Epidemiology, disease Progression, and Economic Burden of Colorectal Cancer
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Epidemiology, disease Progression,
and Economic Burden of Colorectal Cancer
al B. Benson III, MD, FacP
O
aBStract ncology as a specialty has welcomed numerous suc-
BaCkgrOund: Every 3.5 minutes, someone is diagnosed with colorectal
cesses since 2000, especially in colorectal cancer (CRC).
cancer (CrC); every 9 minutes, someone dies from CrC; and every These CRC advances, however, have not been without
5 seconds, someone who should be screened for CrC is not. The 5-year certain challenges for clinicians. Despite numerous advances,
mortality for people diagnosed with CrC is approximately 40%; however, clinical researchers are still learning a great deal from ongoing
survival improves substantially if the cancer is diagnosed while still clinical trials. Additionally, multiple facets of care intersect in
localized.
the treatment of patients with CRC: medical management, phar-
OBjECTIvE: To track and review the rapid progress researchers have made macy management, symptom management, case management,
in CrC.
and patient advocacy. Any apt and timely discussion of these
SuMMary: among patients who have CrC, approximately 50% will
advances will not only highlight the implications of the multi-
eventually develop liver metastases. The oncology field’s significant
advances in the last few years, especially in CrC, challenge clinicians faceted nature of the disease but also underscore recent scrutiny
and patients. Multiple facets of care intersect in CrC: medical manage- from employer groups, insurance companies, and government
ment, pharmacy management, symptom management, case management, agencies about the appropriate use of new advances that those
and patient advocacy. CrC develops over many years as environmental treating cancer and CRC are now facing. With articles such as a
and genetic factors interact. The american Cancer Society recommends
New York Times article, “Hope, at $4,200 a Dose”1 now reaching
screening all men and women older than 50 years and those at high risk
at an earlier age. In the past, patients presenting with the same stage of lay publications, we must expect to accommodate a much more
CrC were considered similar. The staging criteria of the american joint proactive, discerning public and patient.
Committee on Cancer recognizes that subsets of patients with varying
survival statistics can be identified and that each patient requires a ■■ Colorectal Cancer Epidemiology
strategic approach. The u.S. Food and drug administration approval of
Every 7 seconds, someone turns 50 years old; every 3.5 minutes,
irinotecan in 1996 and oxaliplatin in 2002 changed the landscape, and
ultimately, the oral agent capecitabine and the biologics bevacizumab someone is diagnosed with CRC; every 9 minutes, someone dies
and cetuximab also significantly expanded treatment options. from CRC; and every 5 seconds, someone who should be screened
COnCLuSIOn: Clinicians must consider all available treatment options and for CRC is not. The 5-year mortality for people diagnosed with
regimen sequences across multiple lines of therapy, creating an early plan CRC is approximately 40%; however, survival improves sub-
for each patient to extend survival while minimizing side effects. stantially if the cancer is diagnosed while it is still localized. In
kEywOrdS: Bevacizumab, Capecitabine, Cetuximab, Colorectal cancer, a typical general practice with 500 patients older than 50 years,
FOLFOX, Irinotecan, Oxaliplatin, Panitumumab one would expect 100 to 250 of these patients to have colorectal
J Manag Care Pharm. 2007;13(6)(suppl S-c):S5-S18 adenomas. Ten to thirty of these patients would be expected to
Copyright© 2007, Academy of Managed Care Pharmacy. All rights reserved. have CRC, and because only one third are apt to be screened,
two thirds of these patients may die unnecessarily. Unfortunately,
20% of CRC patients who do receive screening may be diagnosed
in the later, less-treatable stages.2
The good news is that CRC’s incidence rate declined by
2.9% annually from 1998 to 2001. Regardless, colorectal cancer
remains the third most common cancer in men and women in
the United States.3 The decline in incidence may have been due,
in part, to increased screening and polyp removal. The National
Author Cancer Institute’s Surveillance, Epidemiology and End Results
AL B. BENSoN III, MD, FACP, is a professor of medicine, Division (SEER) Program monitors the incidence of all cancers throughout
of Hematology/oncology, Feinberg School of Medicine, Northwestern the United States. For both men and women, the incidence of
university, Chicago, Illinois. CRC begins to rise around the age of 40 years. Incidence sharply
increases at age 50 years; 92% of CRCs are diagnosed in persons
AuTHoR CoRRESPoNDENCE: Al B. Benson III, MD, FACP, aged 50 years or older. People in their 80s clearly continue to be
Professor of Medicine, Northwestern Medical Faculty Foundation, at risk for CRC, with 12.5% of cases diagnosed after age 85.2,3
Division of Hematology/oncology, 676 N. St. Clair St., Suite 850,
Because age is a significant risk factor and the American popula-
Chicago, IL 60611. Tel: (312) 695-6180; Fax: (312) 695-6189;
E-mail:a-benson@northwestern.edu
tion is aging, the population of individuals at risk for CRC is larger
than it has ever been.
www.amcp.org Vol. 13, No. 6, S-c August 2007 JMCP Supplement to Journal of Managed Care Pharmacy S5Epidemiology, Disease Progression, and Economic Burden of Colorectal Cancer
taBlE 1
Japan’s experience supports what we know: diet is a leading risk
Risk Factors for Colorectal Cancer (CRC) factor for CRC.
