Download Slow and steady: incremental survival improvements in advanced

REVIEW
Slow and steady: incremental survival
improvements in advanced colorectal cancer
by Michael Vickers, MD, FRCPC
C
olorectal cancer represents a significant
problem in Canada, with an expected
Figure 1. Therapeutic progress in ACRC and improvements in overall survival over time.
23,300 new diagnoses in 2012.1 Advances
in surgical techniques and adjuvant chemotherapy
have improved cure rates in early-stage disease,
but approximately 40% of all patients will be
diagnosed with or develop advanced colorectal
cancer (ACRC) at some point in their disease
trajectory. The past two decades of research
have produced one of the most diverse systemic
armamentariums of any tumour site, including
cytotoxic chemotherapies, monoclonal antibodies against angiogenic targets, monoclonal
antibodies against the epidermal growth factor
receptor (EGFR) and most recently, tyrosine
kinase inhibitors (TKI). With these advances
(and with the increased use of surgical metastectomy), the median survival of patients with
ACRC has doubled (Figure 1) and 5-year survivals have increased to 10%.2 As will be highlighted below, these survival improvements have
come in small, yet steady increments and have
transformed our attitude toward the treatment
of ACRC from nihilistic resignation to genuine optimism.
of overall survival (OS) remained relatively stagnant.6-8
The late ’90s brought the first meaningful improvements
Cytotoxic Therapy
in the management of ACRC, with the publication of two
Introduced into clinical practice in the 1950s, 5-fluorouracil
second-line trials of the topoisomerase I inhibitor, irinotecan.
(5FU) remained the only treatment option for patients with
Rougier et al.9 compared irinotecan to continuous infusion
ACRC for over 40 years. 5FU is a fluoropyrimidine, which
5FU in 5FU refractory patients and demonstrated a 2.3
exerts anticancer effects through inhibition of thymidylate
month improvement in survival (10.8 v 8.5 months; p=0.035)
synthase and subsequent impaired DNA synthesis.3 Since no
in favour of irinotecan. Similarly, Cunningham et al10 compared
randomized study of 5FU compared with supportive care
second-line supportive care plus irinotecan with supportive
has ever been completed, information regarding the absolute care alone. A 2.7-month median survival improvement was
benefit of 5FU in ACRC is lacking. Our best approximation
shown (9.2 vs 6.5 months; p<0.0001), again in favour of
comes from a small study of 40 patients who were randomized irinotecan. In the treatment-naive setting, a North Amerito cisplatin plus 5FU/leucovorin (LV) versus best supportive
can trial investigated the combination of irinotecan plus bolus
care (BSC). The median survival in this study was 11 months 5FU/LV (IFL) as compared with bolus 5FU/LV and showed
compared with 5 months (p=0.006), in favour of chemother- an improvement in OS by 2.2 months (14.8 vs 12.6 months;
apy,4 while others have suggested that the absolute survival
p=0.04).11 At the same time, a European study of irinotecan
benefit of 5FU chemotherapy is on the order of 2–3 months.5
plus infusional 5FU/LV (de Gramont or AIO regimen)
Although improvements in response rates (RR) and progres- compared with infusional 5FU/LV also reported a 3.3-month
sion-free survival (PFS) were achieved through modifications OS advantage for the combination arm (17.4 vs 14.1 months;
in 5FU administration and combinations with LV, estimates
p = 0.031).12 In an attempt to define the optimal first-line
irinotecan regimen, the BICC-C trial compared 5FU infusion
plus irinotecan (FOLFIRI) to IFL and capecitabine plus iri-
Michael Vickers, MD, FRCPC is a Clinical Assistant Professor in
the Department of Oncology at the University of Calgary, and a medical
oncologist at the Tom Baker Cancer Centre, Calgary.
notecan (CapeIri).13 5FU infusion plus irinotecan (FOLFIRI)
was associated with improved progression-free survival (PFS)
as compared with IFL (7.6 vs 5.9 months; p=0.004) and
Sponsorship of distribution of this review article is funded by Bayer HealthCare Pharmaceuticals Inc.
