Добавил:
Sekretar
kiopkiopkiop18@yandex.ru
t.me/Prokururor I Вовсе не секретарь, но почту проверяю
Опубликованный материал нарушает ваши авторские права? Сообщите нам.
Вуз:
Предмет:
Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_927_Библиотеки_им_академика_М_И_Перельмана.pdf
COLON 311
Oxaliplatin
A second key agent that changed the landscape of treatment for
this disease was oxaliplatin. Oxaliplatin is a third-generation platinum analog that has substantial clinical activity in colorectal cancer. Oxaliplatin exerts its eect by the formation of covalent DNA
adducts involving the complexed platinum atom. As a single agent,
oxaliplatin was found to have response rates of 10% to 20% and
demonstrated synergy with 5-FU in preclinical testing. Multiple
clinical trials have evaluated oxaliplatin combined with 5-FU in a
randomized setting. De Gramont and colleagues randomized 420
chemotherapy-naïve patients to infusional 5-FU/LV with or without oxaliplatin (85 mg/m
was found to have superior response rate (51% vs. 22%, P = .0001),
PFS (9.0 vs. 6.2 months, P = .0003), and a trend toward improved
survival (16.2 vs. 14.7 months, P = .12) It is likely that overall survival did not reach statistical signicance because patients were
allowed to cross over aer disease progression occurred upon treatment with 5-FU.
In 2004, a randomized clinical trial compared FOLFOX6 versus
FOLFIRI in the rst-line setting. At the time of disease progression,
220 patients were randomized to the opposite regimen. For patients
who received FOLFOX6 followed by FOLFIRI, the response rate was
54%, whereas in patients treated with FOLFIRI followed by FOLFOX,
it was 56%. No statistically signicant dierence was found in either
median PFS or OS between the groups. First-line FOLFOX6 yielded
a PFS and OS of 8.0 months (95% condence interval [CI], 6.2-9.4),
and rst-line FOLFIRI yielded a PFS and OS of 8.5 months (95% CI,
7.0-9.5). e decision to use one combination versus the other therefore rests in the hands of the treating oncologist and is individualized primarily on the basis of the adverse eect prole. Treatment
with oxaliplatin is associated with high rates of neuropathy and thus
should be used with caution in patients with poorly controlled diabetes or pre-existing neuropathy. Irinotecan is associated with a higher
incidence of diarrhea and alopecia, which are important determinants of quality of life.
Once FOLFOX and FOLFIRI were established as the standard
chemotherapy backbone for metastatic disease, the question of combining three chemotherapeutic agents arose. A total of 508 patients
who were chemotherapy-naïve were randomized to FOLFIRI plus
bevacizumab versus folinic acid, 5-uorouracil, oxaliplatin, and irinotecan (FOLFOXIRI) plus bevacizumab. In the FOLFOXIRI group,
the response rate was increased from 53% to 65% (P = .006), and PFS
was increased from 9.7 to 12.1 months (P = .003). ere was a trend
but a nonsignicant increase in OS from 25.8 to 31 months (P = .054).
e incidence of grade 3 and 4 neurotoxicity, stomatitis, diarrhea,
and neutropenia were signicantly increased in the FOLFOXIRI arm.
is regimen is quite popular in Europe but is used sparingly in the
United States at this time.
2
every 2 weeks). e combination group
MAINTENANCE CHEMOTHERAPY
Aer treatment with months of chemotherapy, patients oen report
cumulative toxicity, most commonly neuropathy and fatigue. e
OPTIMOX trial was designed to answer the question of whether
stopping chemotherapy had an impact on overall survival in patients
with unresectable metastatic disease. e OPTIMOX trial demonstrated that oxaliplatin can be safely stopped aer six cycles in a
FOLFOX regimen, but complete discontinuation of chemotherapy
had a negative eect on PFS when compared with maintenance 5-FU.
A second trial showed that maintenance treatment with capecitabine
and bevacizumab was associated with prolonged PFS (8.5 vs. 11.7
months; P <.0001). Currently, maintenance chemotherapy is oered
to patients with adequate response aer initial treatment who wish to
emphasize quality of life; full “treatment holidays” are generally not
recommended in this setting because of increased risk of progression
while treatment is discontinued.
BIOLOGIC AGENTS
VEGF is an important regulator of tumor angiogenesis. Bevacizumab
is a humanized monoclonal antibody against VEGF that not only
serves as an inhibitor of angiogenesis but also may increase chemotherapy delivery by altering tumor vasculature and decreasing
the elevated interstitial pressure in tumors. In 2004, bevacizumab
was combined with irinotecan, bolus uorouracil, and LV (IFL) for
the rst-line treatment of metastatic disease. A total of 813 patients
were randomly assigned to receive IFL or IFL plus bevacizumab. e
response rate in the IFL plus bevacizumab versus IFL groups was 45%
versus 35%, respectively. A signicant improvement occurred in PFS
(10.6 vs. 6.2 months; P <.001) and OS (20.3 vs. 15.6; P = .001) in the
treatment group. Hypertension was signicantly more common in the
bevacizumab arm (22%), as was the rate of bowel perforation (1.5%).
e mitogen-activated protein (MAP) kinase pathway is involved
in the progression of colorectal cancer. Activating mutations in KRAS
result in constitutive activation of the MAP kinase pathway, resulting in increased cell growth and proliferation. Because patients with
activating mutations do not respond to anti-EGFR agents, biomarker
analysis is critical to patient selection. e most common KRAS mutations are found in exon 2 (codons 12 and 13), and in 2009 the American Society of Clinical Oncology recommended that treatment with
anti-EGFR agents be restricted to the KRAS wild-type (WT) population. More recent data suggest that resistance to EGFR inhibitors also
can be mediated by less common mutations in KRAS (exons 3 and
4) and NRAS (exons 2 and 3). e latest provisional clinical opinion
from the American Society of Clinical Oncology recommends testing
for these “extended RAS” mutations and recommends against use of
anti-EGFR therapy in patients whose tumors harbor such mutations.
Two EGFR inhibitors are currently approved: cetuximab and panitumumab. Cetuximab (Erbitux) is a chimeric monoclonal antibody
directed against EGFR, and panitumumab is a fully humanized monoclonal antibody specic to EGFR. Infusion reactions with cetuximab
are in the range of 3% to 5%, versus less than 1% with panitumumab.
e CRYSTAL study randomly assigned rst-line patients to FOLFIRI with or without cetuximab. In the KRAS WT population (extended
RAS mutations were not available at the time), response rates were signicantly higher in the cetuximab arm (57% vs. 40%, P = .001) in addition to OS (23.5 vs. 20 months, P = .0093). Cetuximab was also studied
in the second-line setting; patients who did not respond to oxaliplatin
were randomly assigned to irinotecan with or without cetuximab. e
cetuximab arm was associated with an increase in response rate (16.4%
vs. 4.2%, P <.0001) and PFS (4.0 vs. 2.6 months, P = .0001), but OS was
similar (10.7 vs. 10 months, P = 0.71).
