, overall survival,
post-operative morbidity and
mortality
(b) Perioperative
chemotherapy
(b) Surgery
alone
(c) Neoadjuvant
chemotherapy alone or
perioperative
chemotherapy
(c) Surgery
alone or
adjuvant
chemotherapy
13 When Should Patients with Liver Metastases from Colorectal Cancer Receive…
152
surgery in relation to liver surgery alone, early versus delayed liver surgery alone,
management of extrahepatic metastases, management of recurrent liver metastases,
use of radiation, use of liver-directed ablative therapies, use of hepatic arterial infusion (HAI), or use of targeted therapy. Retrospective studies featuring fewer than
100 patients were excluded, as were case reports, chapters, comments, and nonsystematic review papers. Review papers focusing on the timing of chemotherapy and
surgery were included. Three randomized control trials (RCT), one pooled analysis,
and three retrospective cohort studies were included in our fi nal analysis. The identifi ed literature was classifi ed using the GRADE system.
Results
No RCT has directly compared outcomes of CLM patients treated with adjuvant
chemotherapy to those treated with perioperative chemotherapy. Our current understanding has therefore been largely shaped by trials comparing each modality to
surgery alone as well as by cohort studies comparing the two modalities. While
providing low-quality evidence, numerous single institution observational studies
of patients undergoing a common sequence of treatments offer some additional
insights. Table 13.3 summarizes the results of major studies comparing treatment
options for CLM.
Two major RCTs examined the benefi ts of adjuvant chemotherapy after marginnegative resection of up to four synchronous or metachronous CLM compared to
resection alone. Both used an adjuvant regimen involving only bolus 5-fl uorouracil
(5-FU) and leucovorin, which was standard at the time of enrollment. Unfortunately,
this regimen is now known to be suboptimal compared to regimens combining 5-FU
with oxaliplatin or irinotecan and therefore both studies have limited applicability
today. Additionally, both trials were closed early and underpowered. The ENG
(EORTC/NCIC-CTG/GVIVO) trial randomized 107 patients to fl uorouracil and
leucovorin or observation after surgery for CLM but also included patients undergoing surgery for lung metastases [ 12 ]. Data initially presented in 2002 showed that
patients who received adjuvant therapy tended to have longer recurrence-free survival (RFS) and overall survival (OS). However, the results lacked statistical signifi cance and were not fully published. The FFCD ACHBTH AURC 9002 trial
randomized 171 patients who had undergone R0 resections of CLM to surgery
alone or adjuvant therapy with fl uorouracil and leucovorin as well [ 13 ]. No differ-
ence in 5-year OS was observed between the two groups, but the 5-year disease-free
survival (DFS) rate was signifi cantly greater among patients receiving adjuvant
chemotherapy. Mitry et al. performed a pooled analysis of data from both trials and
showed no difference in median OS but did demonstrate a trend towards longer
median progression-free survival (PFS) in the chemotherapy group (62.2 months)
compared to the surgery only group (47.3 months) [ 14 ]. Based on these data, resec-
tion of CLM without plans of administering additional cytotoxic therapy was
abandoned.