30
oe
VOL. 12, No. 1, February 2013
REVIEW
trended toward improved OS (23.1 vs 17.6 months; p=0.09). In
addition, FOLFIRI was associated with the most favourable
toxicity profile of the three regimens, thereby establishing it as a
reference standard for treatment-naive patients with ACRC.
During this period of advancement, another active agent
was undergoing investigation. Oxaliplatin is a platinum-based
cytotoxic agent which causes cross-linked DNA adducts and
inhibition of DNA replication.14 In an initial Phase III study,
oxaliplatin plus infusional 5FU (FOLFOX) was compared
to infusional 5FU in the first-line setting. FOLFOX was
associated with a longer PFS (9 vs 6.2 months; p=0.0003),
however no improvement in OS was demonstrated (16.2 vs
14.7 months, p=0.12).15 A subsequent U.S. Intergroup study
(N9741) randomized patients to FOLFOX, IFL or irinotecan
plus oxaliplatin (IROX) and confirmed the superiority of
FOLFOX for RR, PFS and OS.16 The 4.5-month survival
advantage over IFL (19.5 v 15 months, HR 0.66; p=0.0001)
resulted in FOLFOX being considered a standard option
for treatment-naIve ACRC patients. Further attempts to
define the optimal first-line cytotoxic regimen have shown
similar RR and OS for FOLFIRI and FOLFOX.17,18
Also during this time of irinotecan and oxaliplatin investigation, the oral fluoropyrimidine, capecitabine, was added
to the expanding arsenal of cytotoxic chemotherapies for
ACRC.19,20 Although capecitabine did not show a survival
advantage over bolus 5FU, its convenient oral administration
was a first in the management of ACRC.
Targeted Agents
Bevacizumab
Bevacizumab is a humanized monoclonal antibody against the
vascular endothelial growth factor (VEGF) and is thought to
exert its anticancer effect through inhibition of blood vessel
formation, normalization of vasculature and a reduction in
intratumoural hydrostatic pressure.21 In 2004, Hurwitz et al
reported the first-Phase III trial of bevacizumab, which randomized patients to IFL plus bevacizumab or placebo.22 The
addition of bevacizumab was associated with improved RR,
PFS and a 4.7-month survival advantage (20.3 vs 15.6 months,
HR 0.66; p<0.001). A similar effect was seen in a combined
analysis of 3 randomized studies (2 Phase II studies and a
discontinued third arm of the above-Phase III study) involving
infusional 5FU plus bevacizumab in which a 3.3-month survival advantage was seen with bevacizumab.23 As IFL was
shown to be inferior to FOLFOX,16 a confirmatory study of
first-line bevacizumab combined with oxaliplatin-based chemotherapy was initiated (N016966). In this study, 1401 patients
were randomized to FOLFOX/XELOX with or without
bevacizumab. Although this study did meet its primary endpoint of improved PFS, the non-significant 1.4-month OS benefit
was less than desired (21.3 months vs 19.9 months, HR 0.89,
p=0.077).24 In the second-line setting, FOLFOX plus bevacizumab was associated with a 2-month survival advantage over
FOLFOX alone (12.9 vs 10.9 months, HR 0.75; p=0.0011)
in patients who had progressed on irinotecan-based first-line
therapy.25 Further, a systematic review by Welch et al suggested a significant improvement in OS with the addition
of bevacizumab to fluoropyrimidine-based chemotherapy in
the first- or second-line settings (HR 0.79; p=0.0005).26
Epidermal Growth Factor
Receptor Inhibitors
EGFR is a tyrosine kinase transmembrane receptor that is
stimulated by ligands such as amphiregulin, epiregulin and
transforming growth factor α, which leads to signaling of the
Ras-Raf-MAP, PI3K and Akt pathways.27 These pathways
are important for the regulation of cell proliferation and inhibition of apoptosis, and can be activated in colorectal cancers
(CRC).28 The EGFR inhibitors (EGFRIs) act by preventing
ligand binding and subsequent downstream signaling of
oncogenic pathways. These antibodies represent a major
advance in the treatment of ACRC due to their tolerability
