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Neoadjuvant Treatment for Surgically Resectable Metastatic
Colorectal Cancer
Review Article [1] | January 15, 2016 | Oncology Journal [2], Colorectal Cancer [3], Gastrointestinal
Cancer [4]
By Marwan Al-Hajeili, MD [5], John L. Marshall, MD [6], and Brandon G. Smaglo, MD [7]
Here, we review the studies that have explored different treatment regimens, therapeutic
sequencing, and biologic inclusions for the treatment of these patients, with neoadjuvant intent. We
also describe how we have established our own treatment paradigm for the management of
potentially curable metastatic colorectal cancer.
Overview
In the United States, colorectal cancer was predicted to have the fourth highest rate of incidence of
new diagnoses among all cancers in 2015, with over 130,000 new cases expected.[1,2] Twenty
percent of patients with newly diagnosed colorectal cancers present with metastatic disease. The
average 5-year survival for metastatic colorectal cancer is 12.9%.[2] Surgical resection is the only
potentially curative option for patients with this disease. However, there are limitations to its use,
since less than 15% of patients with metastatic colorectal cancer have disease that is considered
resectable at diagnosis,[3] and the failure rate remains high.[4] Thus, a number of studies have
evaluated the role of preoperative medical therapy to improve metastasectomy outcomes, both as
neoadjuvant therapy for resectable metastatic disease and as a method for converting unresectable
metastatic disease into resectable disease.[5] These preoperative medical approaches could also
have implications for patients who have localized disease, since up to 20% of these patients will go
on to develop metastatic recurrent disease within 5 years of their initial diagnosis.[2,6]
The most common site for distant metastases from colorectal cancer is the liver.[7] Among all
patients with hepatic metastases, potential resection is limited to about 15% to 20% upon
presentation. To improve outcomes in patients with unresectable liver metastases, systemic
treatment has been evaluated as a method for converting unresectable to resectable disease.[5]
Certain clinicopathologic features have been identified to suggest which patients could benefit from
hepatic metastasectomy. In the past, the contraindications for hepatic metastasectomy were the
presence of four or more metastases within the liver, the presence of extrahepatic metastases, the
presence of large hepatic metastases, or the inability to obtain more than 1-cm negative margins at
hepatic metastasectomy.[8] However, because of the inconsistent and conflicting prognostic value of
these clinicopathologic features, the paradigm of resectability has changed. The new paradigm
considers the ability to achieve an R0 resection upon metastasectomy as the most relevant
indication for offering this intervention. The limitations to this approach are preserving adequate
functional tissue after surgery, biliary drainage, and vascular inflow and outflow structure, as well as
the need to spare at least two adjacent segments or 20% or more of the liver tissue.[8]
Of all patients with metastatic colorectal cancer, up to 2.3% have lung metastases at presentation,
and up to 22.4% have lung metastases with disease recurrence.[7] There are no defined criteria for
resectability of lung metastases. Certain prognostic factors should be addressed carefully before
surgery because they suggest an association with higher rates of recurrence. These factors include
bilateral lung metastases or more than six lung lesions. Patients who have involvement of other
organ sites are generally considered to be at high risk for recurrence as well.[8] However, surgery
could be attempted if, after multidisciplinary discussion, R0 resection is deemed possible with
acceptable morbidity and mortality.
Preoperative Treatment Approach
Potential advantages of preoperative therapy for liver or other metastases from colorectal cancer are
the earlier treatment of micrometastases, assessment of tumor response to chemotherapy,
avoidance of surgery in patients who have early disease progression, and conversion of unresectable
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to resectable tumors. The drawback to a preoperative approach is potential toxicity from
chemotherapy; for example, liver steatohepatitis has been reported at a rate of 4% to 11% and
sinusoidal liver injury at a rate of 26% to 42%.[9] A further disadvantage is interval disease
worsening that could exclude surgery as an option.[10] The ultimate goal of this preoperative
treatment is of course cure, and different factors have been evaluated as surrogate measures of
outcome to determine the benefit of such treatment in achieving a cure. John et al showed that
5-year survival in patients with R0 resection was 46.7%, compared with 14.6% in patients with R1
resection (P < .001).[11] Similarly, Tan et al reported that 10-year disease-specific survival was 68%
for liver metastasis resection in colorectal cancer patients.[12] Therefore, if a different treatment
approach, such as neoadjuvant therapy, can increase rates of R0 resection, it may in turn lead to
higher rates of cure.