M.D. Sur and E.A. Choi
153
Table 13.3 Studies comparing options for timing of chemotherapy for CLM
Study author and
year Study type
Number of
patients
Outcome
measures Arm 1 results Arm 2 results Statistics
Quality of
evidence
Surgery alone vs. adjuvant chemotherapy
Surgery alone Adjuvant
chemotherapy
Langer 2002
(EORTC/NCIC-
CTG/GIVO trial)
Randomized
controlled trial
107 Median RFS 20 months 39 months p = 0.35 Low
Median OS 43 months 53 months p=0.39
Portier 2006 (FFCD
ACHBTH AURC
9002)
Randomized
controlled trial
171 5-year DFS 26.7 % 33.5 % OR = 0.66 [0.46–0.96],
p = 0.028
Moderate
5-year OS 41.1 % 51.1 % OR = 0.73 [0.48–1.10],
p = 0.13
Mitry 2008 Pooled analysis
of 2 randomized
trials
278 Median PFS 18.8 months 27.9 months HR = 1.32 [1.00–1.76],
p = 0.058
Moderate
Median OS 47.3 months 62.2 months HR = 1.32 [0.95–1.82],
p = 0.095
Surgery alone vs. perioperative chemotherapy Surgery alone Perioperative
chemotherapy
Nordlinger 2008,
2013 (EORTC
Intergroup Trial
40983)
Randomized
controlled trial
364 3-year PFS 29.9 % 39.0 % HR 0.78 [0.61–0.99],
p = 0.035
Moderate
5-year OS 47.8 % 51.2 % p = 0.34
Median OS 54.3 months 61.3 months p = 0.34
Reversible
complications
16 % 25 % p = 0.04
Surgery alone or adjuvant chemotherapy vs. neoadjuvant chemotherapy
alone or perioperative chemotherapy
Surgery alone or
adjuvant
chemotherapy
Neoadjuvant
chemotherapy
alone or
perioperative
chemotherapy
(continued)
13 When Should Patients with Liver Metastases from Colorectal Cancer Receive…
154
Table 13.3 (continued)
Study author and
year Study type
Number of
patients
Outcome
measures Arm 1 results Arm 2 results Statistics
Quality of
evidence
Pawlik 2007 Retrospective
cohort
212 Complications 30.5 % 35.3 % p = 0.79 Low
60-day
mortality
Scoggins 2009 Retrospective
cohort
186 Median DFS 56 months 40 months p = 0.25 Low
Median OS 65 months 56 months p = 0.30
Morbidity 47 % 49 % p = 0.81
90-day
mortality
0.07 % 0 % p = 0.29
Pinto Marques
2012
Retrospective
cohort with
matched pair
analysis and
propensity score
analysis
676 Morbidity
after minor
hepatectomy
16.5 % 17.9 % p = 0.72 Moderate
Morbidity
after major
hepatectomy
14.2 % 23.1 % p = 0.06
5-year OS 55 % 43 % p = 0.009
410
(matched-
pair analysis)
Recurrence 41 % 51 % p = 0.03
5-year DFS 20 % 15 % p = 0.01
5-year OS 54 % 42 % p = 0.09
244
(propensity
score
analysis)
Median OS 69.6 months 56.8 months p = 0.12
Scartozzi 2011 Retrospective
cohort
104 Median OS 48 months 31 months p = 0.0358 Low
Median PFS 25 months 16 months p = 0.031
Recurrence 52.5 % 75 % p = 0.0347
M.D. Sur and E.A. Choi
155
Study author and
year Study type
Number of
patients
Outcome
measures Arm 1 results Arm 2 results Statistics
Quality of
evidence
Spelt 2012 Retrospective
cohort
233 Complications 63.2 % 62.9 % NS Low
90-day
mortality
1.5 % 0 % NS
Araujo 2013 Retrospective
cohort
411 3-year OS 78 % 74 % p = 0.48 Low
5-year OS 60 % 56 %
3-year RFS 44 % 32 % p = 0.036; adjusting for
CRS, p = 0.42 (low
CRS), p = 0.74 (high
CRS)
5-year RFS 38 % 31 %
Complications 39 % 38.3 % p = 0.92
Zhu 2014 Retrospective
cohort
466 5-year OS 48 % 52 % NS Low
30-day
morbidity
25.8 % 33.9 % NS
30-day
mortality
1.2 % 1.7 % NS
RFS recurrence-free survival , DFS disease-free survival, PFS progression-free survival, OS overall survival , OR odds ratio, HR hazard ratio, NS non-signifi cant,
CRS clinical risk score
13 When Should Patients with Liver Metastases from Colorectal Cancer Receive…
156
In 2008, the same year that Mitry et al. published results of the pooled analysis,
Nordlinger et al. published initial data from the EORTC Intergroup 40983 trial [ 15 ].
Long-term results were presented in 2013 [ 16 ]. In this landmark study, 364 patients
with up to four synchronous or metachronous CLM were randomly assigned to
“perioperative” chemotherapy consisting of 6 cycles of neoadjuvant 5-FU, leucovorin, and oxaliplatin (FOLFOX4) combined with six cycles of adjuvant chemotherapy or to surgery alone. Patients who underwent resection following chemotherapy
did have a signifi cantly higher rate of reversible postoperative complications (25 %).
