SURVEILLANCE AFTER CURATIVE RESECTION FOR COLON AND

RECTAL CANCER

Of the almost 1 million patients diagnosed with CRC worldwide every year, two-thirds have curative

intent surgery, but ultimately one-third of them will develop recurrence of disease or a second

colorectal primary. Most recurrences arise within 3 years of the initial treatment, and almost all arise

within 5 years. Recurrences are usually diagnosed at an advanced stage and have an ominous prognosis.

Surveillance regimens aim to identify recurrences before they become symptomatic, and while they are

still potentially resectable.293,294 Several meta-analyses of prospective, randomized trials comparing

intensive or minimal surveillance after curative resection in patients with stage I to III CRC suggest that

recurrences were diagnosed earlier and surgical salvage was more likely in patients undergoing

intensive surveillance.293,295 The survival benefit can only be partly attributed to the improved ability to

resect recurrences; other elements such as increased psychological support, behavior modifications, and

better treatment of comorbid conditions that accompany intensive surveillance regimens are also

thought to contribute to improved survival. Based on this evidence, cancer organizations have

established guidelines for surveillance after curative resection of CRC. All of them include a

combination of regular history and physical examination, determination of CEA level, endoscopy, and

imaging of the chest, abdomen, and pelvis (Table 68-10). Some clinicians recommend surveillance for

stage II/III disease, while others also include stage I. In the future, surveillance will be risk-adapted,

targeting patients more likely to benefit from intensive surveillance based on clinical and molecular

prognostic factors. Despite these recommendations, a recent population-based cohort study of 57

patients concluded that 70% were diagnosed between scheduled examinations.294

TREATMENT OF STAGE IV COLON AND RECTAL CANCER

Between 20% and 34% of all CRC patients have metastasis at the time of diagnosis; these are known as

synchronous metastases. Another one-third of patients will develop metastasis sometime after

undergoing treatment of the primary disease; this is known as metachronous metastasis. Synchronous

metastases are usually more extensive and, in general, carry a worse prognosis compared to

metachronous metastases.

The liver is the most common site of CRC metastasis, and liver metastasis is the most common cause

of cancer death in patients with CRC. Autopsy studies have revealed that 50% of patients dying from

CRC have liver metastasis and, in one-third of them, the liver is the only site of metastatic disease.296

Some patients with liver-only metastatic disease are resectable at the time of diagnosis. Others are not

resectable, due to the involvement of critical structures by large volume of metastatic disease. The

treatment of stage IV CRC patients is complex, and requires consideration of the number of organs

involved, the number and size of the metastasis, the location, the symptoms related to the primary in

the colon or rectum, whether the tumor is resectable or not, and the patient’s performance status.

Treatment decisions should be made after discussion in a multidisciplinary tumor board.297 A simplified

algorithm for the treatment of patients with stage IV CRC is presented in Algorithm 68-3. The discussion

is centered on patients with liver metastasis, but these principles are equally applicable to patients with

lung metastasis. Surgery is the only curative treatment for patients with colorectal metastasis. Other

forms of local therapy, such as ablation, may improve survival. Most patients with metastatic disease

benefit from systemic chemotherapy, either as adjuvant treatment to surgery or as the sole form of

treatment.

Table 68-10 Comparison of Surveillance Options After Curative Resectiona

1806

Algorithm 68-3. Stage IV rectal cancer treatment algorithm.

Treatment of the Primary Tumor in Stage IV CRC

In the past, all patients presenting with synchronous metastasis were recommended to have resection of

the primary tumor, to avoid complications such as obstruction or perforation during treatment of the

metastatic disease. However, recent data suggest that patients with unresectable metastasis and an

asymptomatic primary are unlikely to develop complications related to the primary tumor that require

surgical intervention while the patient is receiving systemic chemotherapy. Currently, primary tumor

resection is recommended for patients undergoing curative-intent resection of all metastatic disease, or

for patients with unresectable metastasis and a symptomatic primary tumor. The treatment of patients

1807

with asymptomatic primary tumor and unresectable metastasis is controversial. The benefit of avoiding

complications related to tumor progression should be balanced against the mortality and morbidity

associated with a noncurative resection, and the delay in starting systemic chemotherapy.

Observational studies and secondary analysis of prospective trials have reported an association

between primary tumor resection and improved survival. A recent meta-analysis found a difference of

6.4 months in survival in patients undergoing resection.298 However, these studies are limited by strong

patient selection bias and outdated chemotherapy regimens. Patients undergoing resection are more

likely to have liver-only disease, single metastasis, and tumors located in the colon. Rectal cancer

patients are less likely to undergo primary tumor resection compared to patients with colon cancer,

probably due to the higher complexity of rectal surgery, the possibility of using palliative CRT, and the

fear of a colostomy.

Resection of asymptomatic tumors in stage IV disease has not consistently shown improvements in

survival, nor does it necessarily reduce the risk of complications.299 A recent analysis of the SEER

database revealed that the proportion of patients with stage IV CRC undergoing primary tumor

resection has been progressively decreasing in the last decade.300 Despite this decrease in primary tumor

resection, relative survival has been increasing during the same period of time. The improvement in

survival has coincided with the introduction of more effective chemotherapy agents. However, the

relative contribution of the declining rate of primary resection and the more active chemotherapeutic

agents is unknown. These data lend support to current guidelines that do not recommend primary tumor

resection in asymptomatic patients with unresectable metastasis.177,301 In the SEER data analysis, more

than half of the patients with stage IV CRC, diagnosed in 2009, had resection of the primary tumor,

suggesting that current treatment practice lags behind evidence-based treatment guidelines.

