ABSTRACT: Median survival of patients with metastatic colorectal cancer (mCRC) has increased significantly, owing to individualized treatment plans developed from the available multidisciplinary options for disease management. These plans include early evaluation for possible resection of hepatic metastases, and metastasectomy, as well as coordinated chemobiotherapy for unresectable patients. This article focuses on current management of mCRC, including resection of liver metastases, which offers the possibility of cure to selected patients; sequential chemobiotherapy, which has been used effectively to increase median survival of patients with unresectable mCRC; the roles of neoadjuvant, conversion, and adjuvant chemobiotherapy in patients who undergo hepatic resection; and the emerging use of biomarkers to guide therapy. Implications for nurses are summarized, underscoring the important role that the nurse plays in the increasingly complex treatment of mCRC.
The majority of colon and rectal cancer cases occurring in the US in 2011, estimated at 141,210, as well as most of the expected deaths this year, estimated at 49,280, could be avoided through effective prevention and screening techniques. In 2011, colorectal cancer (CRC) continues to be ranked third in cancer-related incidence and mortality in both men and women. Although more than 90% of CRCs are diagnosed in men and women 50 years of age and older, with a median age of 72 years at diagnosis, only about half of individuals aged 50 years and older have received recommended screening.
Overall, in the last decade, screening and early-detection efforts, along with changes in lifestyle, have resulted in a decrease in CRC incidence and mortality in most adult patient groups aged 50 years and older. An increased incidence of CRC in young adults 20–49 years old has been noted, however, with the incidence climbing since 1992. The greatest increase in one descriptive study was in patients aged 20–29 years, who had tumors in the distal colon and rectum, but not in the proximal colon; this was thought to result from an increase in the incidence of obesity and poor food and lifestyle choices. Poor food and lifestyle choices described in the study included an increased intake of red meat such as “fast food,” and inadequate levels of exercise.
CRC is preventable and curable through polyp identification and removal (prevention) and identification and removal of early cancers (cure) through colonoscopy. The 5-year survival rate for patients with CRC has risen over the past several decades from 51% (1970) to 67% (1999–2006). Only 39% of patients present with localized disease, however, for which 5-year survival is 90%, compared with 5-year survival of patients with regional disease (70%) and metastatic disease (12%). Despite the fact that CRC can be prevented or cured when it is diagnosed early, many patients either develop metastases or have metastatic disease at diagnosis. In addition, there continue to be disparities in outcomes of CRC among Caucasian and African-American patients; for example, African Americans with private health insurance have a 30% higher relative 5-year survival compared with that of uninsured African Americans.
Advances have been made over the past decade in the treatment of metastatic colorectal cancer (mCRC), so that up to 40% of a select subset of patients with resectable metastases now may live 5 years or longer. Median survival of mCRC increased from 5 months to 2 years between 1993 and 2009, as a result of newer options in chemotherapy and the emergence of effective biotherapy.
This article will focus on current management of mCRC, including the resection of liver metastases, which can cure selected patients. In addition, increased survival in patients with unresectable mCRC has been shown with sequential use of effective chemobiotherapy.
Individualizing Treatment Options for Patients With Metastatic CRC
It is estimated that 50%–60% of patients diagnosed with CRC will develop metastases during the course of their disease (metasynchronous lesions), while about 15%–25% of patients present with metastasis (synchronous lesions). For patients who undergo “curative resection,” of colon cancer, tumor may recur in the peritoneum, liver, and distant organs, whereas in rectal cancer patients, tumor more likely develops locoregionally. Adjuvant chemotherapy with fluorouracil (5-FU)/leucovorin for patients with stage III colon cancer has reduced recurrence in the first 2 years following surgery, as after 2 years the likelihood of recurrence is similar to that observed in patients who have not received adjuvant therapy. Finally, liver metastases are common, and at autopsy more than 50% of patients with mCRC have liver-only metastases. Thus, liver resection in these patients, together with resection of the primary tumor, will offer the opportunity for improved long-term survival, as 35%–58% of patients will survive 5 years.
