Advanced Colon and Rectal Cancer

Nancy Baxter MD PhD FRCSC FASCRS
Assistant Professor of Surgery
St Michael’s Hospital, University of Toronto

Colorectal cancer (CRC) is the second leading cause of cancer death in the United States ; in the year 2007 an estimated 153,760 people will be diagnosed with CRC and 52,180 will die of the disease ^ACS. Advanced CRC can be defined as disease that is metastatic at presentation, disease that progresses to become metastatic, or disease that is so locally advanced resectability is uncertain.

While 70% - 80% of patients present with resectable disease at diagnosis, about half of all patients develop metastatic disease at some point, and in most cases this is fatal. In the United States , approximately 75,000 patients undergo treatment for metastatic colorectal cancer annually ^Goldberg. Of note, chemotherapy given to treat advanced disease is primary (not adjuvant) therapy. (Adjuvant therapy specifically refers to treatment {chemotherapy, irradiation, hormonal therapy} given to increase the probability of cure after the primary therapy has been delivered.)

Until the past decade, the only effective chemotherapeutic option available to patients with metastatic CRC was 5-fluorourcil (5-FU). The use of infusional or bolus 5-FU / leukovorin was proven to prolong survival in patients with metastatic CRC by 4-6 months and delay occurrence or progression of symptoms, resulting in improvements in quality of life ^Young. Although 5-FU remains a key component of most current treatment strategies, numerous new chemotherapeutic and biologic agents have been proven effective and are approved for use in the United States ^Meyerhardt, including capcitebine, oxaliplatin, irinotecan, bevacizumab, and cetuximab (see glossary). The myriad potential drug combinations have lead to what is described as a “creative chaos” ^Goldberg in the management of metastatic CRC and a renewed excitement and focus on this disease in the medical oncology community. Although the optimal strategy is unlikely to be clearly defined (as the number of potential combinations continues to grow) patients benefit by having access to all drugs, have longer survival if treated before becoming symptomatic, and in some cases can become candidates for curative surgical resection if highly responsive.

Role of the Surgeon in the Patient with Metastatic Disease

1. Can the patient be cured? If so, in Stage IV patient should resection of metastatic disease be performed synchronously with the primary or in a delayed fashion? If not, might resection be feasible with significant tumor shrinkage after chemotherapy?

Although most patients who die of colorectal cancer have liver metastases, unfortunately only a minority of patients who develop liver metastases are candidates for potentially curative resection. These patients are of course heterogeneous, and individualized treatment strategies must be developed.

For Stage IV patients (patients who have metastatic disease at diagnosis) with potential for cure, resection of the liver and primary can achieve a 5-year survival of 25-38% and is the only treatment with curative potential ^Adam. Synchronous resection of the liver and primary can be performed safely, however not all patients are candidates; those with significant risk of morbidity and mortality, patients with locally advanced primary tumors, or the need for a major hepatectomy (resection of 3 or more segments) are likely better candidates for delayed hepatic resection, although this does depend on institutional experience. Patients with more than four liver metastases may benefit from receiving chemotherapy prior to surgery, however the number of metastases alone should not determine eligibility for resection - acceptable cure rates can be achieved in patients with more than four metastases, if all are resected ^Pawlik. Although in staged procedures, the primary is treated first, even this strategy has been challenged ^Mentha – resectability and survival rate may be improved by resection of liver metastases first, avoiding the morbidity of a combined operation, but treating the most critical site for long-term survival during the first procedure.