At 3 years, the rate of PFS among eligible patients was 39.0 % in those who received
perioperative chemotherapy compared to 29.9 % in those who underwent surgery
alone (p = 0.035). However, no signifi cant difference in OS was detected between
the two groups, with mortality rates of 59 % of the perioperative chemotherapy
group and 63 % of the surgery only group at a median follow-up of 8.5 years. A
survival benefi t may not have been identifi ed because the study was underpowered
to detect the predefi ned 5 % difference in 5-year OS or because only 63 % of the
perioperative chemotherapy group went on to actually receive post-operative chemotherapy [ 17 ]. Although the study authors advocate for perioperative therapy
based on the demonstrated improvement in PFS alone, others argue that the lack of
a clear survival benefi t challenges the routine use of neoadjuvant chemotherapy
[ 17 ]. Moreover, the trial compared perioperative chemotherapy to surgery alone as
opposed to surgery with adjuvant chemotherapy, and newer therapeutic agents were
not studied.
The NSABP C-11 trial is a phase III RCT currently underway to investigate the
difference in RFS between patients with resectable CLM receiving perioperative
chemotherapy and those receiving adjuvant therapy alone. Patients who are
oxaliplatin- naïve will receive FOLFOX and those who have been previously treated
with oxaliplatin will receive 5-FU, leucovorin, and irinotecan (FOLFIRI).
Randomization will be stratifi ed according to the number of liver metastases, the
planned chemotherapy regimen, and whether the disease is synchronous or metachronous. The results of this study will hopefully add critical insight into the optimal timing of cytotoxic agents in relation to surgery for CLM. The precise role of
targeted therapy for CLM will need to be addressed in further investigations.
In the absence of additional data from RCTs, multidisciplinary decision-making
about the treatment of CLM must rely on several relevant retrospective cohort studies published over the last 10 years. By design, these studies are inherently limited
in their ability to control for all the clinicopathological variables that infl uence the
choice of treatment modalities for individual patients, leading to a considerable risk
of selection bias. For example, patients with signs of more aggressive disease may
be more likely to be offered neoadjuvant therapy . Many of the retrospective reports
are also based on relatively small numbers of patients and thus lack statistical power
to detect signifi cant differences in long-term outcomes . Finally, most of these studies demonstrate signifi cant heterogeneity in the treatment protocols between the
comparative arms. While the RCTs described above had a surgery alone arm, retrospective studies have generally compared patients who received neoadjuvant chemotherapy to those who did not. The latter group sometimes included patients who
M.D. Sur and E.A. Choi
157
received adjuvant chemotherapy as well as those who did not. Multiple chemotherapeutic regimens, some consisting of targeted therapies, as well as local liver-directed
therapies were sometimes included.
Despite these weaknesses, it is valuable to review the major retrospective cohort
studies comparing different therapeutic sequence options for CLM. In 2009, Reddy
et al. published a multi-institutional analysis of outcomes of 499 patients with CLM
stratifi ed into four groups based on the timing of chemotherapy that was ultimately
delivered: pre- hepatectomy alone, post-hepatectomy alone, perioperative (i.e. preand post-hepatectomy), and none [ 18 ]. Not surprisingly, those treated with pre-
hepatectomy chemotherapy were often associated with a larger number of liver
tumor s, a node-positive primary tumor, a major hepatectomy, and ablation procedures in addition to resection . After controlling for factors refl ecting decisions to
treat with upfront chemotherapy, multivariate analysis revealed that posthepatectomy chemotherapy was signifi cantly associated with RFS and OS but prehepatectomy chemotherapy was associated with no survival benefi t. Because
outcomes in those treated with perioperative chemotherapy were similar to those in
the post-hepatectomy chemotherapy alone group, the investigators argued that chemotherapy administered after liver resection had the strongest oncologic benefi t.
The study was limited, however, by substantial variation in resectability criteria,
resection techniques, choice of pre-operative imaging, and chemotherapeutic regimens across the participating institutions. In addition, given the retrospective nature,
patients were grouped according to the chemotherapy schedule they ultimately
received as opposed to the planned chemotherapy schedule. Patients treated with
pre-hepatectomy chemotherapy who developed disease progression that precluded
resection were not included.