Panitumumab was studied in the PRIME trial, wherein chemotherapy-naïve patients were assigned to FOLFOX with or without
panitumumab. Patients in the extended RAS WT population (no
mutations in exon 2, 3, and 4 of KRAS and NRAS) were found to have
a signicant increase in OS (hazard ratio [HR] 0.77, 95% CI 0.64-
0.094, P = .009). However, in the classic WT KRAS population (without mutations in exon 2), in patients with mutations in other exons
(exons 3 and 4), and in NRAS there was no benet from the addition
of panitumumab. Interestingly, these patients had worse (although
not signicant) PFS and OS rates. Based on these data, is it recommended that all patients with metastatic disease receive extended
RAS testing. Of note, dual-antibody treatment has been tested and is
associated with worsened survival, and thus it is not recommended.
Aibercept is a recombinant fusion protein that consists of
VEGF-binding portions from the extracellular domains of human
VEGF receptors 1 and 2 and fused to the Fc portion of the human
immunoglobulin G1 (IgG1). Van Custem and colleagues randomly
assigned 612 patients previously treated with oxaliplatin to FOLFIRI
plus aibercept or FOLFIRI alone (Table 62-2). Results were notable
for a signicant increase in both PFS (4.7 to 6.9 months, P <.0001)
and OS (12.1 to 13.5 months, P = .0032) with combination therapy.
Aibercept was also evaluated in the rst-line setting combined with modied (m) FOLFOX6. A total of 236 patients were
ManageMent of Metastatic colorectal cancer312
TABLE 62-2: Recently Approved Targeted Agents
Treatment Arm Control Overall Survival (Mo) Response Rate
FOLFIRI + aibercept FOLFIRI + placebo 13.5 vs. 12.1, P = .0032 20% vs. 11%
FOLFIRI + ramucirumab FOLFIRI + placebo 13.3 vs. 11.7, P = .0219 13.4% vs. 12.5%
Tipiracil (Lonsurf) Placebo 7.1 vs. 5.3, P <.001 1.6% vs. 0.4%
Regorafenib Placebo 6.4 vs. 5.0, P = .0052 1.0% vs. 0.4%
FOLFIRI, Irinotecan, 5-uorouracil, and leucovorin.
randomized to receive mFOLFOX6 with or without aibercept. No
dierence was found in PFS, and an increased toxicity was present in
the aibercept arm.
Ramucirumab, a human monoclonal antibody directed against
VEGF receptor 2, was evaluated in the RAISE study, a large international phase III trial. A total of 1072 patients who had previously
experienced progression while taking mFOLFOX6 plus bevacizumab
were randomly assigned to receive ramucirumab plus FOLFIRI or
matching placebo plus FOLFIRI. OS was signicantly prolonged in
the ramucirumab arm, from 11.7 months to 13.3 months (P = .0219).
FIRST-LINE TARGETED OPTIONS
With the development of multiple biologic agents during the past 10
years, the question of sequence has arisen, with a particular focus
on whether anti-VEGF or anti-EGFR approaches should be used in
the rst-line setting in combination with systemic therapy. Two large
randomized trials have been completed, one in the United States
and one in Europe. e FIRE-3 trial randomized rst-line patients
who had KRAS WT to receive FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab. PFS was similar between the two arms, but
a signicant improvement in OS favoring cetuximab was identied
(28.7 vs. 25 months, P = .017). In the United States, the larger CALGB/
SOWG 80405 trial compared FOLFOX/FOLFIRI with cetuximab or
bevacizumab. First-line patients with WT KRAS exon 2 received
either FOLFOX (73%) or FOLFIRI (27%) (physician’s choice), combined with either cetuximab or bevacizumab (by randomization).
Interestingly, OS was similar between the two arms (29 vs. 29.9
months, P = .34). e discrepancy in survival results between these
two trials may be a result of a dierence in second-line treatment
and lack of third-party review in the FIRE-3 trial. For now, clinically,
either choice appears appropriate, although most physicians choose
an anti-VEGF approach upfront because of logistics in obtaining RAS
testing results at the time of initiation of rst-line therapy.
THIRD- AND FOURTH-LINE OPTIONS
Two new targeted agents have recently been approved for use in
patients who have not responded to rst- and second-line treatment.
Regorafenib is an oral small-molecule kinase agent that inhibits several protein kinases, including VEGFR1, VEGFR2, VEGFR3, KIT,
RET, and BRAF. e CORRECT trial, published in 2013, randomized
patients who experienced disease progression while receiving multiple lines of treatment, including FOLFOX, FOLFIRI, bevacizumab,
and EGFR inhibition, to receive regorafenib versus placebo. Treatment
with regorafenib was associated with a small but statistically signicant
improvement in both PFS (1.9 vs. 1.7 months; HR 0.49, 95% CI 0.42-
0.058) and OS (6.4 vs. 5 months, HR 0.77, 95% CI 0.64-0.94).
A second oral agent, triuridine/tipiracil, was approved in 2015
for patients with refractory colorectal cancer. Triuridine is a thymidine-based nucleic acid analogue, and tipiracil is a thymidine
phosphorylase inhibitor, tipiracil hydrochloride. is compound was
compared in a 2:1 ratio to placebo in patients who had not responded
to FOLOX, FOLFIRI, bevacizumab, and in some cases regorafenib.
Results were notable for an increase in PFS of 2.0 months versus 1.7
months (HR 0.048; 95% CI 0.41-0.57) and an OS of 7.1 versus 5.0
months (HR 0.68, 95% CI 0.58-0.81).
OLIGOMETASTATIC DISEASE
e liver and lungs are the most common sites of hematogenous
spread in patients with metastatic colorectal cancer. Patients with
oligometastatic disease can be rendered disease-free with durable
survival (potential “cures”) with the combination of systemic treatment and surgical resection. No standard denition exists for resectable liver disease, but it is recommended that a multidisciplinary
treatment discussion be used prior to initiation of treatment in
patients. In patients who obtain an R0 resection, the 5-year survival
can approach 60%, and 10-year survival is 20%.
In patients who present with resectable oligometastatic disease, the
common initial approach is to begin treatment with systemic chemotherapy, which allows the opportunity for upfront treatment of micrometastasis and to learn the natural history of that patient’s disease. e
European Organization for Research and Treatment of Cancer Intergroup trial 40983 enrolled 364 patients with resectable cancer to arms
with or without perioperative FOLFOX. In the most recent update,
there was no statistically signicant dierence in OS, but there was a
trend toward increased 5-year PFS favoring the chemotherapy arm
(38% vs. 33%). Retrospective data suggest that only high-risk patients
benet from neoadjuvant therapy. For patients with more than two risk
factors, neoadjuvant chemotherapy improved 5-year OS (33% vs. 39%,
P = .028), but in low-risk patients, median survival was identical (60
months), as was 5-year OS (64% vs. 57%, P >.05).
e risk of liver recurrence can approach 80%, but repeat resection in eligible patients is safe and associated with survival rates
equivalent to those reported for rst hepatectomy. It is therefore recommended that aer liver resection, patients be monitored closely in
the event that they can be treated with a repeat resection.