CRC is considered a completely preventable disease by most
experts, and the fact that many of its risk factors are related to
lifestyle reflect that belief. High-fat diets with few fruits and
vegetables, inactivity, obesity, smoking, and alcohol use increase
risk. Interest in chemoprevention is high, and trials suggest that
nonsteroidal anti-inflammatory drugs (NSAIDs, such as ibupro-
fen) and cyclooxygenase-2 (COX-2) inhibitors (such as rofecoxib
or celecoxib) may reduce the risk of CRC. The CRC-related mor-
tality has been reduced 40% to 50% in individuals who regularly
take aspirin and other NSAIDs. Additionally, COX-2 is elevated
in 85% to 95% of CRCs; overexpression has been shown to
decrease cancer cell death.10,11 One study of a COX-2 inhibitor
(celecoxib) showed a significant reduction in polyps.12-14
Approximately 70% of CRCs are nonhereditary, or sporadic,
COX-2=cyclooxygenase isoenzyme 2; NSAIDS =nonsteroidal anti-inflammatory and about 20% are familial. Two key hereditary syndromes are
drugs. familial adenomatous polyposis (FAP) and hereditary nonpolyp-
osis colon cancer (HNPCC). The FAP syndrome develops from
inherited mutations of the adenomatous polyposis coli (APC)
CRC is very common worldwide, with 850,000 people gene, and accounts for approximately 1% to 2% of all CRC cases.
developing it annually and 500,000 dying of the disease.4 Patients with FAP develop hundreds to thousands of polyps
Its prevalence and preventable nature makes CRC a primary before age 30, and inevitably develop CRC. Usually, CRC devel-
focus in the oncology community. In fact, estimates indicate that ops at an early age (average, 39 years) in FAP patients, but it can
gastrointestinal cancers represent about 20% of all cancers. The be prevented by surgically removing the colon.15
broad diversity in the types of patients and stages at which Lynch syndrome, or HNPCC, is caused by inherited muta-
the disease is diagnosed creates multidisciplinary challenges. tion in any 1 of 5 mismatch repair (MMR) genes, and accounts
Among patients who have CRC, a majority will eventually for 3% to 5% of all CRC cases. The term nonpolyposis does not
develop liver metastases. In 30% to 40% of CRC patients, metas- mean that the cancer does not emanate from polyps; it is used
tases are confined to the liver when they are initially found. One to distinguish HNPCC from FAP. Polyps do not develop earlier
quarter to one third of patients who are able to undergo resection in people with HNPCC, but once they do, their tendency to
of liver metastases will live 5 years or longer; median survival become malignant more rapidly leads to a 70% to 80% lifetime
after resection is between 24 and 40 months. This high rate of risk of CRC. In these patients, CRC occurs at early age (average
liver metastases has transformed treatment and evaluation in an 44 years). Some patients with HNPCC also elect to have a
effort to improve cure rates.5 More recent data indicate that sur- complete colectomy because of their increased risk of rapid
vival rates may be increasing.6-8 development of colon cancer. Experts stress the need for detailed
The risk factors for CRC for people who live in the United family history to identify individuals who are at risk to provide
States are presented in Table 1. CRC does not discriminate appropriate screening, genetic counseling, and treatment. It has
by gender or ethnicity in terms of incidence or mortality. been recommended that people who have a first-degree relative
Socioeconomic groups in the lower income ranges tend to who has had CRC should be screened annually beginning at
present with more advanced disease. Men tend to develop CRC age 40, rather than at age 50. Family members of patients who
slightly more often than women.2 The disease affects all ethnic developed CRC very early (i.e., before age 50) should be screened
groups, and epidemiologic studies confirm that environmental 10 years before the age at which the relative developed CRC.
exposure is probably a factor. For example, people who immi- For example, if a patient’s brother, or other first-degree relative,
grated to the United States from Japan—where CRC was once developed CRC at age 45, the patient should begin screening at
a low-incidence disease—eventually developed CRC at a rate age 35.16-18
similar to native-born Americans. Today, Japan’s incidence of
CRC is rising dramatically, probably due to Western influence, ■■ The Biology
particularly in diet; dietary intake of milk, meat, eggs, and fat/oil Approximately 70% to 90% of CRCs arise from adenomatous
increased remarkably in Japan from 1950 to 1970, and it remains polyps. Between 15% and 30% of people in the United States
at this elevated level today.9 Globally, some differences in inci- eventually develop polyps—about 30% of all polyps are hyper-
dence remain related to location and low socioeconomic status. plastic with no malignant potential. Others are adenomatous and
S6 Supplement to Journal of Managed Care Pharmacy JMCP August 2007 Vol. 13, No. 6, S-c www.amcp.orgEpidemiology, Disease Progression, and Economic Burden of Colorectal Cancer
are considered premalignant. Polyps larger than 2 cm in diam- This information will allow clinicians to fine-tune the approach
eter have a 50% chance of becoming malignant. Polyp removal, for each individual patient.
although not perfect, dramatically reduces the incidence of colo-
rectal cancer. Previous CRC increases risk for a new primary tumor ■■ Diagnosis and Screening
at least 4-fold; therefore, regular screening with colonoscopy Symptoms of CRC can be nonspecific or quite fulminant. Patients
becomes a lifelong requirement for these patients. In addition, may interpret occult blood in stool as hemorrhoids and fail to
people with inflammatory bowel disease, particularly ulcerative pursue treatment. Then again, blatant hematochezia (bloody
colitis and Crohn’s disease, must be screened very carefully stool) or melena (dark tarry feces containing blood) may cause
because of their substantial risk of developing cancer.19-21 patients to seek immediate treatment. Anemia may be identified
Our understanding of the molecular biology of colon can- serendipitously or during routine physical examination, and
cer has grown exponentially in recent years. Colorectal cancer subsequent evaluation may find otherwise asymptomatic colon
develops over many years as environmental and genetic factors cancer. Change in bowel habits is a common symptom, particu-
interact. Environmentally, a high-fat diet plays a role in the devel- larly among individuals whose tumors grow in the sigmoid colon
opment of CRC, especially in the descending and sigmoid colon. or rectum.