Four years later, Pinto Marques et al. performed the largest of the retrospective
studies known to date and also attempted to control for confounding through
matched pair and propensity score analyses [ 19 ]. Among their 676 study patients,
those who received neoadjuvant chemotherapy were more likely to have a lymph
node positive primary tumor, synchronous disease, and a greater number of liver
metastases. When all patients were considered, post-operative complications were
signifi cantly increased from 14.2 to 23.1 % with the addition of chemotherapy prior
to major but not minor hepatectomy for CLM. Without controlling for baseline
characteristics, 5-year OS was signifi cantly worse in the patients treated with neoadjuvant therapy compared to patients who did receive chemotherapy prior to surgery (43 % vs. 55 %). A 1:1 matched-pair analysis was then undertaken using 205
pairs of patients with similar pathological characteristics. This still revealed a signifi cantly higher rate of recurrence (51 % compared to 41 %, p = 0.03) and lower
rate of 5-year DFS (15 % compared to 20 %, p = 0.01), but the difference in 5-year
OS was not signifi cant. Acknowledging the limitations of matched-pair analyses,
the authors performed a third analysis based on propensity score matching using
244 patients that again revealed no signifi cant difference in median OS. Thus, controlling for baseline characteristics demonstrated neither an advantage nor disadvantage in terms of long-term outcomes with the administration of pre-operative
chemotherapy.
13 When Should Patients with Liver Metastases from Colorectal Cancer Receive…
158
In 2013, Araujo et al. published another notable retrospective study based on
their experience with 411 patients undergoing resection of CLM [ 20 ]. Once again,
patients who received perioperative chemotherapy had generally less favorable disease as evidenced by higher clinical risk scores (CRS). CRS was established in 1999
as a strong marker for recurrence risk after resection of CLM and is determined by
summing the presence of each of the following factors: a node-positive primary
tumor, a disease-free interval from primary tumor to appearance of liver metastases
under 12 months, more than one metastasis, pre-operative carcinoembryonic antigen (CEA) level above 200 ng/ml, and largest tumor size above 5 cm [ 21 ]. Scores
of 2 or less are classifi ed as low CRS while scores of 3 or greater are classifi ed high
CRS. Furthermore, a large number of patients in the adjuvant group received HAI,
which is not routinely used at many institutions. Nonetheless, the authors detected
no signifi cant differences in the rates of post-operative complications, 3-year OS, or
5-year OS between patients who were treated with perioperative chemotherapy and
those who received adjuvant therapy . Although a signifi cantly higher rate of 3- and
5-year RFS among patients treated with adjuvant chemotherapy alone was found on
univariate analysis, this was not observed once adjustments were made for clinicopathological and clinical risk scores (CRS).
Additional retrospective studies comparing outcomes between patients treated
with and without neoadjuvant chemotherapy include investigations by Pawlik et al.
Scoggins et al. Scartozzi et al. Spelt et al. and Zhu et al. [ 22 – 26 ]. Of these, all but
one failed to detect major differences in post-operative morbidity and/or oncologic
outcomes. Based on their analysis of 104 patients with CLM, Scartozzi et al. found
a signifi cantly longer median OS in those who did not receive neoadjuvant FOLFOX
(48 months vs. 31 months, p = 0.0358) [ 24 ]. However, patients treated with neoad-
juvant chemotherapy more often had tumors larger than 5 cm and although CRS
appeared similar in both groups, scores were only available in 69 % of patients. In
addition, it was not clear if the neoadjuvant patients were also treated with adjuvant
chemotherapy (i.e. a perioperative approach). Finally, data regarding surgical margins were not presented and could explain the poor survival among patients treated
in the neoadjuvant setting, especially since the rate of recurrence was substantially
higher in this group (75 % vs. 52.5 %, p = 0.0347).
Additional Considerations
There are three additional considerations that are important in determining the optimal timing of chemotherapy in relation to hepatectomy for CLM. First, CLM may
present in a synchronous or metachronous fashion. In synchronous cases, surgery
may need to be prioritized if the primary colorectal cancer is symptomatic. In the
face of life-threatening bleeding or perforation, the risks of delaying surgery for the
administration of neoadjuvant chemotherapy are increased and should be avoided.
Obstructing cancers can be treated surgically, but endoscopic stent ing may theoretically allow symptom relief while reducing the time-delay to delivery of neoadjuvant
M.D. Sur and E.A. Choi