Aer the liver, the lung is the most common site of metastasis in
persons with colorectal cancer. e selection of patients for lung metastasectomy is largely based on empiric studies. A meta-analysis published
in 2012 aimed to dene risk factors associated with survival aer lung
metastasectomy. e four parameters associated with poor survival were
a short disease-free interval between primary tumor resection and development of lung metastasis (HR 1.59, 95% CI 1.27-1.98), multiple lung
metastases (HR 2.04, 95% CI 1.72-2.41), positive hilar or mediastinal
lymph nodes (HR 1.65, 95% CI 1.35-2.02), and elevated prethoractomy
carcinoembryonic antigen (HR 1.91, 95% CI 1.5-2.32). A more recent
subset analysis found that when compared with lesser resection (wedge
resection), major anatomic resection (pneumonectomy and lobectomy)
was associated with increased disease-free survival, reinforcing the concept of aggressive local control in a select group of patients.
For patients who present with initially unresectable liver disease,
it is recommended that chemotherapy be initiated as a rst-line treatment; in up to 30% of patients, the disease can be converted to become
resectable. Typically, regimens with the highest rate of response are
selected in an attempt to downstage the patient. e triplet regimen
COLON 313
of FOLFOXIRI plus bevacizumab versus FOLFIRI plus bevacizumab
was evaluated in the TRIBE clinical trial. e FOLFOXIRI arm was
associated with higher response rates (65% vs. 53%), but no statistically signicant dierence was found in the R0 liver resection rate.
ROLE OF RESECTION OF PRIMARY LESION
Two major indications exist for removal of the primary lesion
in patients with metastatic disease: (1) to oer curative resection in
patients with oligometastatic disease, and (2) for palliative relief in
patients with pain, bleeding, or obstructive symptoms. For patients
who present with impending bowel obstruction, it is imperative to
facilitate urgent surgery. In general, its takes several weeks for chemotherapy to generate a response, and thus a diverting ostomy is oen
indicated in these patients. Patients who have undergone diversion
oen can begin chemotherapy 4 to 6 weeks aer the operation.
In patients with oligometastatic disease, the major question
regarding resection is based on sequence of treatment. One approach
is to resect the primary lesion and then transition to systemic chemotherapy followed by metastasectomy. A second more common
approach is to initiate systemic chemotherapy upfront because distant
failure oen determines survival. Once a tumor has demonstrated a
response to chemotherapy or at least stable disease, then resection of
the primary lesion can be considered. In patients with rectal cancer, a
short course of radiation is commonly delivered to the primary lesion
prior to resection. It is standard practice for this type of patient to
receive a total of 6 months of chemotherapy either as neoadjuvant or
perioperative treatment.
IMMUNOTHERAPY
e programmed death (PD-1) pathway is a negative feedback system that works to suppress the 1 cytotoxic immune system. When
upregulated, as is oen the case with cancer, tumor cells can proliferate in a nonhostile microenvironment. Blockade of the PD-1 pathway
has led to dramatic clinical responses in some patients, but predictive
biomarkers are lacking. In early trials, patients with colorectal cancer
who had mismatch repair–decient tumors appeared to respond to
such therapeutic approaches. is nding is not surprising because
somatic mutations can be recognized by a patient’s own immune system, and mismatch repair–decient tumors have 10 to 100 times more
somatic mutations than tumors that are mismatch repair– procient.
Based on this rationale, a phase 2 trial was conducted evaluating the
activity of a PD-1 inhibitor, pembrolizumab, in 41 patients with progressive metastatic carcinoma with or without mismatch-repair deciency. e response rate in patients with mismatch repair–decient
colorectal cancer was 40% (95% CI, 12-74) versus 0% (95% CI, 0-20)
in patients with mismatch repair–procient colorectal cancer. ese
preliminary ndings are quite impressive, and larger conrmatory
trials are currently under way.
CONCLUSIONS
We have seen signicant improvement in survival in patients with
metastatic colorectal cancer during the past 10 years. ese strides
have been made possible with the combined eort of improved systemic chemotherapy, more dened targeted biologic agents, and
appropriate deployment of locoregional treatment options.
Ongoing research aims to establish additional biomarkers that will
allow enhanced delivery of personalized medicine. For patients with
incurable disease, predictive biomarkers are crucial to minimize excess
toxicity, thereby improving quality of life. As we continue to develop new
agents, cost will surface as a crucial topic of debate. Several drugs that
have been approved within the past few years cost more than $10,000
per month, but they only prolong survival an average of 4 to 12 weeks.
Pharmaceutical companies will continue to be heavily scrutinized when
bringing expensive noncurative therapies to market. Next-generation
sequencing is becoming standard practice at most large academic institutions and will become more generalized as mutation-dependent study
designs emerge, such as the National Cancer Institute–led MATCH trial.
Much work has been done to prolong the quantity and quality of life of
patients with metastatic colorectal cancer, but a continued focus is essential to reduce the burden of this major illness.
ACKNOWLEDGMENTS
Dr. Khorana acknowledges research support from the Sondra and
Stephen Hardis Endowed Chair in Oncology Research, the Scott
Hamilton CARES Initiative, the Porter Family Fund for Biliary
Genomics Research, and the National Heart, Lung and Blood Institute (1R34HL127156). Dr. Noel serves on the speakers bureau for
Taiho Pharmaceutical.
S u g g e S t e d R e a d i n g
Douillard JY, Oliner KS, Siena S, etal. Panitumumab-FOLFOX4 treatment
and RAS mutations in colorectal cancer. N Engl J Med. 2013;369:1023–34.
Douillard JY, Siena S, Cassidy J, etal. Randomized, phase III trial of pani-
tumumab with infusional uorouracil, leucovorin, and oxaliplatin (FOLFOX4) versus FOLFOX4 alone as rst-line treatment in patients with previously untreated metastatic colorectal cancer: the PRIME study. J Clin
Oncol. 2010;28:4697–4705.
Grothey A, Van Cutsem E, Sobrero A, etal. Regorafenib monotherapy for
previously treated metastatic colorectal cancer (CORRECT): an international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet.
2013;381:303–312.
Heinemann V, Von Weikersthal LF, Decker T, etal. FOLFIRI plus cetuximab
versus FOLFIRI plus bevacizumab as rst-line treatment for patients with
metastatic colorectal cancer (FIRE-3): a randomised, open-label, phase 3
trial. Lancet Oncol. 2014;15:1065–1075.