Multiple chemotherapy agents and antibody therapies have demonstrated effectiveness in the
management of patients with metastatic colorectal cancer. Meanwhile, a limited number of agents
(fluoropyrimidine with or without oxaliplatin) have demonstrated effectiveness in the adjuvant
setting. Many of these regimens have been explored for their preoperative impact in the treatment
of patients with both resectable and unresectable disease. The studies discussed here are
summarized and categorized by these two different intentions in Tables 1 and 2.
FOLFOX and CAPEOX
Doublet chemotherapy regimens using a fluoropyrimidine paired with oxaliplatin have an established
curative role for the adjuvant management of patients with stage III colorectal cancers, and thus
serve as a natural choice of therapy for exploration in the preoperative management of potentially
curable metastatic disease. In a phase II trial, Alberts et al reported outcomes of the use of folinic
acid, fluorouracil (5-FU), and oxaliplatin (FOLFOX) as a conversion therapy in 42 patients with
liver-only metastases that were deemed unresectable due to major liver vasculature involvement or
more diffuse liver metastases.
The median number of treatment cycles was 10; the overall response rate (ORR) was 60% (95%
confidence interval [CI], 46%–75%). Of the 17 patients who underwent surgery, 14 (33% of the total
enrollment) had complete resection (R0). The overall median time to disease recurrence for all
surgical patients who had a relapse was 19 months, and the median 3-year overall survival (OS) was
71%.[13] Adam et al retrospectively evaluated conversion chemotherapy using 5-FU and oxaliplatin
to treat 701 patients with metastatic colorectal cancer deemed to have unresectable disease;
chemotherapy dose schedule was modified and optimized during the study period (1988–1996), in
keeping with then-current standards. Patients received neoadjuvant therapy for a mean of 10.6
months. The conversion rate to resection was 13.6%, and 5-year OS after resection was 34%. Six
patients had a pathologic complete response; of these patients, the 5-year OS was 83%, and 50%
had no evidence of disease at 5-year follow-up.[14] Coskun et al retrospectively reviewed
capecitabine and oxaliplatin (CAPEOX) as a conversion therapy in 35 patients with unresectable liver
metastases. The median number of treatment cycles was 4 (range, 2–9). The ORR was 37.2%;
however, 20% of the patients were converted to surgically resectable disease based on imaging
results. Of the five patients who had surgery, four (11.4%) had an R0 resection.[15]
Neoadjuvant therapy using a fluoropyrimidine/oxaliplatin doublet has also been explored in patients
with metastatic disease that is deemed resectable upon presentation. These investigations have only
been early-phase studies; direct comparisons with upfront surgery have not been carried out. Wein
et al used FOLFOX in the neoadjuvant setting for metastatic colorectal cancer patients who were
considered to have resectable liver metastases upon presentation. Twenty patients were enrolled in
this phase II trial, and all underwent resection, with 80% achieving an R0 resection outcome.
Pathologic complete response was observed in 18.7% of patients.[16] The 2-year disease-free
survival (DFS) among patients who achieved an R0 resection was 52% (95% CI, 23%–81%), and the
median OS was 4.8 years (95% CI, 3.303–6.362).[16,17] Lorenz et al reported the outcome of
neoadjuvant FOLFOX in 42 patients with resectable liver metastases. The phase II part of the study
had two arms, in which patients were assigned to 3 or 6 cycles of FOLFOX. The ORR was 48%, and
36 of the patients (86%) underwent surgical resection. R0 resection was achieved in 31 patients
(74%).[18]
FOLFIRI
In several smaller studies, irinotecan chemotherapy doublets have been explored as preoperative
systemic therapy in potentially curable metastatic colorectal cancer, as an alternative to oxaliplatin.