Fat makes up 40% to 50% of total caloric intake in Western The American Cancer Society recommends screening all men
countries.9 Animals fed high-fat diets develop more carcinogen- and women older than 50 and those at high risk at an earlier
induced colon cancers than do animals on low-fat diets.22,23 age. Unfortunately, many Americans fail to schedule screenings.
Dietary fats are converted into potentially carcinogenic substances Currently, colonoscopy remains the gold standard for screening
and enhance cholesterol and bile acid synthesis by the liver. and diagnosis. Sigmoidoscopy can only evaluate the rectum and
Bacterial flora convert these compounds to secondary bile acids, the left side of the colon, and this is a serious limitation. For
cholesterol metabolites, and other potentially toxic metabolites. example, people with HNPCC syndrome are much more likely
Bile acids may activate protein kinase C—an enzyme involved to have a silent right-sided colon cancer. Flexible sigmoidoscopy
in the transfer of cell signals that, when activated, induce excess may be done every 5 years but must be coupled with fecal occult
cellular production.24 blood testing annually. If an individual has a positive fecal occult
Colorectal cancer arises as genetic alterations that cause blood test even with a negative sigmoidoscopy, that individual
abnormal cellular proliferation, resulting in progression from must be fully evaluated with the colonoscopy. Also, double
normal colonic mucosa to adenomas or adenomatous polyps to contrast barium enema is occasionally used as a screening tool.
adenocarcinoma. This progression can be induced by a series of The standard approach to preventing CRC is to employ routine
inherited or noninherited mutations involving oncogenes and screening and remove colon polyps.
tumor suppressor genes. Inherited APC and MMR mutations are Staging has evolved over time, and we currently use the TNM
responsible for the 2 most common types of hereditary CRC. system, an evaluation system based on 3 variables: primary tumor
These genes are also involved in noninherited mutations, along (T), regional nodes (N), and metastasis (M). Table 2 provides
with Kirsten-ras (K-ras), p53, and other genes. Noninherited the newest CRC staging. In the past, patients presenting with
mutations of the APC gene are also present in 60% to 80% of the same stage of CRC were considered similar. The new staging
sporadic CRC and adenomas. criteria recognize that they are usually quite different. Within the
• hMLH1 is the MMR gene most commonly mutated in sporadic confines of the staging system, subsets of patients with varying
CRCs, especially those occurring in the right or transverse survival statistics can be found. Stage II colon cancer is now
colon. subdivided into stage IIA and stage IIB, and stage III into Stages
• K-ras is an important proto-oncogene involved in the regula- IIIA, IIIB, and IIIC. Fewer than one quarter of patients present
tion of cell proliferation. K-ras mutations are present in about with early disease (Stage I) that is curable by surgical resection.
40% of CRCs. Staging appropriately dramatically improves survival. In large
• p53 is a tumor suppressor gene normally involved in preventing part, the present discussion focuses on stage IV disease, which
cells with damaged DNA from progressing through the cell represents more than 20% of CRC patients at diagnosis.
cycle. This gene also inhibits angiogenesis, possibly by decreas- Managed care pharmacists may be unfamiliar with cancer
ing expression of vascular endothelial growth factor (VEGF). terminology in general, and treatment of CRC specifically. Table 3
Loss of p53 is present in approximately 75% of CRC and is defines some terms necessary to understand recent changes
involved in the conversion of adenoma to adenocarcinoma.21 in its diagnosis and treatment. Surgery has always been the
The sequence of molecular events is not a linear, but rather a treatment of choice for CRC. Radiation generally is restricted to
collection of events that occurs over time. Using large tumor banks rectal cancers. Additionally, readers should keep in mind that
(repositories for tissue specimens), researchers may someday link until the mid-1990s, chemotherapy for CRC was limited to
colon cancer clinical trial efficacy data to develop both prognostic leucovorin and fluorouracil combinations. The U.S. Food and
and predicted strategies based on the tumor’s molecular biology. Drug Administration (FDA) approval of irinotecan in 1996
www.amcp.org Vol. 13, No. 6, S-c August 2007 JMCP Supplement to Journal of Managed Care Pharmacy S7Epidemiology, Disease Progression, and Economic Burden of Colorectal Cancer
taBlE 2 American Joint Committee on Cancer (AJCC) Staging Guidelines for Colorectal Cancer (CRC)
Stage I Stage II Stage III Stage IV
Disease development
Staging
Definition
Usual treatment
Source: AJCC Cancer Staging Manual. 6th ed. National Comprehensive Cancer Network. Clinical practice guidelines in oncology: colon cancer. Vol 1. 2004.