Hurwitz H, Fehrenbacher L, Novotny W, etal. Bevacizumab plus irinotecan,
uorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med.
2004;350:2335–2342.
Le DT, Uram JN, Wang H, et al. PD-1 blockade in tumors with mismatch-
repair deciency. N Engl J Med. 2015;372:2509–2520.
Loupakis F, Cremolini C, Masi G, et al. Initial therapy with FOLFOXIRI
and bevacizumab for metastatic colorectal cancer. N Engl J Med.
2014;371:1609–1618.
Mayer RJ, Van Cutsem E, Falcone A, etal. Randomized trial of TAS-102 for re-
fractory metastatic colorectal cancer. N Engl J Med. 2015;372:1909–1919.
Nordlinger B, Sorbye H, Glimelius B, et al. Perioperative FOLFOX4
chemotherapy and surgery versus surgery alone for resectable liver metastases from colorectal cancer (EORTC 40983): long-term results of a
randomised, controlled, phase 3 trial. Lancet Oncol. 2013;14:1208–1215.
Saltz LB, Cox JV, Blanke C, etal. Irinotecan plus uorouracil and leucovorin
for metastatic colorectal cancer. Irinotecan Study Group. N Engl J Med.
2000;343:905–914.
Tabernero J, Yoshino T, Cohn AL, et al. Ramucirumab versus placebo in
combination with second-line FOLFIRI in patients with metastatic colorectal carcinoma that progressed during or aer rst-line therapy with
bevacizumab, oxaliplatin, and a uoropyrimidine (RAISE): a randomised,
double-blind, multicentre, phase 3 study. Lancet Oncol. 2015;16:499–508.
Tournigand C, Andre T, Achille E, etal. FOLFIRI followed by FOLFOX6 or
the reverse sequence in advanced colorectal cancer: a randomized Gercor
study. J Clin Oncol. 2004;22:229–237.
Van Cutsem E, Kohne CH, Lang I, etal. Cetuximab plus irinotecan, uoroura-
cil, and leucovorin as rst-line treatment for metastatic colorectal cancer:
updated analysis of overall survival according to tumor KRAS and BRAF
mutation status. J Clin Oncol. 2011;29:2011–2019.
Van Cutsem E, Tabernero J, Lakomy R, et al. Addition of aibercept to
uorouracil, leucovorin, and irinotecan improves survival in a phase III
randomized trial in patients with metastatic colorectal cancer previously
treated with an oxaliplatin-based regimen. J Clin Oncol. 2010;30:3499–3506.
M
C L
M
Terence Jackson, Nikita Neha Machado, and Christopher T. Siegel
INTRODUCTION
e liver is the most common site for colorectal cancer (CRC) metastases; 15% to 20% of patients present with synchronous lesions, and
metachronous metastases occur in 40% to 50% of patients. Liver metastases are present in 60% to 70% of all patients who die of colorectal
cancer. However, management of colorectal liver metastases (CRLM)
has changed a lot during the past decade, and overall survival aer
liver surgery for colorectal metastatic disease has more than doubled.
Resection is currently the gold standard of treatment, with 5-year overall survival rates ranging from 27% to 52%, but only 15% to 20% of liver
metastases are considered resectable at the time of diagnosis. Patients
with untreated CLRM have a median survival of 5 to 12 months.
DIAGNOSIS AND PREOPERATIVE WORKUP
Workup begins with a focused history and physical examination to
assess the patient’s general functional status, medical comorbidities,
and symptoms from the primary colorectal lesion such as obstruction, perforation, or bleeding. Patients with symptoms from the primary tumor typically undergo treatment. Staging studies should be
performed before surgery. Laboratory tests are performed, including a baseline carcinoembryonic antigen (CEA) level.
Imaging
Preoperative staging commonly entails use of a chest computed
tomography (CT) scan with use of contrast material and abdominal
imaging. Our preference for abdominal imaging is contrast-enhanced
liver magnetic resonance imaging (MRI), although triple-phase CT
can be equally informative (Table 63-1). For rectal cancer, pelvic MRI
is useful to dene the extent of the tumor. Positron emission tomographic imaging has not been shown to be an eective screening tool,
but it may be useful in determining the nature of ambiguous nodes
and liver lesions.
Serologic and Molecular Markers
CEA levels are used as a preoperative prognostic indicator in patients
with known CRC, as well as postoperatively to detect asymptomatic recurrences of colorectal cancer and to monitor the response of
metastases to treatment.
KRAS mutation analysis, with reex BRAF testing in cases of
wild-type KRAS, is used to predict a lack of response to cetuximab
and panitumumab in the treatment of metastatic CRC.
Histology
Needle Biopsy
A needle biopsy is indicated when diagnosis of a liver lesion is
in doubt or in patients with unresectable disease when histologic diagnosis would modify treatment. In the setting of prior
CRC, characteristic CT or MRI findings, and raised CEA levels, a
needle biopsy may not be necessary and can adversely affect outcome. In a retrospective study, patients who underwent a needle
biopsy prior to resection were found to have a higher incidence
of needle-track implants and were more likely to have a worse
prognosis.
Multidisciplinary Planning
Case discussion involving oncologists, pathologists, radiologists,
colorectal surgeons, and a surgeon experienced in the treatment of
hepatobiliary and extrahepatic metastases is an essential part of treatment planning.
STAGING AND PROGNOSIS
The following staging system for metastatic disease was proposed
by European Colorectal Metastases Treatment Group in 2007:
• M0:Nometastases
• M1a:Resectablelivermetastases
• M1b:Potentiallyresectablelivermetastases
• M1c:Livermetastasesthatareunlikelytoberesectable
Poor prognostic factors for liver resection include more than
four liver tumors, poorly differentiated tumor, bilobar lesions,
bulky lesions, hilar/celiac lymph nodes, inoperability of the primary tumor, local recurrence, lung metastases, other extrahepatic metastases, age older than 70 years, and cardiovascular/
respiratory disease. The presence of portal nodal metastasis has
been consistently associated with poorer prognosis, particularly
when the hepatic artery group of nodes is involved. These patients
appear to benefit most from multimodality treatment, including
chemotherapy followed by surgical resection. When tumors are
discovered intraoperatively, tumor response to chemotherapy has
been used to guide further resection.
Postoperatively, infectious complications are associated with
decreased overall survival. Bilobar disease, more than eight tumors,
more extensive treatment than a hemihepatectomy, and R1 margin status have been associated with increased postoperative
complications.
