Colorectal Cancer: Metastatic (Palliation)

Abstract

• Approximately 20 % of colorectal cancer patients present with established distant metastases. A diagnosis of stage IV disease allows for appropriate operative and oncologic planning.

• Among these patients there is enormous heterogeneity with respect to sites of disease, extent of disease, symptoms, performance status, and comorbidities. The clinical spectrum at the time of diagnosis ranges from the asymptomatic patient with a single metastatic lesion to the rapidly deteriorating patient with colon obstruction and advanced, multiorgan metastases.

• While treatment algorithms may exist for some forms of metastatic disease such as a solitary liver lesion, others are still being defined.

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Introduction

• Approximately 20 % of colorectal cancer patients present with established distant metastases. A diagnosis of stage IV disease allows for appropriate operative and oncologic planning.

• Among these patients there is enormous heterogeneity with respect to sites of disease, extent of disease, symptoms, performance status, and comorbidities. The clinical spectrum at the time of diagnosis ranges from the asymptomatic patient with a single metastatic lesion to the rapidly deteriorating patient with colon obstruction and advanced, multiorgan metastases.

• While treatment algorithms may exist for some forms of metastatic disease such as a solitary liver lesion, others are still being defined.

• Despite considerable progress in the treatment of advanced colorectal cancer, the vast majority of stage IV patients are not curable by current treatment protocols. A recent analysis of data from the SEER population-based database estimates that the 5-year survival rate for stage IV patients diagnosed between 1991 and 2000 was 8 %.

• Despite a low overall cure rate, treatment options are available to extend survival and enhance quality of life. Systemic chemotherapy, endoscopic treatments to palliate obstruction, surgical diversion, and surgical resection all have important roles in treatment of stage IV patients.

• Treatment approaches must be individualized based on the extent and resectability of local and distant disease, the presence or absence of bowel obstruction, performance status, and comorbidities.

• For patients with good performance status and minimal symptoms from their primary cancers, standard treatment is systemic chemotherapy, which is well documented to increase survival and quality of life.

• Surgical resection of the primary tumor and if indicated of the metastatic lesions can provide excellent palliation and in some cases can provide lasting cure.

• First-line therapy with either FOLFOX or FOLFIRI now yields major responses in up to 50 % of previously untreated patients and achieves minor responses or stable disease in an additional 20 % of patients. Multiple effective drug combinations are available as well, and second-line chemotherapy has become more effective and more likely to impact survival.

• Over the past 10 years, the median survival for patients with metastatic disease who are treated with chemotherapy has improved from 12–14 to 21 months. Although cure from chemotherapy alone remains extremely rare, effective chemotherapy combined with aggressive surgery may be increasing the overall cure rate.

Biology of Metastatic Disease

• Metastasis is defined as the spread of malignant cells from a primary tumor to a distant organ. It is estimated that 90 % of all cancer deaths are a result of metastasis.

• The biologic process of metastasis is poorly understood. The process relies on properties of the tumors cells, as well as the microenvironment of the primary and secondary sites. A series of major events must occur (Fig. 47.1).

  Fig. 47.1

  

  Schematic illustrating the multistep process involved in the development of metastasis (With permission from DeVita VT Jr., Hellman S, Rosenberg SA. Cancer: Principles and Practice of Oncology, 6th ed., Lippincott Williams and Wilkins, copyright 2001)

• The first step is tumorigenesis, which occurs after the initial malignant transformation. The tumor proliferates into a small mass of heterogeneous cells that are of varying metastatic or malignant potential. These tumor cells undergo multiple and sequential genetic changes, characterized by the appearance of oncogenes and a decrease in tumor suppressor genes. As the tumor grows beyond 1 mm in diameter and becomes relatively hypoxic, angiogenesis is initiated. The process of tumor angiogenesis is tightly regulated by pro- and anti-angiogenic factors secreted by both the tumor and its environment.

• As tumors successfully grow, suppressors of angiogenesis are inhibited and pro-angiogenic factors predominate, resulting in neovascularity and further growth of the tumor. Some tumors may grow by utilizing other existing blood vessels in nearby tissues.

• In the next step, some cells will develop an invasive phenotype. Most researchers believe that there is a selection process resulting in the clonal expansion of certain cell subpopulations with growth advantages and invasive properties.