For patients presenting with metastatic disease, recent advances in therapy, including treatments directed at reducing the size of liver metastases, increasing the liver reserve, and decreasing the amount of liver parenchyma removed or destroyed, have resulted in an expansion of the number of patients eligible for curative resection. It is therefore essential that patients with metastatic disease are evaluated by a multi-disciplinary team, and that patients are reassessed after chemotherapy is initiated to determine change in status with respect to resectability with response to therapy; with current highly effective chemotherapy for advanced disease, up to 24% to 54% ^Folprecht of patients with unresectable isolated liver metastases are down-staged by chemotherapy and can undergo liver resection. Such patients have a 33% survival at 5 years ^{Adam et al}. The use of radiofrequency ablation (RFA) has expanded the group of patients who can be treated for potential cure, however, RFA even for solitary metastasis is associated with a higher local recurrence rate and shorter survival than hepatectomy. Therefore, RFA should not substitute for resection in patients who are eligible ^Aloia

2. If the with Stage IV disease cannot be cured, has the primary been resected? If not, should the primary be resected?

Elective resection in patients with Stage IV disease has been recommended in the past for asymptomatic patients to reduce complications due to the primary tumor, including bleeding, obstruction, and perforation. Population-based studies have demonstrated that close to 70% of patients presenting with Stage IV disease have cancer directed surgery. ^{Cook, Temple} However because of recent advances in medical palliation and endoluminal stenting, along with the rarity of certain complications, (bleeding in particular) this approach is increasingly being questioned. Data from case series ^{Ruo, Scoggins} indicate that the majority of patients managed non-operatively do not require surgical intervention. However, patients treated non-operatively in these series had a shorter life expectancy than those treated surgically and the studies were performed prior to the common use of the newer chemotherapeutic regimens. With new, more effective treatment strategies it may be more important to start therapy as soon as possible; immediate systemic treatment may, in some cases, down-size the metastatic disease and enable potential resection for cure. In patients who are asymptomatic with respect to their primaries, but have a heavy burden of metastatic disease, initial treatment with chemotherapy should be strongly considered -- in such a scenario quality of life and life expectancy will largely be determined by the progress of the metastatic disease, not the primary. However, with the increased life expectancy associated with more effective therapies, patients have a longer time period to develop complications related to their primaries and more may require surgical intervention in a delayed fashion. Stage IV patients represent an extremely heterogeneous group and therefore care must be individualized.

3. Is there a role for Hepatic Artery Infusion?

The role of hepatic artery infusion (HAI) in the era of highly effective chemotherapy for advanced colorectal cancer is unclear. HAI takes advantage of the differential perfusion of liver metastases (hepatic artery) and liver parenchyma (portal vein), and because drugs are extracted by the liver during first pass, there is less systemic toxicity. Floxuridine, an analogue of 5-FU is generally the drug of choice. Although benefits of HAI have been demonstrated in clinical trials in the metastatic setting and “adjuvant” setting (after resection of liver metastases), ^Kelly the technique requires expertise and experience and is commonly used only in centers with special interest. The role of HAI after liver resection is currently being evaluated in a randomized trial conducted by the NSABP.

4. Is there a role for cytoreductive surgery with intraperitoneal chemotherapy?

Approximately 3% of patients with colorectal cancer will develop isolated peritoneal metastases. Highly selected patients with peritoneal carcinomatosis from CRC – those patients with metastatic disease confined to the peritoneal cavity without evidence of wide spread hematogenous metastases – may be candidates for potentially curative cytoreductive surgery and intraperitoneal chemotherapy. Patients undergoing this treatment in expert centers have a reported median survival of 42 months ^Esquivel, and a randomized trial has demonstrated that this strategy results in better survival than non-operative treatment with 5-FU leukovorin. ^Verwaal Patients generally benefit only if complete cytoreduction (no macroscopic residual disease) is achieved, and high quality imaging is essential prior to surgery to predict individuals who are most likely to benefit. After recovery from surgery, best systemic therapy is generally recommended. Cytoreductive surgery remains controversial because of the significant toxicity associated with the procedure and the lack of evidence of benefit over treatment with newer chemotherapeutic agents. Nevertheless, this treatment may be appropriate in highly selected patients. As there are relatively few patients eligible for cytoreductive surgery, and the treatment is associated with substantial morbidity and mortality, patients should be referred to expert centers for consideration.