In a phase II study of 35 patients with hepatic metastases considered resectable upon presentation,
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Bathe et al evaluated the benefits of neoadjuvant folinic acid, 5-FU, and irinotecan (FOLFIRI). The
ORR was 40%. All 30 patients who proceeded to surgery achieved an R0 resection. The median DFS
for all resected patients was 23 months from the time of liver tumor resection, and the 2-year OS
was 93%.[19]
In a study of 40 patients who presented with liver metastases deemed unresectable, Pozzo et al
assessed FOLFIRI as a conversion therapy. They reported an ORR of 47.5%. All 13 patients (32.5%)
who went to surgery had an R0 resection.[20] The median DFS in resected patients was 52.5
months, and the 5-year survival was 62%.[21] Ho et al reported similar results in 40 patients given a
median of 12 cycles of FOLFIRI as conversion therapy. The ORR was 55% (95% CI, 39.5%–70.4%),
but only 10% of the patients were able to undergo surgical resection.[22]
FOLFOXIRI
As a natural extension of the doublet therapies using oxaliplatin or irinotecan with fluoropyrimidines,
Falcone et al explored the combination of all three drugs for conversion therapy. This phase III study
demonstrated the efficacy of folinic acid, 5-FU, oxaliplatin, and irinotecan (FOLFOXIRI) vs FOLFIRI in
unresectable liver metastases. The median number of cycles was 11 for FOLFOXIRI and 10 for
FOLFIRI. The ORR was 60% vs 34%, favoring FOLFOXIRI (P < .0001), and the rate of R0 resection also
favored FOLFOXIRI (15% vs 6%; P = .033).[23] Masi et al reported the follow-up results of three
different trials for patients who underwent treatment with FOLFOXIRI for unresectable liver
metastasis. The total number of patients was 196, and the median number of chemotherapy cycles
was 11. The ORR was 70%, and R0 resection was achieved in 37 patients (19%). The 5-year survival
in the R0 resection group was 42%.[24]
Antibody therapy
Beyond chemotherapy, preoperative antibody therapies have also been explored. Gruenberger et al
assessed neoadjuvant CAPEOX combined with bevacizumab in 56 patients with metastatic colorectal
cancer and resectable hepatic metastases. In this phase II trial, the median number of treatment
cycles was 6. The ORR was 73.2%, and the R0 resection rate was 93%.[25] Wong et al assessed
preoperative CAPEOX combined with bevacizumab in 46 patients with metastatic disease with both
resectable and unresectable liver metastases. The phase II trial had an ORR of 78% (95% CI,
63%–89%). The rate of R0 resection was 20%, and 40% of unresectable metastases were converted
to resectable.[26] Uetake et al reported that after 6 cycles of the combination of FOLFOX and
bevacizumab, 19 patients with resectable disease had an ORR of 68.4% and 16 of these patients
(84.2%) had an R0 resection. In the same study, 26 patients with unresectable disease had an ORR
of 46.2% and 4 patients (15.4%) had R0 resections.[27] In a study by Bertolini et al, 21 patients with
unresectable liver metastasis were given 6 cycles of FOLFOX combined with bevacizumab. The ORR
was 57.1%. Thirteen patients (61.9%) achieved R0 resections. The progression-free survival (PFS)
and the OS in the surgical group were 12.9 months and 22.5 months, respectively.[28] Recently,
Gruenberger et al assessed the effect of combining bevacizumab with either FOLFOXIRI or FOLFOX in
80 patients with unresectable liver metastasis. The ORR was 81% vs 62%, favoring the FOLFOXIRI
arm. For patients who underwent surgery, R0 resection was achieved in 20 (49%) and 9 (23%)
patients, respectively, again favoring the FOLFOXIRI arm. The PFS was 18.6 months (95% CI,
12.9–22.3 months) and 11.5 months (95% CI, 9.6–13.6 months), favoring the FOLFOXIRI arm.[29]
Masi et al evaluated the effect of combining preoperative FOLFOXIRI with bevacizumab in 57
patients with unresectable liver metastasis. The median number of cycles was 12. The ORR was
77%; 18 patients (32%) had surgery, and 15 (26%) achieved an R0 resection.[30]
TO PUT THAT INTO CONTEXT
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Steven R. Alberts, MD
Mayo Clinic
Rochester, Minnesota
What Have Prior Efforts to Improve Outcomes for Patients With Resectable Metastatic
Colorectal Cancer Achieved?