314
COLON 315
TABLE 63-1: Features of the Different Imaging
Modalities
Imaging
Modality Features
CT Triple-phase CT is highly accurate; it oers subcen-
timeter slices, high-resolution images, and options
for vascular reconstruction and volumetrics
MRI Better at identifying and characterizing liver lesions;
least aected by postchemotherapy hepatic steatosis;
preferred imaging modality in neoadjuvant setting;
better at delineating “missing metastasis” aer
neoadjuvant chemotherapy
PET Signicantly superior in detecting extrahepatic spread;
PET/CT provides precise localization of a CT and
functional data of PET; high costs and restricted
availability make it a poor screening test
IOUS Helpful in accurately delineating liver lesions during
liver resection or ablation; lesions may be hypo-/
hyper-/isoechoic on ultrasound; contrast-enhanced
ultrasound, though not yet approved by the FDA,
hasbeenshowntodetect97%oflesionsseenon
helical CT
CT, Computed tomography; FDA, Food and Drug Administration; IOUS,
intraoperative ultrasound; MRI, magnetic resonance imaging; PET, positron
emission tomography.
PROGNOSTIC SCORES
Over the years, the following scoring systems have been proposed to
help with risk stratication and patient selection for liver resection:
• Fongetal—scoringsystem(1999)
• Iwatsukietal(Pittsburghriskscore,1999)
• Nagashimaetal—scoringsystem(2006)
• Zakariaetal(2007)
• Reesetal(2008)
esescoringsystemswereanalyzedbyGregoireetalin2010,who
concluded that no single prognostic factor was common for all the
scores. However, the most common factors included the number and
size of the largest metastases, the disease-free interval between diagnosis of the primary cancer and development of liver metastases, CEA
level, a stage III primary cancer, and presence of extrahepatic disease.
It has become clear that generalized criteria may not be appropriate for
every patient and that a more individualized approach is warranted.
TREATMENT
e combination of 5-uorouracil (5-FU) and leucovorin was a
signicant advance, and combination regimens of infusional 5-FU
with either oxaliplatin (FOLFOX) or irinotecan (FOLFIRI) currently are the mainstay of CRLM management. Targeted therapy
using biologic agents is mostly used as an adjunct to systemic chemotherapy. Bevacizumab (anti–vascular endothelial growth factor)
has been shown to improve overall survival and protects against
oxaliplatin-induced injury, and cetuximab (anti–epidermal growth
factor receptor) is eective against tumors containing wild-type
KRAS. Panitumumab (anti–epidermal growth factor receptor) and
Perifosine (anti-AKT and nuclear factor–κB) are other examples of
biologic therapy.
Neoadjuvant Chemotherapy for Resectable Liver Disease
Preoperative chemotherapy for resectable liver metastasis has been a
matter of debate. e principles of neoadjuvant chemotherapy are to
eradicate micrometastases (Table 63-2) and shrink tumors to a more
resectable size. However, the response of tumors to preoperative chemotherapy correlates with improved overall survival. e EORTC
40983prospectiverandomizedclinicaltrialshowedanimprovement
in progression-free survival in patients who underwent perioperative chemotherapy (oxaliplatin) combined with resection compared
with the group having surgery alone (36.2% vs 28.1%, P = .041),
andNationalComprehensiveCancer Networkguidelines nowrec-
ommend 6 months of perioperative chemotherapy for patients with
resectable CRLM.
In patients receiving neoadjuvant chemotherapy, chemotherapyassociated liver injury is a concern. Oxaliplatin and 5-FU derivatives
are associated with sinusoidal obstruction and steatohepatitis, which
may result in increased perioperative morbidity and mortality, along
with poor regeneration (especially in the case of patients undergoing
portal vein embolization [PVE]). However, studies have shown safe
administration of chemotherapy before even extensive hepatic resection, with no deleterious eects on hypertrophy of the future liver
remnant aer PVE. is nding indicates that chemotherapy can be
continued through the course of PVE.
Another potential disadvantage of neoadjuvant chemotherapy is
that some small metastatic lesions disappear aer therapy (“miss-
ingmetastases”).Benoistetal showed that in 66% to83%of these
lesions, macroscopic or microscopic residual disease is found during surgery, which emphasizes the fact that radiologic resolution of
hepatic metastases does not necessarily mean complete cure. Serial
imaging, repeat resection, or ablative therapy may be used to treat
these sites. It has been suggested that marking metastatic sites with a
ducial prior to chemotherapy may facilitate diagnosis with intraoperative ultrasound.
e duration of chemotherapy and timing of surgery aer chemotherapy have also been debated. Surgery is usually scheduled
6 weeks aer the end of chemotherapy, which allows the liver to
regenerate. However, this timing needs to be discussed in a multidisciplinary board. Patients with synchronous unresectable or
multiple liver metastases are ideal candidates for neoadjuvant
chemotherapy.
Initial treatment of a patient presenting with CRLM depends on his or
her presentation. A useful starting point is to determine if the patient
has symptoms relating to the primary tumor. In patients with signs
and symptoms suggestive of hemorrhage, perforation, or obstruction, initial treatment should be resection or palliation of the primary
tumor. In an asymptomatic patient, the initial treatment should be
discussed by a multidisciplinary tumor board.
Chemotherapy
Chemotherapy for CRC started with uoropyrimidines in the
1950s,which signicantlyimprovedmedianoverallsurvivalrates.
Neoadjuvant Chemotherapy for Unresectable Liver Disease
e role of conversion chemotherapy in downstaging metastatic liver
tumors and rendering them resectable has been studied in a number
of prospective trials, with subsequent resectability rates ranging from
3% to 40%, depending on the regimen used and the individual criteria for resectability dened by the study.
Adjuvant Chemotherapy
FOLFOX is widely used as the protocol of choice for adjuvant therapy. In case of rectal cancer, combined modality therapy (i.e., including pelvic radiotherapy) is used to reduce local recurrence.
ManageMent of ColoreCtal liver Metastasis316
TABLE 63-2: Four Categories of Chemotherapeutic
Interventions
Type of Chemotherapy Advantages
1. Preoperative chemotherapy
for initially unresectable
tumors
2. Neoadjuvantchemotherapy
for resectable liver disease
3. Adjuvant systemic
chemotherapy
4. Hepatic arterial infusion
Floxuridine infusion
Chemo-embolization
Decreases tumor load; vascular
pedicles may become free
of tumor; large lesions may
shrink enough for radiofrequency ablation (<3 cm)
Allows limited hepatectomy,
treatment of micrometastases,
evaluation of possible response
to further chemotherapy
Treatment of remnant “dormant”
tumor cells aer resection;
decreases recurrence rates
Localized, targeted therapy
using drug-eluting beads;
useful adjunctive therapy in
persons who do not respond
to rst- and second-line
chemotherapy
Hepatic Arterial Infusion
Hepatic arterial infusion (HAI) is based on the dierential blood
supply of tumor and normal liver. Tumor cells are supplied with
blood by the hepatic artery, and the remnant liver is supplied by the
portal venous system. e agent of choice is oxuridine (FUDR), a
pyrimidine antimetabolite, because of its short half-life and high rate
ofextractionbytheliver(90%). A shorthospital stayandminimal
immediate postoperative complications are clear advantages of HAI.