Today patients with resectable metastatic disease have a chance for cure. Of those who present with liver metastasis, an estimated 10%–20% have resectable metastases. Patients with synchronous metastases tend to have more sites of liver involvement and a worse prognosis than patients who develop liver metastases later in the course of their disease (those with metachronous lesions).
The first step in individualization of treatment is to determine if the patient has resectable metastatic disease, or whether, with neoadjuvant chemobiotherapy, the metastatic site will become resectable. This offers 5-year survival rates in the range of 20%–50% among carefully selected patients who can be completely resected, and 10-year survival of 20%–28% of patients.[4,11–15] Additional modalities introduced to further individualize care of the patient with mCRC include portal vein embolization, to increase the size and function of the liver remnant so that resection is possible; radiofrequency ablation (RFA), to help downsize liver metastases so that resection is possible; and chemobiotherapy (eg, as neoadjuvant, conversion, and adjuvant treatment), for a variety of reasons. Other investigational approaches include radioembolization together with systemic therapy, to downstage the liver metastases and thereby increase the chance of tumor-free margins at resection. The National Comprehensive Cancer Network (NCCN) suggests that patients with limited lung metastases can also undergo surgical resection (metastectomy).
Advanced CRC and Liver Metastases: Standard of Treatment
The NCCN Guidelines (v3.2011) recommend that initial evaluation of resectability of all tumor, as well as metastases, should occur immediately upon diagnosis, and that the patient should undergo consult by a multidisciplinary team that includes an experienced hepatobiliary surgeon. Compared with care of advanced CRC in the 1980s, there has been a shift in the definition of resectability: In the past it was defined by what areas needed to be resected, whereas the current focus is on ensuring adequate liver function reserve following complete resection of the liver. In order for a patient to be deemed resectable, 1) all hepatic and extrahepatic disease must be resectable with negative surgical margins (R0), 2) at least two adjacent liver segments must be preserved, 3) vascular and biliary inflow and outflow to the remaining liver segments must be intact, and 4) the liver remnant after surgery must be adequate in volume and function (greater than 20%).
Initially only a small number of select patients will be resectable, as all known disease must be completely resectable with adequate functional organ reserve remaining. Patient evaluation should also include an assessment of comorbidities and the patient’s ability to tolerate complex surgery. In addition, the institution and providers must be experienced in this multidisciplinary treatment, as the mortality rate is 1.6 times higher for patients treated in institutions not skilled in hepatectomy. Some patients will not have adequate hepatic reserve unless another procedure is performed prior to resection. Normally, the liver remnant should be > 20%–30% of the normal liver volume; in cases of liver damage such as steatosis or cirrhosis, a reserve of 30%–50% is needed. Portal vein embolization can be performed preoperatively to cause the liver to hypertrophy, which can increase the reserve by 8%–16%. Radiofrequency ablation (RFA) of liver tumors can enable some patients to undergo hepatic resection.
Radioembolization together with radiosensitizing systemic chemotherapy is being studied, as this approach also appears promising in downsizing liver metastases so that resection is possible. Radioembolization is the administration of radioisotope (90Y)-containing resin or glass microspheres into the arterial blood supply of the liver. It is also called selective internal radiotherapy. Tumor cells in the liver are supplied by the hepatic artery, and because the tumor blood vessels are narrow, the microspheres containing the radioisotope are preferentially trapped there, providing localized radiation of tumor cells. The US Food and Drug Administration (FDA) has approved use of 90Y resin microspheres in combination with adjuvant hepatic arterial infusion of floxuridine (FUDR) for treatment of unresectable liver metastases from CRC, based on a study showing greater tumor response (shrinkage) and time to disease progression when the combination was used (44% and 15.9 months, respectively) compared with hepatic artery infusion of chemotherapy alone (18% and 9.7 months, respectively).