Image adapted from http://www.exactsciences.com/pregen26/professionals/about_hnpcc/_index.htm#. Accessed January 16, 2004.
and oxaliplatin in 2002 changed the landscape, and ultimately, adenocarcinoma, NCCN suggests separating patients into
the biologics bevacizumab and cetuximab also significantly 3 groups: those with liver metastases, those with lung metas-
expanded treatment options. Oncology is also a field that uses tases, and those with more disseminated disease.
many (and sometimes confusing) acronyms. These, too, are For patients presenting with liver metastases at the first
addressed in Table 3. Sometimes, clinicians, researchers, or diagnosis, clinicians can select one of several pathways. Treatment
institutions modify standard regimens, and they are then given a might begin with chemotherapy with a biologic, and depend-
similar but new name (e.g., FOLFOX4, FOLFOX6). ing on patient response, make a decision about whether to
The most common treatment for patients with localized proceed with the primary tumor removal and liver resection.
CRC is surgery, which is frequently curative. Although adju- Alternatively, the oncologist might schedule surgery to remove
vant chemotherapy in stage II disease has been investigated, its the primary colon lesion and perhaps remove the liver lesion.
use remains controversial, with overall survival ranging from Liver resection, if feasible, can also be scheduled for a later time.
approximately 75% to 80% with surgery alone. Surgery and Another option is colectomy followed by neoadjuvant chemo-
adjuvant chemotherapy are common treatments for patients therapy and then liver resection.
with stage III disease. Conversely, the overall survival among Patients unable to undergo curative resection must be evalu-
individuals with stage IIIC colon cancer, even after surgical resec- ated for symptoms. Bleeding or obstruction may be an indication
tion, is as low as 15%. The differences in survival are striking. for surgery before chemotherapy. In relatively asymptomatic
Combination chemotherapy is given for metastatic disease when patients, proceeding with chemotherapy can shrink the primary
possible. Chemotherapy with radiation is given before (favored) tumor as well as metastatic disease. Oncologists generally find
or after surgery in most patients with stage II or III rectal cancer. that among patients with hepatic metastases, approximately 70%
Thus, one strategy for all patients is inappropriate.25 Case 1 intro- are considered unresectable at diagnosis. However, a sizable
duces these issues (see Sidebar 1). number of patients even with multiple lesions may be able to
Fortunately, guidance is available for clinicians. The NCCN undergo successful surgery.
has created treatment guidelines for almost every cancer and for Numerous studies have examined surgical rates in patients
the most common treatment-induced symptoms.26 All are avail- with metastatic colon cancer who have had surgical resection,
able online at www.nccn.org. The colon cancer guidelines are and the 5-year survival rate (the point at which oncologists
currently under evaluation and are reviewed at least annually, but consider a patient cured) ranges from 25% to nearly 60%,
rapid changes in CRC have prompted NCCN to revise and update compared with patients with metastatic disease who have not
the guidelines more often. In the algorithm for a patient like the had resection; their 5-year survivorship rate is between 5%
one described in Case 1 (see Sidebar 1) with proven metastatic and 10%.27-33
S8 Supplement to Journal of Managed Care Pharmacy JMCP August 2007 Vol. 13, No. 6, S-c www.amcp.orgEpidemiology, ",,
*"%"($( 7 Disease Progression, and (&(%"
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Sidebar 1
Case 2
=! 1: B*!/B
Patient «Þ ÌÀi>ÌiÌ Ì >Ì Ã }Ûi >vÌiÀ V«iÌi
A 7 ÀiÃiVÌ v V>ViÀ° ÌÃ > Ã Ì ÌÀi>Ì «ÀiÃÕi`
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: ./ After
ÀiÃ`Õ> VÀiÌ>ÃÌ>ÌV `Ãi>Ãi°
successful 4=3 "&
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3"> months4 * of $=>(:
adjuvant &=*3*=3"&
fluorouracil
>ÀViLÀÞV >Ì}i] > ÃiÀÕ >ÀiÀ vÌi iiÛ>Ìi` and &=*>*3"(/
( leucovorin. 4: Last '*(:
month her carcinoembryonic (:" (
3 3"(*'3A*(" antigen -
(CEA, =4used 4 as a :='*3
tumor
«i«i ÜÌ Ãi >`iV>ÀV>Ã] «>ÀÌVÕ>À
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proceed? *=&Would A*= you *do a *&*(*4*,A
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computed :*'* 3,
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«>ÌiÌÃ ÜÌ «>VÀi>Ã] LÀi>ÃÌ] Û>ÀÞ] À Õ} V>ViÀ°
à À>Þ «À`ÕVi` `ÕÀ} Ì i `iÛi«iÌ v > viÌÕð scan *
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pelvis, a ,*4":3*(
positron '"44"*(
emission :*'* 3,
tomographyA
*À`ÕVÌ ÃÌ«Ã LivÀi LÀÌ ] >` Ì ÕÃÕ>Þ Ã >Þ -(PET) scan, *3
. 4( or (
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nuclear '""(
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appropriate. This patient’s 3"4
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! «ÞiÌ v V iÌ iÀ>«Þ À V iÀ>`>Ì Ì . ` Ì ÕÃ Ài`ÕVi Ì i VV> ÃÌ>}i or a 4*(
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Sidebar 2 subsequently responded to systemic chemotherapy and eventu-
Case 2 ally allowed surgical resection.8 They used prognostic factors of
A 56-year-old male presents with a nearly obstructing sigmoid cancer with outcome to create a model predicting survival in a preoperative
extensive liver metastases. He undergoes sigmoid resection. Four weeks setting. In a consecutive series of 1,439 patients with colorectal
postoperatively, his performance status is 2 and his CEA is significantly elevated liver metastases from 1988 to 1999 at one hospital, 335 (23%)
at 1,800 ng/L. Options include capecitabine, FOLFIRI, FOLFOX, IFL, infusional received initial resection, and 1,104 (77%) initially unresectable
fluorouracil, fluorouracil/leucovorin, bevacizumab plus chemotherapy, and patients were treated with oxaliplatin-based or irinotecan-based
cetuximab plus chemotherapy. chemotherapy, although 12% of patients received fluorouracil and
This patient actually was treated with daily continuous venous infusion leucovorin alone. After a documented response to chemotherapy
fluorouracil but required a dose reduction secondary to mucositis. Fortunately, was observed, 138 (12.5%) of patients underwent secondary
he achieved a partial response and his performance status improved significantly.
hepatic resection resulting in a 33% 5-year survival. An average
Although he is now asymptomatic, his liver metastases have progressed.
of 10 courses of chemotherapy were administered preoperatively.