Bouchahdaetalperformedameta-analysisof10randomizedtrials,
which showed that HAI was associated with a higher intrahepatic
response but not an overall survival advantage compared with sys-
temicchemotherapy. Kemenyetalshowedamediansurvivalof41
months in a study that combined HAI with systemic oxaliplatin and
irinotecan for patients with unresectable liver metastases, indicating
that it has a use as an adjunctive therapy, rather than as rst-line therapy. Although arterial chemoembolization alone may not provide
adequate control of metastatic disease, drug-eluting beads soaked
in irinotecan are safe and eective when used in conjunction with
systemic chemotherapy in patients who do not respond to rst- and
second-line chemotherapy and in patients with advanced disease.
Radioembolization using radioactive beads (yttrium-90) has been
shown to be equally eective. 90Y is a brachytherapy treatment option
that has shown radiographic response rates of up to 40% and is a
viable option in persons with nonablatable and nonoperable disease.
Resectability
Inthe1980s,resectabilitycriteriaincludedamaximumofthreeliver
lesions, absence of extrahepatic spread, and a clear resection margin
of 1 cm. Better understanding of liver physiology, advanced surgical
techniques, and improved chemotherapy have dramatically changed
the denition of unresectable metastases.
Future liver remnant (FLR) is the most important factor in deciding if resection can be undertaken. e minimum FLR is about 1%
of the total body weight in a patient with normal liver histology. If
steatosis is present, the minimal FLR size is increased. e remnant
liver must be supplied by a portal vein, hepatic artery, and bile duct.
e resection margin is another important factor in resection
planning.Althoughithasbeenshownthat98%ofintrahepaticmicrometastasis is located within less than 1 cm of the gross tumor, debate
has ensued about the need for a 1-cm resection margin. Because the
distribution of micrometastasis cannot be evaluated preoperatively, a
resection margin of at least 1 cm should be the goal.
Resectable Liver Disease
Hepatic resection is the gold standard of treatment for CRLM, and
recent series have shown a 5-year survival rate greater than 50%.
Patients with advanced liver metastases also may be considered candidates for surgical resection as long as all the liver metastases can be
resected and at least two contiguous liver segments can be preserved
with biliary drainage, blood supply, and residual volume.
Laparoscopic liver resection or combined liver and colorectal primary resection is a safe and feasible option not only for resection of
the le side of the liver or for nonanatomic wedge resections but for
tumors located in segments that are dicult to expose and approach.
Intraoperative ultrasound helps delineate the lesion and obtain R0
resection. Laparoscopic liver resections are associated with reduced
hospital stay with similar complication rates compared with open
procedures.
Although a 1-cm resection margin is recommended, in patients
with multiple CRLM where achieving an adequate margin may not
be possible, the concept of “parenchymal-sparing surgery” has gained
acceptance as a result of the advances in neoadjuvant chemotherapy
and minimally invasive treatment of CRLM. Studies have shown no
signicant dierences in terms of complication rates, positive resection margins, or recurrence when comparing nonanatomic resection
(NAR)andanatomicresection(AR),makingNARaviableoptionfor
treatingmetastaticdisease.NARisdenedasresectionoftheCRLM,
including a rim of microscopically normal tissue, whereas AR is the
resection of two or more hepatic segments (based on Couinaud’s
classication/Brisbaneclassication).NARmaximizestheamountof
viable residual liver parenchyma, which is essential aer neoadjuvant
chemotherapy and its propensity to cause steatohepatitis and pro-
gressiveliverfailure.NARalsoincreasestheamountofhepatictissue
for local therapy in case of an intrahepatic recurrence.
Synchronous Liver Metastasis
Traditionally, patients have undergone a two-staged procedure with
resection of the primary tumor followed by chemotherapy and subsequent liver resection. With this approach, many patients fail to
receive optimal therapy because of postoperative complications from
the rst procedure. e long treatment regimen also leads to psychological fatigue, encouraging some patients to refuse further treatment.
Advances in anesthesia and operative techniques have now made it
possible to resect the colorectal primary and metastatic liver lesion
simultaneously, with similar surgical outcomes. Simultaneous laparoscopic resection can also be carried out when R0 resection is feasible.
FirstdescribedbyMenthaetal,the“liverfirst”approachhas
been described as a feasible method of management of advanced
colorectal liver metastasis, particularly locally advanced metastatic rectal cancer requiring complex chemoradiation and pelvic
surgery. The classic approach of primary resection prior to liver
resection would cause a significant delay in treatment of CRLM
and carries a significant risk of hepatic disease progression. This
delay is avoided by using induction chemotherapy/chemo-radiotherapy followed by resection of CRLM prior to resection of the
rectal primary tumor. This treatment may be followed by more
chemo-radiotherapy before resection of the primary tumor. Retrospective studies have shown that the “liver first” approach is
used in patients with a significantly higher number of liver lesions
compared with traditional or simultaneous approaches. This
COLON 317
(C) ALPPS stage II
Segment resected
approachpermitsearlycontrolofCRLM.DeJongetaldescribed
their 5-year experience with “liver first” procedures and found
thatitwasfeasiblefor80%oftheirpatients.
Unresectable Liver Disease
Systemic conversion chemotherapy is the management of choice for
patients with unresectable disease limited to the liver. e primary aim
of this line of treatment is to facilitate potentially curative resections.
Two-stage hepatectomy, which was introduced by the Paul
Brousse group, may be used in patients who require extensive resection with suboptimal FLR. e initial stage of the hepatic resection is
intended to remove the highest possible number of metastases, followed by chemotherapy to prevent further tumor progression and a
second hepatectomy when adequate FLR is obtained. e rst hepatectomy can be combined with colorectal primary resection. Portal
vein embolization during the rst surgery may be used to hasten liver
hypertrophy of the contralateral side.
Portalvein embolizationwasrstintroducedbyMakuuchiet al
for the management of Klatskin tumors, but it has since found signicant use in the treatment of CRLM. Embolization or ligation of
portal branches (PVE) supplying the segment to be resected helps
increase the size of the FLR. It can be accomplished by either surgical
ligation or endoluminal embolization. Percutaneous embolization is
the treatment of choice in cases of one-stage hepatic resection, and
patients undergoing a two-stage hepatectomy are ideal candidates for
surgical ligation. Response to PVE correlates directly with postoperative liver function, and ecacy is assessed by an increase in volume
2 to 4 weeks aer the procedure. Possible complications include subcapsular hematoma, hemobilia, arteriovenous stula, or formation of
an arterial pseudoaneurysm.
Associating liver partition and portal vein ligation for staged hepatectomy is a two-step procedure that involves ligation of the portal venous
supply to liver segments planned for resection and in situ partitioning of
liver segments (Fig. 63-1). is technique induces accelerated hypertrophy in the remaining liver by release of growth factors. Devascularization
of segments prevents neovascularization and interlobar perfusion. is
technique has been shown to provide FLR hypertrophy ranging from
57%to 159% dependingon the timeinterval betweenthe two procedures. A longer time interval between the procedures provides greater
hypertrophy but makes the second procedure more dicult.