and the associated identification of a predictive biomarker. In
an initial Phase II study of the chimeric monoclonal antibody
cetuximab, monotherapy was compared with cetuximab plus
irinotecan in irinotecan-refractory ACRC. RR and time to
progression were improved with the combination, but OS
was not statistically different.29 The first reported Phase III
study of EGFRI compared panitumumab (fully humanized
monoclonal antibody) plus best supportive care (BSC) to
BSC alone in patients whose disease progressed despite 5FU,
irinotecan and oxaliplatin. Median PFS was minimally improved
(8 vs 7.3 weeks, HR 0.54; p<0.0001) while there was no
difference in OS.30 It is important to note that crossover was
integrated in this study, and 76% of patients in the BSC arm
received panitumumab. Emerging data suggested that mutations in KRAS (Kirsten rat sarcoma-2 virus oncogene) could
result in a constitutively active protein and predict non-response
to EGFRIs. Analysis of available specimens revealed that
approximately 40% of patients had a mutation of KRAS that
predicted lack of response to panitumumab, while those with
wild-type KRAS (WT KRAS) had significantly longer PFS
(12.3 vs 7.3 weeks) with panitumumab.31 At the same time, a
Phase III trial (NCIC CO.17) randomized patients who had
previously received (or had contraindication to) 5FU, irinotecan and oxaliplatin to cetuximab plus BSC or BSC alone. Initial
results showed improvements in RR, PFS and a 1.5-month
(6.1 vs 4.6 month, HR 0.77, P=0.005) survival advantage vs
cetuximab.32 Shortly thereafter, the predictive significance
of the KRAS gene was examined, and those patients with
WT KRAS tumours experienced a 4.7-month OS improvement
(9.5 vs 4.8 months, HR 0.55, p<0.001), while those with
mutations of KRAS derived no benefit from the antibody.33
EGFRIs have been examined in earlier settings of ACRC
with contradictory results. The original publication of the
CRYSTAL study showed that the addition of cetuximab to
FOLFIRI resulted in improved PFS, while an updated analysis
revealed a 3.5-month survival advantage over FOLFIRI (23.5 v
20 months, HR 0.796, p=0.0093) for WT KRAS patients.
A trend toward improved OS (23.9 vs 19.7, p=0.07) was also
suggested for WT KRAS patients in the PRIME study of
FOLFOX with or without panitumumab.36 Conversely, the
MRC COIN trial did not show any benefit from adding
cetuxi­mab to FOLFOX even in the WT KRAS population,
oe
VOL. 12, No. 1, february 2013
31
REVIEW
Table 1. Trials reporting significant improvements in overall survival
by line of therapy.
Study
1st line
(months)
Scheithauer et al 4
11 vs 5
2nd line
(months)
Rougier et al9
10.8 vs 8.5
Cunningham et al 10
9.6 vs 6.5
Saltz et al 11
14.8 vs 12.6
Doulliard et al 12
17.4 vs 14.1
Goldberg et al 16
19.5 vs 15
Hurwitz et al 22
20.3 vs 15.6
Giantonio et al
Karapetis et al
12.9 vs 10.9
25
9.5 vs 4.8*
33
Van Cutsem et al
Bennouna et al
35
23.5 vs 20*
11.2 vs 9.8
43
Van Cutsem et al
3rd line
(months)
13.5 vs 12.06
46
6.4 vs 5.0†
Grothey et al 48
* WT KRAS; †3rd/4th line
nor from the addition of cetuximab to bolus 5FU plus
oxaliplatin (FLOX) in the first-line setting.37,38 In the secondline setting, neither cetuximab nor panitumumab resulted
in significant improvements in OS when combined with irinotecan-based chemotherapy.39,40
Recent advances
Bevacizumab beyond progression
Based on preclinical and observational data, it has been hypo­
thesized that improvements in disease may be achieved with
ongoing VEGF inhibition with bevacizumab after disease progression.41,42 To test this hypothesis, a European study (ML18147)
randomized patients who had previously progressed on firstline bevacizumab (with irinotecan or oxaliplatin-based chemotherapy) to bevacizumab plus chemotherapy or chemotherapy
alone.43 Disease control rates (68% vs 54%) and PFS (5.7 vs
4.1 months) were superior, while the median OS was improved
by 1.4 months (11.2 vs 9.8 months, HR 0.81; p=0.0062)
in favour of continuation of bevacizumab. No new safety