The key point in this case is that patients with bulky disease who are chemo-
therapy-naïve and are symptomatic pose clinical challenge. Some clinicians,
The 5-year survival was 48% for the initial surgical resection
concerned about the patient’s performance status, would opt for infusional fluo- group. Four preoperative risk factors (a rectal tumor, an elevated
rouracil or capecitabine or fluorouracil and leucovorin. This would be an appropri- CA 19-9, tumor larger than 10 cm, and 3 or more metastatic
ate choice according to the NCCN guidelines. This may be the sole chance for sites) predicted poorer outcome from this strategy. Neoadjuvant
treatment, however, and giving this individual the best opportunity for response therapy results are changing the way oncologists think about
may be critical. Although this patient responded to infusional fluorouracil, that patients with metastatic disease, introducing the concept of sur-
is not always the case. Some oncologists might favor combination therapy up gical resection for patients with previously unresectable disease.
front even with an impaired performance status, hoping for rapid response and Survival expectancy at 5 years for patients with risk factors was
improved overall outcome. also reported: 1 risk factor, 23% to 41%; 2 risk factors, 14%; and 3
Case 3 or 4 risk factors, 0% to 1%. Although chemotherapy can produce
Two years ago, a 70-year-old male underwent a right hemicolectomy for a stage a complete response as measured by CAT scan, most patients will
II colon cancer and did not receive adjuvant therapy. His CEA is now 100 ng/mL, have residual tumor cells visible in pathology specimen; there-
and his chemistries are normal. Despite an excellent performance status, he has fore, we can not say at this time that neoadjuvant chemotherapy
lung and liver metastases. In this case, FOLFOX or FOLFIRI with bevacizumab alone is curative.
would be favored by most oncologists as first-line therapy. With FOLFOX, the maximum reduction in tumor size is
Single-agent fluorouracil was the mainstay of treatment for CRC for decades.
usuallyseenwithin3months.Inaddition,longerperiodsofchemo-
Advances in the treatment of CRC were galvanized by Saltz and colleagues’
2000 New England Journal of Medicine publication,49 promulgating irinotecan as
therapy administration can produce liver toxicity with non-
first-line therapy; concurrently, oncology’s philosophy about therapy also shifted. alcoholic steatohepatitis, which can potentially increase surgical
In 1996, the FDA approved irinotecan, a topoisomerase I inhibitor, as a second- morbidity. Therefore, NCCN currently recommends adminis-
line treatment for patients with metastatic CRC. Capecitabine, an oral fluoropy- tering approximately 3 months of chemotherapy, then surgery,
rimidine prodrug, was approved in 1998 for metastatic breast cancer. In 2002, and then additional chemotherapy after surgery. Clinical trials
the FDA approved an additional indication—metastatic CRC—for capecitabine. are currently exploring this approach. The strategy is identical
Capecitabine is converted to fluorouracil by a 3-enzyme pathway including for people with isolated lung metastases.26
thymidine phosphorylase. Advanced metastatic disease is usually terminal. NCCN
recommends that for patients who present with, for example,
abdominal peritoneal disease, clinicians first rule out obstruction.
Experience with radiofrequency ablation (RFA, the use of Chemotherapy is an immediate option in nonobstructing disease,
electrodes to heat and destroy abnormal tissue) in patients but other options (colon resection, colostomy, bypass, or stenting)
with hepatic metastasis from CRC is increasing. Open surgery, must be considered if an obstruction is present. Cases 2 and 3
percutaneous RFA, and laparoscopic RFA have been studied. demonstrate some of these principles (see Sidebar 2).26
Findings cannot confirm that RFA is curative—recurrence rates In 2002, the FDA approved oxaliplatin, a third-generation
range from very low to almost 50% depending on the underlying platinum analog that induces DNA cross-links and results in
presentation and number of lesions.41-48 If cure is the goal, surgi- apoptosis. Currently, it is approved for both the first- and sec-
cal resection remains the gold standard, but in patients who are ond-line therapies of CRC. The biologics made their entry shortly
not good surgical candidates, RFA may be an option. Currently, thereafter. Bevacizumab is a humanized monoclonal antibody to
many surgical patients have a combination of surgical resection VEGF, a key regulator of tumor angiogenesis. Approved in 2004,
with concurrent interoperative RFA for lesions that cannot be it is used in combination with fluorouracil regimens as first-line
resected; the cure rate is unknown. or second-line treatment for metastatic CRC. Cetuximab is a chi-
Adam et al. evaluated the long-term survival of patients meric antibody to the epidermal growth factor receptor (EGFR)
who initially had inoperable colorectal liver metastases that and was approved in 2004 for the treatment of second-line
S10 Supplement to Journal of Managed Care Pharmacy JMCP August 2007 Vol. 13, No. 6, S-c www.amcp.orgEpidemiology, Disease Progression, and Economic Burden of Colorectal Cancer
metastatic CRC in patients who over-express EGFR. Cetuximab infusion regimens, including FOLFOX and FOLFIRI. In the
in combination with irinotecan is indicated for patients who are United States, researchers and clinicians emphasized bolus
refractory to irinotecan-based chemotherapy. As a single agent, therapy. The evidence, however, now indicates continuous
cetuximab is indicated for patients who are intolerant to irinote- intravenous infusion (CIV) is clearly safer.52
can-based chemotherapy. The Meta-analysis Group in Cancer conducted a meta-
Grothey and colleagues analyzed data from 7 phase 3 trials analysis of all randomized trials (N=1,219) that compared
(N = 3187) in advanced CRC to compare the proportion of fluorouracil bolus with CIV, including toxicities, especially
patients receiving fluorouracil-leucovorin, irinotecan, and oxali- grades 3 to 4 anemia, thrombocytopenia, leukopenia, neutropenia,
platin administered over time with median overall survival (OS), nausea/vomiting, diarrhea, mucositis, and hand-foot syndrome.