Surgical Treatment of Colorectal Metastasis

Overall, only 6% of CRC patients with liver metastasis survive beyond 5 years, but in patients with

resectable liver metastasis the reported 5-year survival rate ranges from 25% to 40%. Patients with a

single, isolated liver metastasis have 5-year overall survival rates as high as 71%. Liver metastases are

considered resectable with curative intent if all disease can be removed, with negative resection margin,

while preserving adequate liver reserve. Incomplete resection or tumor debulking is not recommended,

because it is associated with morbidity without impacting survival. The size of the metastasis is not a

contraindication for surgery. When a curative liver resection may potentially result in insufficient liver

remnant, portal vein embolization of the involved liver lobe is recommended to induce hypertrophy of

the contralateral lobe of the liver. Repeated resection of recurrent liver metastasis is feasible, but the

probability of survival decreases with each subsequent resection.

The role of nonsurgical liver-directed therapy for the treatment of liver-only or liver-dominant

metastatic disease is controversial. Tumor ablation is indicated in patients who are amenable to local

therapy, but are not candidates for surgical resection due to comorbidities. It can also be combined with

surgery in patients with mixed resectable and unresectable lesions due to their anatomical location or

insufficient liver remnant.302 Other liver-directed therapies for which there is no consensus regarding

efficacy are liver-directed chemotherapy using a hepatic artery infusion pump, transarterial hepatic

chemoembolization/radioembolization, and liver-directed radiation.

Colorectal lung metastasis can also be surgically removed following the same principles outlined for

liver metastasis. Resection must be complete, based on the anatomic location of the disease, and with

maintenance of adequate respiratory function. Resection of both liver and lung metastasis is feasible in

selected cases, but resection in the presence of nonhepatic extra-pulmonary disease should be reserved

for carefully selected patients. Ablation and radiation are also options for patients with nonresectable

lung metastasis.301

Chemotherapy for Metastatic Disease

Principles of Chemotherapy

6 A number of antineoplastic agents such 5-FU or capecitabine, oxaliplatin, and irinotecan, and new

biologic agents, such as bevacizumab, ziv-aflibercept, cetuximab, panitumumab, and regorafenib, are

currently used in combination or as single agents in patients with metastatic CRC. The putative

mechanism of action and the toxicity profile of each drug are presented in Table 68-11. The choice of

the treatment regimen is based on the goals of therapy, the type and time of previous therapy, and the

toxicity profile of the constituent drugs.177,301 The chemotherapy regimens commonly used as first-line

therapy in patients appropriate for intensive therapy include: FOLFOX (5-FU/LV/oxaliplatin), FOLFIRI

1808

(5-FU/LV/irinotecan), CapeOx (capecitabine/oxaliplatin), infusional 5-FU/LV, capecitabine as a single

agent, or FOLFIRINOX (5-FU/LV/oxaliplatin/irinotecan). Cetuximab or bevacizumab can be added to

first-line therapy in patients with KRAS/NRAS wild-type CRC, and other combinations such as

FOLFOXIRI with bevacizumab have shown promising results.303,304 The role of maintenance therapy

after first-line therapy, and treatment after progression of metastatic disease on first-line therapy, is

beyond the scope of this chapter. Median survival of patients with unresectable metastatic CRC, which

previously rarely exceeded 12 months, now exceeds 30 months when these agents are used. Increasing

evidence suggests that the selection of chemotherapeutic agents will continue to be guided by molecular

and genomic characterizations. Early reports have indicated that combined therapy with BRAF and

EGFR inhibitors may be effective in treating BRAF V600E metastatic CRCs specifically.305

Adjuvant Chemotherapy in Resectable Disease

The majority of patients who undergo resection for CRC liver metastasis ultimately relapse in the liver.

It is theorized that the addition of systemic therapy provides treatment of occult micrometastatic

disease, reducing the risk of relapse. A number of randomized controlled trials have found a modest

improvement in RFS, but not in OS, with chemotherapy delivered before or after liver resection,

compared with resection alone. The optimal timing of chemotherapy remains unknown.306 The potential

advantages of preoperative therapy include earlier treatment of micrometastatic disease, evaluation of

tumor responsiveness, and the possibility of avoiding resection in patients with tumor progression

during therapy. The main disadvantages of preoperative chemotherapy are the progression of

nonresponsive tumors that become unresectable during systemic chemotherapy, and the increase in

perioperative morbidity due to chemotherapy-induced liver toxicity. The EORTC Intergroup Trial – the

only randomized trial evaluating the role of perioperative FOLFOX (3 months before and 3 months after

liver surgery) in the management of resectable liver metastases – demonstrated an absolute increase of

7.3% in 3-year progression-free survival in the combined treatment group, compared with the resectionalone group.307,308 This trial demonstrated an increased rate of postoperative complications in the

chemotherapy group (25%) compared with surgery-alone (16%), specifically showing a doubling in

biliary fistula and hepatic failure rates. The study concluded that perioperative chemotherapy may

improve cancer-specific outcomes, but at the cost of increased rates of postoperative complications,

including liver dysfunction. Long-term follow-up has revealed the same benefit in progression-free

survival, but no difference in OS with the addition of perioperative chemotherapy. The chemotherapy

regimens used in the adjuvant setting are the same as those used in first-line therapy. However,

bevacizumab can be added as long as it is discontinued at least 6 to 8 weeks before surgery and not restarted for 8 weeks after surgery, because it interferes with wound healing.309 Cetuximab and

panitumumab have been added to first-line regimens in patients with KRAS/NRAS wild type, but the

benefits have been inconsistent. In fact, recent data suggest these could even be detrimental; therefore,

they are not recommended at this time.310

Table 68-11 Main Chemotherapeutic Agents

Chemotherapy in Borderline Resectable Disease

A few patients present with liver-only metastases that are not amenable to a complete resection, due to

close proximity to essential anatomical structures. Systemic chemotherapy in this setting aims to

1809