concerns were identified with continuation of bevacizumab
and an exploratory analysis revealed that the treatment effect
was not dependent on KRAS mutation status. In this selected
population, the median OS from the start of first-line therapy
was 23.9 months with bevacizumab and 22.5 months (p=0.17)
with chemotherapy alone. Similarly, a smaller Phase III Italian
study has recently reported improved PFS with continuation
of bevacizumab beyond progression.44
Aflibercept
Aflibercept is a recombinant fusion protein of the extracellular
domains of VEGF receptor 1(VEGFR1) and VEGFR2 fused
with the constant region of human immunoglobulin G1.45
32
oe
VOL. 12, No. 1, February 2013
This protein binds VEGFA, VEGFB and placental growth
factor, which are thought to be important regulators of angiogenesis and progression. Since preliminary studies suggested
tolerability and disease stabilization in ACRC, a large Phase
III trial (VELOUR) was undertaken to explore the effect of
aflibercept (or placebo) added to FOLFIRI in the second-line
setting after progression on oxaliplatin-based chemotherapy.46
In addition to improved RR and PFS, aflibercept was associated with an improvement in median survival by 1.44 months
(13.5 vs 12.06 months, HR 0.817, p=0.0032). In a prespecified
analysis, benefits were also seen in those patients who had
received prior bevacizumab. Adverse events (Grade 3/4) were
more common in the aflibercept arm (83.5% vs 62.5%) and
included those typical of anti-VEGF therapy (hypertension,
hemorrhage, arterial/venous thromboembolic events and proteinuria), as well as increased chemotherapy-associated toxicities (diarrhea, asthenia, stomatitis, infections, palmar-plantar
erythrodysesthesia, neutropenia and thrombocytopenia).
Regorafenib
Regorafenib is an oral multikinase inhibitor of several protein
kinases, including VEGFR1-3, TIE2, KIT, RET, RAF1, BRAF,
PDGFR and FGFR which are involved in angiogenesis,
oncogenesis and the microenvironment.47 Due to promising
disease control rates in a Phase Ib study in ACRC, a Phase
III trial (CORRECT) randomized patients (ECOG 0-1)
whose disease had progressed (or had toxicity) on fluoropyrimidine, oxaliplatin, irinotecan, bevacizumab, cetuximab or
panitumumab (WT KRAS), to regorafenib or placebo.48 The
primary endpoint was OS and patients were randomized 2:1
to regorafenib 160 mg daily or matched placebo for 3 weeks
of a 4-week cycle. Disease control rates (41% vs 15%) and
PFS were significantly better for the experimental arm, and
a median survival benefit of 1.4 months was observed in
favour of regorafenib (6.4 vs 5.0 months, HR 0.77, p=0.0052).
Grade 3 or 4 adverse events were more common with regorafenib (54% vs 14%) with the most common being hand-foot
skin reaction, fatigue, diarrhea, hypertension, and rash/
desquamation. There was no difference in deterioration of
quality of life and health status from baseline to end of treatment in both arms of the study. This study also gives us
some modern-day survival information in patients who are
well enough to receive third/fourth line therapy, as the
median time from diagnosis of metastases to randomization
in this trial was 31 and 29.9 months for regorafenib and
placebo patients, respectively.
Conclusion
Over the past 15 years, significant advancements in the management of ACRC have occurred and resulted in a doubling
of median survivals. These gains can be attributed to advances
in surgical oncology, as well as the plethora of cytotoxic and
targeted agents now available for ACRC. As history has shown
us, systemic therapy achievements have come in small incremental gains ranging from 1.4 to 4.7 months (Table 1), and
importantly, they have not been at the cost of quality of life.
The pharmacoeconomics of ACRC therapies have always
REVIEW
been a matter of debate; hopefully future molecular studies
will identify predictive biomarkers and subgroups of patients
most likely to benefit.