As noted in this review, a portion of patients with metastatic disease, principally in the liver or lungs,
may achieve long-term survival following resection of their metastatic colorectal cancer. While a
prior intense focus on refining surgical approaches, the use and timing of chemotherapy, and
selection of patients increased the number of patients benefiting from this approach, the field has
made few advances in the last decade. A sizable percentage of patients with limited organ
involvement continue to die of their metastatic disease despite the use of multimodality therapy.
What Is Needed to Move Forward From Here?
It appears that we are reaching the limits of what surgery or ablative techniques may achieve, and
we continue to be limited by the small number of systemic agents available to treat colorectal
cancer. Thus, there is a strong and continued need to rethink our approach to patients in this setting,
utilizing both the tools we have available and the growing body of molecular knowledge to develop
new and innovative approaches. Identifying novel therapies that can control and ultimately eradicate
micrometastatic disease appears to be one of the fundamental missing links in our ability to achieve
meaningful advances. For now, however, it remains critical that patients with limited metastatic
disease undergo multidisciplinary review prior to initiation of therapy. A small but meaningful
number of patients do truly benefit from this approach.
The use of anti–epidermal growth factor receptor antibody therapy has also been explored. Primrose
et al assessed the benefit of adding cetuximab to chemotherapy vs chemotherapy alone for
resectable liver metastases in tumors that were KRAS wild-type at exon 2. The chemotherapy
regimens were FOLFOX, FOLFIRI, and CAPEOX; cetuximab was the antibody used in those arms
where included. Complete or partial tumor responses occurred in 73 of 117 patients (62%) receiving
chemotherapy alone and in 83 of 119 patients (70%) receiving chemotherapy plus cetuximab. The
ORR was 62% for patients receiving chemotherapy alone and 70% for patients receiving
chemotherapy plus cetuximab (P = .59). The rate of R0 resection was 15% in both groups.[31] In a
smaller study, Hatano et al assessed the addition of cetuximab to FOLFOX in 35 patients with
unresectable liver metastases. The ORR was 77.3%, and the R0 resection rate was 50%.[32] Seven
cycles of FOLFIRI combined with cetuximab in 23 patients with unresectable liver metastases
resulted in an ORR of 39.1%. Although the rate of R0 resection was not reported, 7 patients (30.4%)
had curative surgery.[33] Van Cutsem et al reported on the use of preoperative FOLFIRI with or
without cetuximab in patients with unresectable liver metastasis and both KRAS-mutant and
wild-type tumors. The ORRs were 57.3% and 39.7%, favoring the cetuximab arm for KRAS wild-type
tumors. The rates of R0 resection were 7.9% and 4.6%, again favoring the cetuximab arm in KRAS
wild-type tumors.[34,35] Saridaki et al demonstrated the effect of the preoperative combination of
FOLFOXIRI and cetuximab in 30 patients with KRAS wild-type colon cancer and unresectable liver
metastases; 24 patients (80%) had previous adjuvant therapy. The planned duration of preoperative
therapy was 6 months. The ORR was 70%, and 11 patients (37%) achieved R0 resection.[36]
Cetuximab given with either FOLFOX or FOLFIRI has also been evaluated in patients with metastatic
colorectal cancer and unresectable liver metastases. Folprecht et al retrospectively identified 64
patients whose tumors were KRAS and BRAF wild-type and showed an ORR of 72%. The rates of R0
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resection were not reported for KRAS and BRAF wild-type subsets.[37,38] Ye et al assessed the