Repeat Resections for Multiple Liver Metastases
A16-yearprospectivestudybySaiuraetaldemonstratedanincreased
risk of intrahepatic recurrence in patients with a higher number of initial metastases, likely because of a higher rate of occult metastases at
the time. eir study, along with others, also showed that repeat resections have the same outcome as the primary hepatectomy and still have
the potential for cure.
Local Ablative Therapy
Patients with unresectable liver metastases or those who are unt for
surgery form a growing proportion of CRLM patients, and ablative
therapy has emerged as an alternative for these patients during the past
2 decades.
Radiofrequency Ablation
Radiofrequency ablation (RFA) uses thermal ablation generated by
electrical conduction across the lesion. Its advantages include low postoperative morbidity and mortality and shorter hospital stays. Recurrence rates aer RFA range from 10% to 50%, and risk factors for
recurrence include lesions larger than 3.5 cm, proximity to vasculature
(heat sink phenomenon), multiple lesions, and subcapsular location.
Lesions greater than 6 cm generally are not considered amenable to
(A) Preoperative
Segment resected
during stage II
Colorectal liver
metastasis
(B) ALPPS stage I
Segment
undergoing
hypertrophy
Hepatic artery
and bile duct
ligation
during stage I
Portal vein
ligation
Line of liver
partition
FIGURE 63-1 Associating liver partition
and portal vein ligation for staged
hepatectomy (ALPPS) is a two-step
procedure that involves ligation of the
portal venous supply to liver segments
planned for resection and in situ
partitioning of liver segments.
A, Preoperative. B, ALPPS stage I.
C, ALPPS stage II.
ManageMent of ColoreCtal liver Metastasis318
treatment with RFA. e current consensus is that RFA should be used
as an adjunct to resection and chemotherapy and not as a stand-alone
treatment.
Microwave Ablation
Microwave ablation provides a larger area of coverage than RFA and
is not aected by the “heat sink” phenomenon or heat loss from adjacent blood vessels, which are known to decrease the ecacy of RFA.
Cryotherapy
Benets of cryotherapy are similar to those of RFA and microwave
ablation but have been associated with increased mortality and
morbidity. Cryoshock is a complication of cryotherapy caused by a
systemic response to cryotherapy that involves formation of free radicals, resulting in multiorgan failure.
Irreversible Electroporation
Irreversible electroporation is an emerging nonthermal and nonchemical technique that uses electrical current to render cells permeable to drugs and genes.
Colorectal Liver Metastases with Extrahepatic Spread
Ideally, surgical resection should be carried out in patients with
metastatic disease only if complete resection of all metastatic sites
is deemed possible, and multiple modalities of treatment may be
required, depending on the tumor location. e following stratication of 5-year survival by location of extrahepatic disease has been
performedbyEllisetal:lung(33%),peritoneum(26%),portallymph
nodes (27%), aortocaval lymph nodes (7%), and multiple sites (14%).
Lung
Aer the liver (33%), the second most common metastatic site is the
lung (22%), and combined resection of tumors at both sites have been
associated with 5% to 13% mortality. However, patients who undergo
resection have a higher long-term survival rate.
Peritoneal
In cases of peritoneal spread, a combination of cytoreductive surgery
and hyperthermic intraperitoneal chemotherapy with mitomycin C
can improve long-term survival in a select group of patients with limited peritoneal disease.
Lymph Node Involvement
Although lymph node involvement has long been thought to be a poor
prognosticfactor, Adam et al (2008)publisheda study showing that
a hepatectomy combined with concurrent regional lymphadenectomy
couldoera5-yearsurvivalrateof18%withnooperativemortality.In
this study, patients with pedicular regional lymph node involvement
had more favorable outcomes than did patients with celiac/para-aortic
lymph node involvement (25% vs no 5-year survivors), as did patients
younger than 40 years (45% vs 10% 5-year survival).
Inferior Vena Cava
Involvement of the inferior vena cava was previously considered a
contraindication to surgical resection, with poor 5-year survival.
With improvements in vascular isolation and surgical technique,
direct suturing or autologous patch or vascular prosthesis are now
being used to complete the resection.
Recurrence
e liver is the most common site of recurrence aer CRLM resection. Recurrence rates range from 40% to 75%, with two thirds showing intrahepatic recurrence, one third having solely liver recurrences,
and half the patients having extrahepatic recurrence. A rectal primary, disease-free interval less than 12, a history of RFA, and a high
clinical risk score have been found to be associated with recurrence,
whereas synchronous presentation of the primary and liver secondary tumor, R1 margin status, and history of RFA were associated with
an increased risk of intrahepatic recurrence.
Another emerging site of unrecognized involvement is intrabili-
ary growth of CRLM, shown to be approximately 16.5% of the cohort
ina studybyJhaverietal.Itsimportancelies inthefactthatthis is
a potential source for unanticipated recurrence if it is not identied
preoperatively. ese CRLM are usually diagnosed by a portal phase
helical CT scan, on which dilated ducts and ne punctate intraductal
calcications may be seen.
SURVEILLANCE
Patients are scheduled to have follow-up visits every 3 to 6 months for the
rst 2 years, then every 6 months for up to 10 years. Any deviation from
baseline CEA levels suggests recurrence. CEA levels are obtained during
each follow-up visit. Surveillance CT scans are obtained annually as well.
CONCLUSION
Recent advances in the approach to CRLM have allowed patients with
extensive disease to undergo surgery with improvement in overall
survival. Recently published data show that even patients with extensive disease, aer undergoing conversion chemotherapy followed by
R0resection,had a median overall survivalrangingfrom35.9%to
71.9% with acceptable morbidity and mortality. Staged resection,
PVE with resection, laparoscopic resection, and associating liver partition and portal vein ligation for staged hepatectomy have increased
our ability to oer patients options for cure. However, the optimal
strategy still needs to be determined.
S u g g e S t e d R e a d i n g S
Adam R. Chemotherapy and surgery: new perspectives on the treatment of
unresectable liver metastases. Ann Oncol. 2003;14(suppl 2):ii13–6.
Adam R, Laurent A, Azoulay D,etal.Two-stagehepatectomy:aplannedstrat-
egy to treat irresectable liver tumors. Ann Surg. 2000;232:777.
Capussotti L, Muratore A, Baracchi F,etal.Portalveinligationasanecient
method of increasing the future liver remnant volume in the surgical treatment of colorectal metastases. Arch Surg.2008;143:978.
Cho JY, Han H-S, Yoon Y-S, Shin S-H. Outcomes of laparoscopic liver resec-
tion for lesions located in the right side of the liver. Arch Surg.2009;144:25.