Population-level studies will be important in determining
whether or not the most recent benefits seen in clinical trials
are additive and translate into meaningful survival improvements
for ACRC as a whole. With the recent genomic profiling of
colorectal cancers by the Cancer Genome Atlas project 49 and
ongoing efforts to molecularly subtype colorectal cancers, we
have good grounds to be optimistic about further progress.
References
1. Canadian Cancer Society’s Steering Committee on Cancer Statistics. Canadian Cancer
Statistics 2012. Toronto, ON: Canadian Cancer Society; 2012.
2. Sanoff HK, Sargent DJ, Campbell ME, et al: Five-year data and prognostic factor analysis
of oxaliplatin and irinotecan combinations for advanced colorectal cancer: N9741.
J Clin Oncol 26:5721-7, 2008.
3. Pinedo HM, Peters GF: Fluorouracil: biochemistry and pharmacology. J Clin Oncol
6:1653-64, 1988.
4. Scheithauer W, Rosen H, Kornek GV, et al: Randomised comparison of combination
chemotherapy plus supportive care with supportive care alone in patients with
metastatic colorectal cancer. BMJ 306:752-5, 1993.
5. Nordic Gastrointestinal Tumor Adjuvant Therapy G: Expectancy or primary chemotherapy
in patients with advanced asymptomatic colorectal cancer: a randomized trial.
J Clin Oncol 10:904-11, 1992.
6. de Gramont A, Bosset JF, Milan C, et al: Randomized trial comparing monthly low-dose
leucovorin and fluorouracil bolus with bimonthly high-dose leucovorin and fluorouracil
bolus plus continuous infusion for advanced colorectal cancer: a French intergroup
study. J Clin Oncol 15:808-15, 1997.
7. Efficacy of intravenous continuous infusion of fluorouracil compared with bolus
administration in advanced colorectal cancer. Meta-analysis Group In Cancer.
J Clin Oncol 16:301-8, 1998.
8. Thirion P, Michiels S, Pignon JP, et al: Modulation of fluorouracil by leucovorin in
patients with advanced colorectal cancer: an updated meta-analysis. J Clin Oncol
22:3766-75, 2004.
9. Rougier P, Van Cutsem E, Bajetta E, et al: Randomised trial of irinotecan versus
fluorouracil by continuous infusion after fluorouracil failure in patients with metastatic
colorectal cancer. Lancet 352:1407-12, 1998.
10. Cunningham D, Pyrhonen S, James RD, et al: Randomised trial of irinotecan plus
supportive care versus supportive care alone after fluorouracil failure for patients
with metastatic colorectal cancer. Lancet 352:1413-8, 1998.
11. Saltz LB, Cox JV, Blanke C, et al: Irinotecan plus fluorouracil and leucovorin for meta­
static colorectal cancer. Irinotecan Study Group. N Engl J Med 343:905-14, 2000.
12. Douillard JY, Cunningham D, Roth AD, et al: Irinotecan combined with fluorouracil
compared with fluorouracil alone as first-line treatment for metastatic colorectal
cancer: a multicentre randomised trial. Lancet 355:1041-7, 2000.
13. Fuchs CS, Marshall J, Mitchell E, et al: Randomized, controlled trial of irinotecan
plus infusional, bolus, or oral fluoropyrimidines in first-line treatment of metastatic
colorectal cancer: results from the BICC-C Study. J Clin Oncol 25:4779-86, 2007.
14. Raymond E, Faivre S, Woynarowski JM, et al: Oxaliplatin: mechanism of action and
antineoplastic activity. Semin Oncol 25:4-12, 1998.
15. de Gramont A, Figer A, Seymour M, et al: Leucovorin and fluorouracil with or without
oxaliplatin as first-line treatment in advanced colorectal cancer. J Clin Oncol
18:2938-47, 2000.
16. Goldberg RM, Sargent DJ, Morton RF, et al: A randomized controlled trial of fluorouracil
plus leucovorin, irinotecan, and oxaliplatin combinations in patients with previously
untreated metastatic colorectal cancer. J Clin Oncol 22:23-30, 2004.