addition of cetuximab to either FOLFOX or FOLFIRI as a conversion therapy for unresectable liver
metastases in KRAS wild-type colorectal cancers. The ORR was 57.1% vs 29.4%, favoring the
addition of cetuximab (P < .01). The rates of R0 resection were 25.7% vs 7.4%, also favoring the
cetuximab arm (P < .01).[39,40] In a phase II trial, the efficacy of adding cetuximab to FOLFOX was
assessed in patients with unresectable liver metastases and KRAS wild-type tumors.[41] Of the 73
patients enrolled, 46 completed 12 weeks of therapy. The ORR was 73%, and the rate of R0
resection was 27%. The median time to progression for those who had R0 resection was 14.1 months
(95% CI, 1.3–30.8 months).[41] In a retrospective review of 151 patients with unresectable liver
metastases who received cetuximab combined with irinotecan, oxaliplatin, or both, the ORR was
15.2% and the R0 resection rate was 9%.[42]
Adding panitumumab to CAPEOX in 49 patients with unresectable liver metastases produced an ORR
of 65%. Surgery was performed in 21 of the patients (43%), and 14 (67%) had R0 resections.[43]
Discussion
In patients with stage IV colorectal cancer and a limited extent of metastatic disease, an upfront
multidisciplinary discussion to consider the feasibility of resecting all metastases is required. This
process and its timing are critical, since, based on the evidence we have summarized, the sequences
of surgery and medical therapy should be quite different. No therapy or surgery should be
undertaken until both medical and surgical providers have jointly discussed and agreed upon the
plan of care.
The studies of preoperative medical therapy for the management of patients with metastatic disease
that is deemed completely resectable at time of presentation, and thus curable, consistently suggest
that there is no benefit to the use of upfront medical therapy in these patients. This remains so
despite a number of different regimens used, including both chemo- and biologic therapies (again, as
summarized in Table 1). Most of these studies were phase II studies and lacked a comparator arm in
which the patients received upfront surgery. The single phase III study that compared neoadjuvant
chemotherapy with upfront surgery did not demonstrate superiority with neoadjuvant
chemotherapy.[37] Thus, our preferred treatment paradigm for these patients is to proceed directly
to surgery, as would be the case with any lower stage of colon cancer. Medical therapy for the
management of residual microscopic metastatic disease in these patients should be reserved for the
postoperative setting, administered in a conventional adjuvant manner.
Conversely, for those patients who have a metastatic tumor burden deemed unresectable but
potentially convertible to resectable if the burden were adequately reduced, the evidence does
support the use of upfront medical therapy to achieve this conversion (as summarized in Table 2).
Several regimens have been explored for conversion, and none has been shown to be clearly
superior. However, in two phase III studies,[23,44] triplet chemotherapy with FOLFOXIRI achieved a
better ORR, more frequent R0 margins of resection, and more surgical candidates than did treatment
with a doublet of FOLFIRI. Therefore, for those patients whose performance status suggests that they
would tolerate FOLFOXIRI, this is our preferred approach. While no studies have compared
FOLFOXIRI/antibody therapy with FOLFOXIRI alone, Gruenberger, Masi, and their colleagues have
demonstrated that the addition of bevacizumab is a feasible approach with good outcomes, and
Saridaki and colleagues have demonstrated the same with cetuximab.[29,30,36] Barring a
contraindication to the antibody, the addition of either bevacizumab or cetuximab to FOLFOXIRI is
appropriate.