5. Are there important surgical considerations for patients undergoing treatment with new agents?

Bevacizumab has a long half-life (mean 20 days) and as this is an anti-angiogenic drug there are theoretical risks for wound healing after administration ^Thornton . There are few studies in this area, however a recent review, Scappiticci et al ^Scappiticci found that the use of Bevacizumab after surgery (28-60 days) was not been associated with an increased risk of wound complications. While the risk of wound complications was increased in patients having surgery during therapy with Bevacizumab (13% risk of wound complications in patients on Bevacizumab vs. 3.4% in patients not on the drug) the majority of patients did not suffer adverse sequelae. Of note, the literature in this area is sparse, and experience growing. For example, there have been recent case reports of delayed anastomotic leakage, up to 10 months after initial surgery in patients treated with Bevacizumab. ^{Abbrederis, Adenis} Patients receiving Bevacizumab also are at increased risk of ischemic events and this may be in part responsible for the increased risk of bowel perforation found in Bevacizumab trials ^Heinzerling. Perforation may also be a complication when there is rapid lysis of a transmural tumor in response to therapy.

In patients being considered for liver resection, pre-treatment with chemotherapy may be associated with peri-operative morbidity. Hepatic steatosis and steatohepatitis can occur with 5-FU therapy and irinotecan. Irinotecan-associated steatohepatitis may affect hepatic reserve and has been associated with increased morbidity and mortality after hepatectomy ^Zorzi. Although response to chemotherapy may be a critical determinant of resectability, both response rate and toxicity should be considered when selecting a particular chemotherapeutic regimen and considering duration of chemotherapy prior to surgery.

Because the rectum lies within a fixed anatomic structure, invasion of adjacent structures by the primary tumor occurs in 5-15% of patients. Less commonly, adjacent structures can be involved by primary colon cancers. Appropriate management dictates resection of the primary with adjacent attached structures, i.e. multivisceral resections when possible, as the majority of attachments between the primary and adjacent structures are malignant. Although in some cases adhesions are inflammatory, intraoperative assessment is inaccurate and cannot be relied upon. The literature supports this approach in terms of reduction of local recurrence and improvement in long-term survival ^Govindarajan, although the extensive resections necessary to resect such tumors may be associated with substantial morbidity. In a population-based study evaluating the use of multi-visceral resection for patients with adjacent organ involvement, only one-third of patients underwent a multivisceral resection ^{Govindarajan.} Those who underwent multi-visceral resection experienced significantly better long-term survival than those who did not, without an increase in short-term mortality.

Role of the Surgeon in Locally Advanced Disease

1. Pre-operative evaluation, decision making, and treatment

In every patient undergoing resection of a colorectal primary, the surgeon should determine extent of local invasion. Although some patients at laparotomy will have more extensive disease than predicted, a careful pre-operative evaluation with appropriate imaging should avoid many intraoperative surprises. For patients predicted to have adjacent organ involvement requiring multi-visceral resection for cure, care should be directed to achieving cure when technically possible, when such an approach can be tolerated by the patient, and when the extent of resection is within the wishes of a well-informed patient. Multispecialty involvement early in the assessment of such patients is key, and may include medical oncology, radiation oncology, gynecology, urology, hepatobiliary surgery, plastic surgery, neurosurgery, or orthopedic surgery depending on the pattern and extent of disease. Because care of such patients is complex, and treatment is associated with substantial morbidity and mortality, referral of patients to specialized centers should be considered when extensive resections are required. Attention should be paid to ensuring adequate reconstruction is planned to optimize perioperative recovery and minimize the impact of surgery on post-operative function.

Patients who present with locally advanced colorectal cancer have a substantial risk of non-R0 resections. In rectal cancer, the use of neo-adjuvant chemoradiotherapy is accepted as standard in such patients, and has been demonstrated to decrease local recurrence as compared with post-operative therapy ^Sauer. Given the availability of highly active chemotherapeutic agents, neo-adjuvant chemotherapy (where months of chemotherapy are given before surgery) for locally advanced colon and rectal cancer may have a role. Advantages of a neo-adjuvant approach to chemotherapy include increasing the rate of complete tumor resection, and gauging response to therapy. Potential disadvantages include the possibility of tumor progression or tumor perforation as well as the potential to increase peri-operative morbidity rates, and a possible increase in patient anxiety. ^Glynne-Jones The role of neo-adjuvant therapy for colorectal cancer is being studied in a number of phase II trials.