17. Tournigand C, Andre T, Achille E, et al: FOLFIRI followed by FOLFOX6 or the reverse
sequence in advanced colorectal cancer: a randomized GERCOR study. J Clin Oncol
22:229-37, 2004.
18. Colucci G, Gebbia V, Paoletti G, et al: Phase III randomized trial of FOLFIRI versus
FOLFOX4 in the treatment of advanced colorectal cancer: a multicenter study of the
Gruppo Oncologico Dell’Italia Meridionale. J Clin Oncol 23:4866-75, 2005.
19. Hoff PM, Ansari R, Batist G, et al: Comparison of oral capecitabine versus intravenous
fluorouracil plus leucovorin as first-line treatment in 605 patients with metastatic
colorectal cancer: results of a randomized phase III study. J Clin Oncol 19:2282-92, 2001.
20.Van Cutsem E, Twelves C, Cassidy J, et al: Oral capecitabine compared with intra­
venous fluorouracil plus leucovorin in patients with metastatic colorectal cancer:
results of a large phase III study. J Clin Oncol 19:4097-106, 2001.
21. Kramer I, Lipp HP: Bevacizumab, a humanized anti-angiogenic monoclonal antibody
for the treatment of colorectal cancer. J Clin Pharm Ther 32:1-14, 2007.
22.Hurwitz H, Fehrenbacher L, Novotny W, et al: Bevacizumab plus irinotecan, fluorouracil,
and leucovorin for metastatic colorectal cancer. N Engl J Med 350:2335-42, 2004.
23.Kabbinavar FF, Hambleton J, Mass RD, et al: Combined analysis of efficacy: the
addition of bevacizumab to fluorouracil/leucovorin improves survival for patients
with metastatic colorectal cancer. J Clin Oncol 23:3706-12, 2005.
24. Saltz LB, Clarke S, Diaz-Rubio E, et al: Bevacizumab in combination with oxaliplatinbased chemotherapy as first-line therapy in metastatic colorectal cancer: a randomized
phase III study. J Clin Oncol 26:2013-9, 2008.
25.Giantonio BJ, Catalano PJ, Meropol NJ, et al: Bevacizumab in combination with
oxaliplatin, fluorouracil, and leucovorin (FOLFOX4) for previously treated metastatic
colorectal cancer: results from the Eastern Cooperative Oncology Group Study E3200.
J Clin Oncol 25:1539-44, 2007.
26.Welch S, Spithoff K, Rumble RB, et al: Bevacizumab combined with chemotherapy
for patients with advanced colorectal cancer: a systematic review. Ann Oncol
21:1152-62, 2010.
27. Garrett CR, Eng C: Cetuximab in the treatment of patients with colorectal cancer.
Expert Opin Biol Ther 2011.
28.Lockhart AC, Berlin JD: The epidermal growth factor receptor as a target for colorectal
cancer therapy. Semin Oncol 32:52-60, 2005.
29.Cunningham D, Humblet Y, Siena S, et al: Cetuximab monotherapy and cetuximab
plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med
351:337-45, 2004.
30.Van Cutsem E, Peeters M, Siena S, et al: Open-label phase III trial of panitumumab
plus best supportive care compared with best supportive care alone in patients with
chemotherapy-refractory metastatic colorectal cancer. J Clin Oncol 25:1658-64, 2007.
31. Amado RG, Wolf M, Peeters M, et al: Wild-type KRAS is required for panitumumab
efficacy in patients with metastatic colorectal cancer. J Clin Oncol 26:1626-34, 2008.
32.Jonker DJ, O’Callaghan CJ, Karapetis CS, et al: Cetuximab for the treatment of
colorectal cancer. N Engl J Med 357:2040-8, 2007.
33.Karapetis CS, Khambata-Ford S, Jonker DJ, et al: K-ras mutations and benefit from
cetuximab in advanced colorectal cancer. N Engl J Med 359:1757-65, 2008.
34.Van Cutsem E, Kohne CH, Hitre E, et al: Cetuximab and chemotherapy as initial
treatment for metastatic colorectal cancer. N Engl J Med 360:1408-17, 2009.