using a weighted analysis.50 They reported median OS correlated They found that fluorouracil bolus was more likely to cause hema-
significantly with the percentage of patients who received all tologic toxicity, mainly neutropenia (31% with bolus versus 4%
3 drugs (but no biologics) in the course of their disease. It did with CIV; PEpidemiology, Disease Progression, and Economic Burden of Colorectal Cancer
higher (median 17.4 as opposed to 14.1 months). Patients receiv- Tournigand et al. randomized patients to FOLFOX6 or FOLFIRI
ing irinotecan were more likely to develop some grade 3 and 4 and allowed crossover to the other regimen after disease progres-
toxic effects, but did so in a predictable manner. Adverse events sion.56 In arm A, 109 patients received FOLFIRI and 81 of these
were reversible, noncumulative, and manageable. The investiga- patients were treated with second-line FOLFOX upon progression.
tors suggested that the combination therapy be considered as a In arm B, 111 patients received FOLFOX and 69 of these patients
reference first-line treatment for metastatic CRC. were treated with second-line FOLFIRI upon progression. Median
survivals were similar in the arms: 21.5 months in arm A versus
Evolving First-Line Treatments 20.6 months in arm B. Median second progression-free survival
Goldberg et al. looked at 3 different 2-drug combinations in was 14.2 months in arm A versus 10.9 months in arm B. First-
patients with advanced metastatic CRC who were previously line response rates were similar, 54% and 56%, respectively.
untreated.54 Patients were randomly assigned to receive Grade 3/4 mucositis, nausea/vomiting, and grade 2 alopecia
• irinotecan and bolus fluorouracil plus leucovorin (IFL, control were more frequent with FOLFIRI, and grade 3/4 neutropenia
combination), or and neurosensory toxicity were more frequent with FOLFOX6.
• oxaliplatin and infused fluorouracil plus leucovorin This trial indicates that the sequence used is irrelevant; overall
(FOLFOX), or survivorship of about 21 months is expected with either
• irinotecan and oxaliplatin (IROX). approach. Either regimen is an appropriate platform on which
The investigators accrued 795 patients between May 1999 to build other treatment approaches. The differences in toxicities
and April 2001. FOLFOX was associated with a median time- may guide treatment choice.
to-progression of 8.7 months, response rate of 45%, and
median survival time of 19.5 months. These results were sig- Enter Oral Agents
nificantly superior to all endpoints observed for IFL (6.9 months, Two randomized phase 3 trials compared oral capecitabine
31%, and 15 months, respectively) and for time-to-progression monotherapy with the Mayo regimen of intravenous bolus
and response for IROX (6.5 months, 35%, and 17.4 months, fluorouracil and leucovorin (daily for 5 days) as first-line
respectively). The FOLFOX regimen’s adverse event profile was therapy in patients with newly diagnosed metastatic CRC.57,58
significantly better in terms of severe nausea, vomiting, diarrhea, Data obtained from each trial were pooled.59 Patients received
febrile neutropenia, and dehydration. It was, however, associated either capecitabine 2,500 mg/m2 daily (1,250 mg/m2 twice daily)
with more sensory neuropathy and neutropenia. Thus, the inves- on days 1 to 14 every 21 days, or fluorouracil 450 mg/m2 plus
tigators found the FOLFOX regimen active and comparatively leucovorin 20 mg/m2 IV daily on days 1 to 5 every 28 days.
safe. In addition to supporting FOLFOX as first-line treatment The primary endpoint was the overall objective tumor response
for metastatic CRC, the irinotecan/oxaliplatin regimen is an rate (RR: complete response and partial response). Capecitabine
appropriate alternative for fluorouracil-intolerant individuals. treatment was associated with significantly higher RR than
In Europe, the FOLFOX and FOLFIRI infusion schedules fluorouracil and leucovorin (25.7% versus 16.7%, respectively).
were both used. An Italian research group compared FOLFIRI However, no difference in overall survival (median of 12.9months
with FOLFOX4 in previously untreated patients (N=360) with with each) between treatments was observed. Subgroup analysis
advanced CRC.55 Patients were randomly assigned to receive, indicated that the difference in response was observed irrespec-
every 2 weeks, either tive of previous adjuvant therapy, site of metastasis, or age.59
• arm A (N=164) FOLFIRI: irinotecan 180 mg/m2 on day 1 A dose of capecitabine 2,500 mg/m2 daily is higher than would be
with leucovorin 100 mg/m administered as a 2-hour infusion generally used in clinical practice in the United States, with most
before fluorouracil 400 mg/m2 administered as an intrave- practitioners administering 2,000 mg/m 2. By observation,
nous bolus injection, and fluorouracil 600 mg/m2 as a 22- clinicians have determined that people in the United States
hour infusion immediately after fluorouracil bolus injection do not tolerate capecitabine in the same doses that Europeans
on days 1 and 2 [LV5FU2]) or do. One theory is that the heavily fortified diet in the United
• arm B (N=172) FOLFOX4: oxaliplatin 85 mg/m2 on day 1 States is folate-rich, accounting for increased fluoropyrimidine
with the LV5FU2 regimen). toxicity.