2. Intra-operative evaluation, decision making and treatment

Intra-operatively, the surgeon must assess the abdomen for evidence of metastatic spread and local invasion of adjacent structures. Although adhesions between the tumor and adjacent organs may not be involved in cancer, failure to perform an enbloc resection is associated with an increased risk of local recurrence and worse survival. In many cases, an en bloc resection can be performed without substantially increasing the morbidity of the procedure, for example, segmental involvement of the small bowel, or tumor adherent to the dome of the bladder. However, in other cases, such as duodenal involvement or involvement of the trigone, appropriate therapy may greatly add to the complexity of the procedure, and significantly alter quality of life for the patient. In cases where the extent of disease was unpredicted, or if surgery is performed for urgent indications, the most prudent course of action may be to deal with complications or impending complications of the primary (for example diverting a patient at high risk of obstruction) without resection of the primary, with a plan to perform a more extensive procedure when adequately prepared and after consideration of neo-adjuvant therapy. Some patients with extensive disease, for example those requiring a pancreaticoduodenectomy, sacrectomy, or cystectomy with colorectal resection may be best treated at specialized centers and may be candidates for intraoperative radiotherapy where available.

Fluoropyrimidines

5-Fluoruracil: Anti-metabolite that inhibits RNA processing, protein synthesis and cell division by inhibiting the formation of thymidylate. Can be given using an intermittent bolus or a continuous infusion regimen. Proven effective in the metastatic setting as compared to best supportive care. Main dose-limiting toxicity is diarrhea. Severe toxicity can rarely be experienced by patients with dihydropyrimindine dehydrogenase (DPD) deficiency, the main enzyme responsible for catabolism of 5-FU. The drug is usually administered with Leukovorin, which stabilizes the binding of 5-FU to thymidylate synthase, enhancing effectiveness.

Capecitabine (Xeloda):Oral pro-drug of 5-FU. Partially metabolized in the liver. Broken down to 5-FU in the tumor where effect is similar to infusional 5-FU. Side effect profile similar to 5-FU, but increased risk of hand-foot syndrome.

Oxaliplatin

This is a platinum-based chemotherapeutic agent, and effectiveness is better in 5-FU combinations than alone. Neuropathy is a common toxicity - the majority of patients experience acute neurotoxicity which may occur at the time of infusion, is worse with exposure to cold, and tends to be self-limited. Chronic neuropathy is dose dependent, and occurs in 12-15% of patients.

Irinotecan (Camptosar, CPT-11)

Topoisomerase 1 inhibitor with a high level of activity in CRC. Proven of benefit in advanced CRC. Not used in the adjuvant setting. Combinations with 5-FU (FOLFIRI, IFL), Capecitabine (CAPIRI), and Oxaliplatin (IROX) common, but can be used as single drug. Diarrhea is common.

Monoclonal Antibodies

Bevacizumab: Vascular endothelial growth factor (VEGF) inhibitor. VEGF is critical to tumor angiogenesis and growth and VEGF is over expressed in many cancers. Bevacizumab is a recombinant humanized monoclonal antibody to VEGF and is generally used in combination with chemotherapeutic agents. Clinically meaningful improvement in survival over IFL in randomized trials have been demonstrated. Risk of bowel perforation – 1.5%.

Cetuximab: Epithelial Growth Factor Receptor (EGFR) Inhibitor. EGF is important for tumor growth and is over expressed in many patients with colorectal cancer. Cetuximab is a monoclonal antibody to EGFR. Specific skin rash associated with therapy – predicts tumor response, however EGFR levels do not. Recent trials have demonstrated clinically significant improvement in outcome even in heavily pretreated populations.

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