Radiosensitizing drugs that can be used to treat mCRC are 5-FU, capecitabine (Xeloda, a 5-FU prodrug), irinotecan, oxaliplatin (Eloxatin), bevacizumab (Avastin), and cetuximab (Erbitux). Nicolay et al describe the potential side effects related to radioembolization as being fever; abdominal pain; nausea; fatigue; lymphopenia; abnormal liver function tests; radiation gastritis, radiation-induced liver disease, and radiation-induced pancreatitis; cholecystitis; and pneumonitis.
Emergency surgery may be necessary to treat pancreatitis, acute cholecystitis, and gastrointestinal ulceration. When surgery is combined with chemotherapy, neutropenia may be severe. This promising treatment can be given only at specialized centers with a multidisciplinary team experienced in hepatic artery therapies. Currently at least 10 prospective clinical trials are evaluating the effectiveness of radioembolization.
Neoadjuvant chemotherapy is often administered in initially resectable patients who are at high risk of surgical failure, to increase the likelihood of an R0 resection and to evaluate the chemotherapy and biotherapy agents that will be used again, if effective in the neoadjuvant setting, as adjuvant therapy after surgery. In addition, theoretically neoadjuvant therapy will kill any existing nonmeasurable micrometastatic disease. Nordlinger et al demonstrated that patients who received perioperative chemotherapy with FOLFOX (FOL = folinic acid [leucovorin], F = fluorouracil [5-FU], OX = oxaliplatin), 3 months prior to surgery then for 3 months as adjuvant therapy following surgery, had a significantly longer progression-free survival time (36.2 months) compared with those who had surgery alone (28.1 months, P = .041). When individualizing the treatment plan, however, the potential risks of chemotherapy side effects and higher operative morbidity have to be weighed against the potential benefit of neoadjuvant therapy.
Mayo and Pawlik describe the following advantages and disadvantages of neoadjuvant chemotherapy: The advantages of neoadjuvant chemotherapy are:
• If the patient progresses on neoadjuvant therapy, then the hepatic resection will be cancelled and the patient will not undergo a procedure that is likely to fail.
• It provides an opportunity to evaluate response to chemotherapy that can be used as adjuvant therapy postoperatively.
• Patient response to neoadjuvant therapy may be a prognostic factor.
• Patient response may allow for a smaller operation and improve the likelihood of an R0 resection.
• It may treat occult micrometastases, thus preventing recurrence postoperatively.
Disadvantages of neoadjuvant chemotherapy noted by Mayo and Pawlik are:
• Metastases may make the patient unresectable.
• Hepatotoxicity may occur.
• If responsive metastatic sites disappear, this may make resection of the correct site impossible unless the site of removal is marked.
The surgical procedure may be performed in one or two stages. If the patient has synchronous metastases, then the planned surgery depends upon the patient’s individual factors, the extent of disease, and the experience of the surgeon. If three or fewer segments of liver are involved, resection is called minor, and it can be performed as a single procedure with resection of the colorectal primary tumor. If the liver has more than three segments involved, then a synchronous resection of the primary tumor and metastases carries a higher mortality rate, and in most cases a two-stage (sequential) procedure is recommended. This is also recommended if both sides of the liver are involved.
Mayo and Pawlik describe the procedures. Commonly, the first-stage surgery removes minor disease, usually via a wedge resection of the involved areas in the left side of the liver, together with ligation of the right portal vein to cause hypertrophy of the liver remnant. Alternatively, the patient might have a right portal vein embolization postoperatively. Prior to the second-stage surgery 2–3 months after the first surgery, the patient may receive chemotherapy to reduce the extent of disease in the right liver lobe. Approximately 20%–30% of patients progress during this time, and will move on to chemotherapy exclusively, without resection, as resection should be performed only for cure. For other patients, the involved segments of the right lobe are removed as a major resection. Complications of hepatectomy are pleural effusion, pneumonia, liver failure, bile leak/biliary fistula, and perihepatic abcess, and they are associated with a mortality rate of less than 5%.