Overall response rates were 31% in arm A and 34% in arm Studies of combinations of capecitabine identical to those
B. Median time-to-progression, duration of response, and overall using FOLFOX and FOLFIRI have been reported. Building
survival were similar in both arms. Patients in arm A reported on their previous work, Grothey et al. designed a random-
more alopecia and gastrointestinal disturbance; those in arm B ized phase 2 trial whereby patients received either XELOX
experienced more thrombocytopenia and neurosensorial adverse (N=80) or XELIRI (N=77) and upon progression were then
effects. Serious toxicity was uncommon for both regimens. Both treated with the alternative regimen: XELIRI (N =34) or XELOX
therapies are equally effective as first-line treatments, although (N=31).60 The doses for each 22-day cycle included capecitabine,
their toxicity profiles differ. 1,000 mg/m2 twice daily on days 1 to 14; irinotecan,
S12 Supplement to Journal of Managed Care Pharmacy JMCP August 2007 Vol. 13, No. 6, S-c www.amcp.orgEpidemiology, Disease Progression, and Economic Burden of Colorectal Cancer
1,000 mg/m2 twice daily on days 1 and 8; and oxaliplatin, optimizes overall survival. Exposing patients to more active
70 mg/m2 on days 1 and 8. Overall survival for the 2 sequen- drugs, now including biologics, may push median survivorship
tial regimens was similar for first-line XELOX versus XELIRI even farther.
(16.5 months versus 18.8 months, respectively) as was initial The Eastern Cooperative Oncology Group sponsored a trial
response rate (51% versus 41%, respectively) and progression- for CRC patients who progressed after therapy with either
free survival (6.2 months versus 7.1 months, respectively). fluorouracil or irinotecan plus fluorouracil.64 Patients were
randomized to receive (1) bevacizumab plus FOLFOX4 or
Enter the Biologics (2) FOLFOX4 alone or (3) bevacizumab alone. Response rate,
The next major advancement for CRC was the introduction of progression-free survival, and overall survival were improved
biologics, a form of targeted therapy. Bevacizumab is an anti- when bevacizumab was added to FOLFOX. The addition of
body directed against VEGF, a soluble protein instrumental second-line bevacizumab 10 mg/kg every 2 weeks to FOLFOX4
in angiogenesis.61 Use of targeted therapies in combination significantly improved median overall survival from 10.7 to 12.5
with cytotoxic agents is expanding options within the lines of months. As a single agent, however, bevacizumab had minimal,
therapy. if any, activity and therefore is not recommended as a therapeutic
To determine whether the addition of bevacizumab to IFL choice outside the clinical trial.
improves survival among metastatic CRC patients, Hurwitz and A randomized phase 2 trial by Hochster et al. added
colleagues62 randomly assigned 813 patients in a blinded fashion bevacizumab to oxaliplatin combination chemotherapy in
with previously untreated metastatic CRC to receive either IFL patients with metastatic CRC.65 This randomized study assesses
(the standard at the time) plus bevacizumab (N=402) or IFL the safety and tolerability of each of 3 oxaliplatin plus fluoropy-
plus placebo (N=411). A third arm included fluorouracil and rimidine regimens (bolus, infusional, or oral fluoropyrimidine)
leucovorin plus bevacizumab. After a predetermined interim alone in TREE1, and with bevacizumab in TREE2. Regardless of
safety analysis confirmed the safety of the IFL regimen with the chemotherapy employed, adding bevacizumab improved the
bevacizumab, the fluorouracil and leucovorin arm of the trial response rate. These data with bevacizumab in colon cancer are
was discontinued. Patients received 5 mg/kg bevacizumab every consistent across trials and across chemotherapy regimens. The
2 weeks. The primary endpoint was overall survival, and sec- trial by Hochster et al. also suggested that the bolus fluorouracil/
ondary endpoints were progression-free survival, response rate, oxaliplatin regimen is inferior for patients with advanced colon
duration of response, safety, and quality of life. cancer and cannot be recommended.65
Adding bevacizumab to irinotecan plus bolus fluorouracil Clinicians need to monitor bevacizumab for its potential
and leucovorin (IFL) resulted in a significant and clinically adverse events. There is a risk of bleeding, which often manifests
meaningful improvement in survival (20.3 versus 15.6 months; as mild epistaxis. The risk of venous thromboembolism does not
PEpidemiology, Disease Progression, and Economic Burden of Colorectal Cancer
surgery. Because of its long half-life, patients receiving P=0.007). Median time-to-progression was also significantly
bevacizumab-containing regimens must be bevacizumab-free greater in the combination therapy group. The addition of iri-
for a minimum of 6 weeks before surgery. The risk of arterial notecan increased toxicity (i.e., diarrhea and neutropenia) as
thromboembolism is a concern, particularly for the elderly with expected. Thus, cetuximab’s activity alone (unlike that of bevaci-
a previous history of arterial thromboembolism, such as cardio- zumab alone) or in combination with irinotecan was determined
vascular accident, myocardial infarction, transient ischemic to be significant. Because this work is from phase 2 trials, we do
attacks, or angina.66 not have survivor statistics for cetuximab.