Gregoire E, Hoti E, Gorden D,etal.Utilityorfutilityofprognostic scoring
systems for colorectal liver metastases in an era of advanced multimodal
therapy. Eur J Surg Oncol.2010;36:568–574.
Gur I, Diggs BS, Wagner JA,etal.Safetyandoutcomes followingresection
of colorectal liver metastases in the era of current perioperative chemotherapy. J Gastrointest Surg. 2013;17:2133–2142.
Jones O, Rees M, John T,etal.Biopsyofresectablecolorectallivermetastases
causes tumor dissemination and adversely aects survival aer liver resection. Br J Surg.2005;92:1165–1168.
KemenyNE, Melendez FDH, Capanu M,etal.Conversiontoresectabilityus-
ing hepatic artery infusion plus systemic chemotherapy for the treatment
of unresectable liver metastases from colorectal carcinoma. J Clin Oncol.
2009;27:3465–3471.
LalmahomedZS,AyezN, van der Pool AE,etal.Anatomicalversusnonana-
tomical resection of colorectal liver metastases: is there a dierence in surgical and oncological outcome? World J Surg. 2011;35:656–661.
Machado MAC, Makdissi FF, Surjan RC. Totally laparoscopic ALPPS is feasi-
ble and may be worthwhile. Ann Surg. 2012;256:e13.
COLON 319
Mayo SC, Pulitano C, Marques H,etal.Surgicalmanagementofpatientswith
synchronous colorectal liver metastasis: a multicenter international analy-
sis. J Am Coll Surg. 2013;216:707–716.
Turrini O, Viret F, Guiramand J,etal.Strategiesforthetreatmentofsynchro-
nous liver metastasis. Eur J Surg Oncol. 2007;33:735–740.
Xu L-H, Cai S-J, Cai G-X, Peng W-J. Imaging diagnosis of colorectal liver
metastases. World J Gastroenterol. 2011;17:4654.
Yamashita S, Hasegawa K, Takahashi M,etal.One-stagehepatectomyfollow-
ing portal vein embolization for colorectal liver metastasis. World J Surg.
2013;37:622–628.
C M
L
Philip A. Linden
INTRODUCTION
Colorectal carcinoma metastasizes to the lung in 10% to 15% of
patients. e decision about whether to perform surgery for a patient
with lung metastasis must take into account the patient’s ability to
tolerate surgery, as well as the likelihood of achieving long-term survival. Most reports detailing the treatment of lung metastases are
single-center retrospective reviews that have used overall survival
as the endpoint. During the past 10 to 15 years, several multicenter
reviews have been published, and a single prospective randomized
trial has been initiated. is chapter will review the indications for
resection of metastases to the lungs, prognostic factors derived from
prior single and multi-institution reports, the issue of combined lung
and liver metastases, the surgical approach, and the concepts behind
the development of a prospective randomized trial.
INDICATIONS FOR RESECTION OF COLORECTAL METASTASES
Many factors are involved in the decision of whether to oer the
option of surgical resection to a patient with metastatic disease to the
lungs. A basic set of criteria has long been adopted by most surgeons:
1. e operative risk for the patient must be acceptable. Severe
comorbidities such as recent congestive heart failure, unstable
angina, and severe or critical aortic stenosis would preclude
most patients from any procedures except for immediately
lifesaving operations. In addition, pulmonary capacity and
the ability to withstand lung resection must be taken into account. Patients should undergo full pulmonary function testing, including forced expiratory volume in the rst second of
expiration (FEV1) and diusion capacities. Commonly held
parameters for lung resection dictate that the postoperative
FEV1 or diusion capacity (when adjusted for hemoglobin
and total alveolar ventilation) should not be less than 35% to
40% of predicted. Patients with numbers below these values
have been shown to have an excess of perioperative complications and postoperative respiratory problems. A preoperative FEV1 is obtained, and the percentage of functioning segments that would be removed is estimated to obtain a number.
ese calculations are typically used in reference to anatomic
resections such as lobectomies or segmental resections. Small,
peripheral wedge resections usually do not have a signicant
eect on lung function and oen can be performed even in
persons with very poor baseline function.
2. A complete resection of all metastatic disease should be achievable. is goal has recently been modied with the development of stereotactic body radiation, which delivers fairly good
long-term control for lesions smaller than 3 cm in diameter.
320
3. e primary malignancy should be removed, and the patient
should have no evidence of recurrence.
4. Patients should have no evidence of disease elsewhere. Certain
patients with combined hepatic and lung metastases who may
have good long-term outcomes are an exception to this dictum.
OUTCOMES OF PATIENTS UNDERGOING RESECTION AND PROGNOSTIC FACTORS
More than 100 single-institution reports describing outcomes of
patients undergoing resection of colorectal lung metastases have
been published. Each report represents what is likely a highly selected
group of patients cared for by a unique group of surgeons in a unique
facility. e results achieved in these patients by these surgeons in
these facilities may not apply to other institutions. Nonetheless, they
represent the mainstay of our literature. Girard etal retrospectively
reviewed 86 patients with metastatic colorectal cancer who underwent lung resection at a single French hospital. Twenty-one patients
underwent bilateral surgery, and 10 had an incomplete resection. e
estimated 5-year and 10-year survival was 24% and 20%. Complete
resection, the number of lung metastases, and preoperative carcinoembryonic antigen (CEA) levels were all noted to be independent
predictors of prolonged survival. Inoue etal retrospectively reviewed
128 patients in Osaka, Japan, who underwent resection. e overall
5-year survival rate was 45.3%. In univariate analysis, the number of
metastases, unilateral location, preoperative CEA levels, absence of
hilar or mediastinal nodal metastases, and node negativity of colon
primary were all predictors of long-term survival. In multivariate
analysis, however, only negative nodes in the colon primary cancer
resection and the unilateral nature of lung metastases were signicant
independent predictors. Saito etal reviewed the cases of 165 patients
who underwent lung resection for colorectal carcinoma in Japan
between 1990 and 2000. In the majority of patients (57%), the site
of their primary cancer was in the rectum. Sixty-three percent of the
patients who underwent lung operations had a solitary metastasis,
23% had three or more metastases, and 16% had hepatic metastases, which were resected before the lung metastases. e patients in
this series were all treated with a thoracotomy. (It should be noted
that in the United States today, a signicant percentage, and possibly the majority, of these resections at academic institutions are performed by video-assisted thoracic surgery [VATS]). Overall 5-year
and 10-year survival rates were 39.6% and 37.2%, respectively. e
authors noted that 5-year survival was much better for patients with
a prethoracotomy CEA of less than 10 ng/mL (42.7%) than for those
with a level of greater than 10 ng/mL (15.1%). e 5-year survival of
patients without hilar or mediastinal nodal metastasis was 53.6% versus 6.2% for patients with metastases. e 10-year survival of patients