35.Van Cutsem E, Kohne CH, Lang I, et al: Cetuximab plus irinotecan, fluorouracil,
and leucovorin as first-line treatment for metastatic colorectal cancer: updated
analysis of overall survival according to tumor KRAS and BRAF mutation status.
J Clin Oncol 29:2011-9, 2011.
36.Douillard JY, Siena S, Cassidy J, et al: Randomized, phase III trial of panitumumab
with infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX4) versus FOLFOX4
alone as first-line treatment in patients with previously untreated metastatic
colorectal cancer: the PRIME study. J Clin Oncol 28:4697-705, 2010.
37. Maughan TS, Adams RA, Smith CG, et al: Addition of cetuximab to oxaliplatin-based
first-line combination chemotherapy for treatment of advanced colorectal cancer:
results of the randomised phase 3 MRC COIN trial. Lancet 377:2103-14, 2011.
38.Tveit KM, Guren T, Glimelius B, et al: Phase III trial of cetuximab with continuous or
intermittent fluorouracil, leucovorin, and oxaliplatin (Nordic FLOX) versus FLOX
alone in first-line treatment of metastatic colorectal cancer: the NORDIC-VII study.
J Clin Oncol 30:1755-62, 2012.
39.Sobrero AF, Maurel J, Fehrenbacher L, et al: EPIC: phase III trial of cetuximab plus
irinotecan after fluoropyrimidine and oxaliplatin failure in patients with metastatic
colorectal cancer. J Clin Oncol 26:2311-9, 2008.
40.Peeters M, Price TJ, Cervantes A, et al: Randomized phase III study of panitumumab
with fluorouracil, leucovorin, and irinotecan (FOLFIRI) compared with FOLFIRI alone
as second-line treatment in patients with metastatic colorectal cancer. J Clin Oncol
28:4706-13, 2010.
41. Giantonio BJ: Targeted therapies: Goldie-Coldman and bevacizumab beyond disease
progression. Nat Rev Clin Oncol 6:311-2, 2009.
42. Grothey A, Sugrue MM, Purdie DM, et al: Bevacizumab beyond first progression is
associated with prolonged overall survival in metastatic colorectal cancer: results
from a large observational cohort study (BRiTE). J Clin Oncol 26:5326-34, 2008.
43.Bennouna J, Sastre J, Arnold D, et al: Continuation of bevacizumab after first
progression in metastatic colorectal cancer (ML18147): a randomised phase 3 trial.
Lancet Oncol 14:29-37, 2013.
44.Masi G, Loupakis F, Allegrini G, et al: A randomized phase III study evaluating the
continuation of bevacizumab (BV) beyond progression in metastatic colorectal
cancer (mCRC) patients (pts) who received BV as part of first-line treatment: results
of the BEBYP trial by the Gruppo Oncologico Nord Ovest (GONO). Ann Oncol 2012;
23 (suppl 9): LBA 17.
45.Tang PA, Cohen SJ, Kollmannsberger C, et al: Phase II clinical and pharmacokinetic
study of aflibercept in patients with previously treated metastatic colorectal cancer.
Clin Cancer Res 18:6023-31, 2012.
46.Van Cutsem E, Tabernero J, Lakomy R, et al: Addition of aflibercept to fluorouracil,
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 30:3499-506, 2012.
47. Wilhelm SM, Dumas J, Adnane L, et al: Regorafenib (BAY 73-4506): a new oral
multikinase inhibitor of angiogenic, stromal and oncogenic receptor tyrosine kinases
with potent preclinical antitumor activity. Int J Cancer 129:245-55, 2011.
48.Grothey A, Cutsem EV, Sobrero A, et al: Regorafenib monotherapy for previously
treated metastatic colorectal cancer (CORRECT): an international, multicentre,
randomised, placebo-controlled, phase 3 trial. Lancet 2012.
49.Cancer Genome Atlas N: Comprehensive molecular characterization of human colon
and rectal cancer. Nature 487:330-7, 2012.
oe
VOL. 12, No. 1, february 2013
33