One of the most significant findings in modern colon cancer Cetuximab’s complete prescribing information indicates that
therapy is that chemotherapy compared with best supportive care cetuximab is appropriately used in tumors that stain positive
(BSC) is superior even when toxicity is considered. Two trials for EGFR; however, neither EGFR-staining nor the percent-
have also examined irinotecan as second-line therapy.67,68 age of cells expressing EGFR correlate with response rate.70
A British study compared irinotecan to BSC prospectively; 279 Furthermore, there are now data to support the use of cetuximab
patients with metastatic CRC who had failed fluorouracil ther- for EGFR-negative patients.71
apy were randomized 2:1 to receive either BSC plus treatment With cetuximab and other EGFR-targeted therapies, skin
with irinotecan 350 mg/m 2 every 3 weeks, or BSC alone. In the toxicity may actually be a surrogate for efficacy. Trials have
BSC group, 14% of patients were still alive at 1 year compared shown that those who develop the most pronounced acne-form
with the 36% of patients alive at 1 year after treatment with rash are those who are most likely to benefit.72
irinotecan (P = 0.001).67 Patients receiving irinotecan lived sig- Because cetuximab and bevacizumab have different toxicity
nificantly longer without performance status deterioration; and profiles and biologic targets, theoretically it would be appropriate
deterioration in quality of life (50% reduction from baseline) to look at cetuximab and bevacizumab combinations. A random-
occurred significantly later in the irinotecan-treated patients ized phase 2 trial examined cetuximab and bevacizumab
than in controls. with or without irinotecan.73 The response rate was significant
Rougier and colleagues evaluated 101 patients randomized to for patients receiving second-line or third-line treatment and
receive 1 of 3 second-line regimens68: superior for patients treated with the irinotecan-cetuximab-beva-
• irinotecan 180 mg/m2 on day 1 followed by a leucovorin cizumab combination (38%, 8.5 months time-to-progression,
200 mg/m2 infusion, before a fluorouracil 400 mg/m2 bolus compared with 23% time-to-progression for cetuximab and
followed by a 5-FU 600 mg/m2 infusion (LV5FU2 regimen), bevacizumab).
on days 1 and 2 every 2 weeks (N=35); or These data have stimulated the development of additional
• oxaliplatin 85 mg/m2 on day 1 followed by the LV5FU2 randomized phase 3 trials. It is now clear that second-line and
regimen on days 1 and 2 every 2 weeks (N=33); or third-line treatment can extend the benefit of first-line treatment.
• oxaliplatin 85 mg/m2 followed by irinotecan 200 mg/m2, both It increases response rates across treatment lines, extends overall
on day 1 every 3 weeks (N=33). survival using combinations of cytotoxic and targeted therapies,
Overall survivals were 12.2 months (95% CI, 9.2-16.0), and appears to sensitize previously refractory tumors.
11.5 months (95% CI, 9.0-14.1), and 11.0 months (95% CI, 8.1- The challenge of these new regimens is that toxicity can
12.2), respectively. These researchers determined that second- be significant and patients grow weary of ongoing treatment.
line treatment with irinotecan/LV5FU2, oxaliplatin/LV5FU2, To address this problem, researchers are now examining “stop
or irinotecan/oxaliplatin controls tumor growth well, increases and go” approaches. One particular strategy drops the oxalipla-
survival, and is safe. The intention-to-treat objective response tin after a defined period of time, introducing it again at disease
rates (ORRs) were 11.4% (95% CI, 3.2-26.7), 21.2% (95% CI, 9.0- progression.74 Initial studies suggest doing so is safe and uncom-
38.9), and 15.2% (95% CI, 5.1-31.9), respectively, in the 3 arms. promising of the overall strategy. This suggests that at maximum
Tumor growth control was ≥60% for all 3 combinations. response, patients might be afforded either complete breaks
in therapy or less intensive therapy until the disease progresses.
Cetuximab At progression, combination therapy can be reintroduced. This
Cetuximab is a monoclonal antibody that specifically blocks may alleviate toxicities and reduce costs.
EGFR. Cunningham et al. examined cetuximab’s efficacy The many choices for advanced metastatic CRC are reflected
in combination with irinotecan with that of cetuximab alone in in the NCCN guidelines. NCCN has identified choices for
metastatic CRC refractory to irinotecan.69 Patients (N=329) whose people who cannot tolerate intensive therapy with agents such
CRC progressed during or within 3 months of treatment with an as capecitabine or infusional fluorouracil. For the less fit patient,
irinotecan-based regimen were randomized to receive cetuximab it is important to weigh the risk of therapy, including combina-
plus irinotecan (N=218) or cetuximab monotherapy (N=111). tion therapy, with the need to achieve the best response as an
The combination-therapy group was significantly more likely to effort to most effectively achieve disease control and improved
respond than the cetuximab-alone group (22.9% versus 10.8%; performance status.
S14 Supplement to Journal of Managed Care Pharmacy JMCP August 2007 Vol. 13, No. 6, S-c www.amcp.orgYou can also read