Unfortunately, 60% of patients who undergo liver resection surgery will experience disease recurrence. Patients who meet the same criteria as those for the initial resection can undergo another liver resection, however. Adam et al showed that patients had a 5-year survival rate of 44% after repeat resection. Sofocleous et al, in an investigation of RFA to treat recurrent liver metastases, found that patients with high-risk features (tumor size > 3 cm, disease-free interval of < 12 months, > 1 liver tumor, lymph node–positive primary tumor) had an overall survival of 21 months, compared with 35 months for low-risk patients.
Intraoperative ultrasound should be performed to identify liver metastasis that is not seen on preoperative imaging or appreciated on surgical palpation; in 10%–12% of cases, at least one malignant lesion is found. Up to 67% of surgical procedures are revised based on intraoperative ultrasound findings.
The majority of patients, however, are unlikely to initially have resectable disease. Approximately 15%–20% of selected patients with unresectable liver metastases can be downsized or converted to the resectable-disease category with conversion therapy. Treatment should only be continued until the tumor is resectable, not up to the point when the maximal response occurs. The treatment window may be narrow, and individualized therapy must be planned to take advantage of tumor shrinkage so that disease can be resected at the optimal time without excess chemobiotherapy, which may cause significant hepatotoxicity (eg, irinotecan-induced steatohepatitis, and oxaliplatin-induced sinusoidal liver injury) or allow tumor progression. For these patients, the NCCN (v3.2011) recommends surgical re-evaluation every 2 months, so that they can be operated on during the optimal surgical timeframe, without developing toxicity.
The combination therapies used are determined by 1) patient comorbidities, 2) whether chemotherapy has been used in the preceding 6 months, and 3) the patient’s response to prior therapy. Also important in drug selection are potential toxicities, and this is a reason for a precise treatment window. Extended treatment with 5-FU, oxaliplatin, or irinotecan can cause liver injury. Steatosis is associated with all three agents, and can increase the risk of postoperative infection and morbidity. Steatohepatitis, which is inflammation and ballooning of hepatocytes, also may occur. Oxaliplatin is associated with sinusoidal injury and increased perioperative bleeding. Bevacizumab increases tumor response but brings with it the risk of perforation, fistula formation, and bleeding. Studies suggest, however, that when bevacizumab is carefully administered together with chemotherapy, there is no increased incidence of bleeding or wound complications after resection of liver metastases.[33,34]
The NCCN recommends that there be at least a 6-week interval between the last dose of bevacizumab and elective surgery. This corresponds to two half-lives of bevacizumab, with each half life being 20 days (range, 11–50 days). Because the goal is to “seize the moment” when the patient becomes resectable and avoid unnecessary hepatotoxic chemotherapy, the NCCN advises that the patient be evaluated every 2 months so that the clinician can assess the patient’s response to treatment and anticipate how soon resection can be performed.
Patients with the following characteristics are at risk for a poor outcome: 1) synchronous metastasis (which may be indicative of more disseminated disease, is more likely to involve an increased number of hepatic metastatic sites, and is more likely to be characterized by bilobar metastases); 2) a carcinoembryonic antigen level (CEA) > 200 mg/dL; 3) PET or CT imaging showing nonsolitary metastases and/or mesenteric/portal/retroperitoneal node involvement; 4) disease that does not appear to be resectable with clear margins; and 5) medical comorbidities.[10,24] Other factors that suggest a less-than-optimal response are a post-chemotherapy disease-free interval of < 12 months if the patient has received prior chemotherapy.
The NCCN recommends that, following surgical resection of the primary and metastatic lesion(s), patients receive adjuvant chemotherapy, for a combined pre- and post-operative total treatment period of 6 months. Unfortunately, more than half of patients with resected liver metastases experience disease recurrence within 2 years. Some patients will be able to undergo repeat metastectomy.
Patients with rectal cancer undergo similar evaluation and treatment planning, following current NCCN guidelines. Primary treatment (neoadjuvant or conversion) consists of 2–3 months of combination chemobiotherapy, with or without chemoradiotherapy, followed by staged or synchronous resection of the rectal lesion and metastases, or by chemoradiotherapy followed by surgery. Postoperatively, the patient should receive adjuvant chemoradiotherapy, for a total perioperative treatment duration of 6 months.
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