The administration of FOLFOXIRI is not universally feasible, given its highly toxic nature (adverse
effects include marrow suppression, fatigue, and emetogenicity). While not all toxicity can be
anticipated, the oncologist should consider whether the patient is likely to tolerate this regimen well
enough to remain on the recommended dosage schedule. If not, an alternative chemotherapy
doublet should be recommended. Since different studies have suggested better outcomes with
either FOLFOX or FOLFIRI, we have no preference between the two as a standard paradigm and we
select agents based on individual patient preference. This might include, for example, using FOLFOX
in patients who prefer to avoid alopecia or who have baseline diarrheal symptoms, or using FOLFIRI
in patients who have a baseline peripheral neuropathy. Even for those patients who cannot tolerate
FOLFOXIRI, the addition of a biologic agent to the selected chemotherapy doublet is appropriate for
incorporation in the conversion therapy.[26-28,30,32,33,35,37-39,41,43]
As with chemotherapy doublets, no clearly superior outcome has been described for an antibody
class. Therefore, whether chemotherapy consists of FOLFOXIRI, FOLFOX, or FOLFIRI, we select an
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antibody again based on individual patient preference and anticipated tolerance. However, the lower
cost and absence of skin toxicity often tend to favor bevacizumab over cetuximab or panitumumab.
Regardless of the regimen administered with intent of conversion to resectable disease, close
monitoring of tumor response is essential in order to optimize timing of any surgery. As summarized
in Table 2, there was a wide range in total number of cycles of therapy across the various trials. It is
not appropriate to predetermine the number of cycles that should be used preoperatively. Rather,
close monitoring of disease response should be undertaken, with repeat radiographic assessment
and multidisciplinary consideration every 2 to 3 months. When it is agreed that maximal response
has been achieved, based on this close interval monitoring, the multidisciplinary team should then
consider whether surgery is feasible. Should the tumor response be inadequate for surgical attempt,
there are no data to suggest that an alternative, second chemotherapeutic regimen is likely to
achieve this outcome. If surgical resection is achieved, there is no strong evidence for an alternative
adjuvant strategy beyond standard FOLFOX. Our usual approach is to recommend the standard 12
cycles of adjuvant FOLFOX therapy, with any chemotherapy that was administered neoadjuvantly
omitted. While clinicians may elect to pursue another strategy (eg, use of other agents based on
neoadjuvant tumor response, extended maintenance therapy with fluoropyrimidine monotherapy), it
is imperative that the patient understand that there is not a strong level of evidence for such
approaches and that the oncologist present the risks and benefits to the patient with an emphasis on
the large extent of the unknown.
Future studies could conceivably establish a single best medical approach for the conversion of
metastatic colorectal cancer to a resectable degree of disease, and moreover, that such an approach
could offer benefit to patients in the neoadjuvant setting. However, given our increasing
understanding of the diversity of colorectal cancer from patient to patient, it is much more likely that
a variety of approaches will continue to be validated, with therapeutic recommendations relying on
individual tumor characteristics and individual patient preferences and comorbid conditions. This
variety again highlights how critical it is for a multidisciplinary team to synthesize treatment
recommendations before commencing therapy or proceeding to surgery.
Financial Disclosure: Dr. Smaglo has financial arrangements with Taiho. Dr. Marshall has financial
arrangements with Amgen, Bayer, Celgene, and Genentech. Dr. Al-Hajeili has no relevant
disclosures.
Oncology (Williston Park). 30(1):10-16, 28.
Table 1. Upfront Systemic Therapy for the
Management of Metastatic Col...
Table 2. Systemic Conversion Therapy for the
Management of Metastatic ...
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Links:
[1] http://www.cancernetwork.com/review-article
[2] http://www.cancernetwork.com/oncology-journal
[3] http://www.cancernetwork.com/colorectal-cancer
[4] http://www.cancernetwork.com/gastrointestinal-cancer
[5] http://www.cancernetwork.com/authors/marwan-al-hajeili-md
[6] http://www.cancernetwork.com/authors/john-l-marshall-md
[7] http://www.cancernetwork.com/authors/brandon-g-smaglo-md
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