• Malignant invasion is characterized by downregulation of cell adhesion, resulting in detachment of the cell from the primary tumor mass and the extracellular matrix. Stromal invasion is accomplished through interactions with the basement membrane, including adhesion, proteolysis, and migration, ultimately resulting in detachment and invasion through the basement membrane. This invasive phenotype also enables these cells to enter thin-walled lymphatics and vasculature, allowing access to systemic circulation.

• Once inside the vascular system, cells or cell clumps (emboli) are circulated and must survive hemodynamic filtering as well as immune surveillance. They must then arrest in a distant organ. There is likely a complex interaction between the malignant cell and the endothelium or exposed basement membrane, allowing cell arrest. Once arrested in a tissue bed, the cells extravasate into the tissue, enabling formation of a metastatic focus.

• These metastatic cells can become dormant or proliferate; what determines this fate is not fully understood. Growth in the distant organ after deposition is a major limiting factor in the formation of metastasis.

• Recent studies have shown differences in the genetic fingerprints of matched primary tumors and their lymph node metastasis suggesting that tumors may undergo continual mutagenesis.

• This finding appears to confirm that there are genes specific to tumorigenesis, invasion, angiogenesis, and other steps.

• These discoveries provide a sense of the future challenge in elucidating the multiple, stepwise, and specific changes that regulate a cell’s ability to metastasize. Advances in this field will have obvious and profound implications for the treatment of cancer.

Diagnosis/Staging

• Spiral CT scanning of the chest/abdomen/pelvis is a highly accurate and efficient method of detecting metastases.

• PET scanning detects occult disease not seen on CT scan in 20 % of stage IV patients and should be considered if such findings might affect patient management.

• Increasingly, more patients are undergoing combination CT/PET scans to evaluate both the primary and metastatic lesions as this combined modality allows for better localization of tumor deposits and can assist with operative planning as well as radiation-based therapy.

• Once the extent of disease workup is complete and distant metastases have been documented, the surgeon must make three important judgments.

• First is whether the patient is fit for aggressive treatment. Patients with poor performance status or serious comorbidities may not tolerate chemotherapy or major surgery.

• Second is whether the primary tumor presents a clinically significant risk of bowel obstruction. Symptoms, radiographic findings, and endoscopic findings are important considerations. If the proximal colon is not dilated on radiographic studies and a colonoscope can traverse the tumor, it is generally safe to begin treatment with chemotherapy.

• The third determination is whether the patient’s metastases are surgically resectable, and the patient can be treated with curative intent. If complete resection of all disease can be expected, then surgical intervention should be attempted.

Multidisciplinary Evaluation

• Management of patients with advanced disease is complex, and multidisciplinary evaluation can be helpful in determining initial therapy. The multidisciplinary team or “tumor board” ideally involves a surgeon, medical oncologist, radiation oncologist, pathologist, radiologist, and gastroenterologist.

Palliative Management of the Primary Cancer: Laser, Fulguration, and Stents

Incidence and Presentation

• 8–29 % of patients with colorectal cancer initially present with symptoms of partial or complete bowel obstruction.

• In a review of 713 obstructing carcinomas, 77 % were left-sided and 23 % were right-sided cases.

• The majority of patients with obstructing colorectal carcinomas have either stage III or stage IV disease.

• Acute malignant colon or rectal obstruction is an indication for emergent surgical intervention. However, these emergency operations are associated with a mortality rate of 15–34 % and a morbidity rate of 32–64 % despite advances in perioperative care.

• Therefore, alternative palliative endoluminal strategies aimed at relieving obstruction have gained increasing popularity.

• The initial symptoms of bowel obstruction include mild discomfort and a change in bowel habits. With disease progression and luminal narrowing, the symptoms may worsen ranging from crampy abdominal pain, abdominal distension, nausea, abdominal tenderness, and obstipation.

• Leukocytosis is a concerning finding and may indicate a near or complete obstruction. Without treatment, the process can progress to complete obstruction, ischemia, and perforation. The risk of cecal perforation is greatest in patients who have a competent ileocecal valve, which does not allow decompression of the large intestine into the proximal small intestine.

• In the setting of metastatic cancer, the clinician must first answer the following critical question, “is the colon or rectal obstruction a contraindication for systemic chemotherapy or radiotherapy?”

• The degree of obstructive symptoms, endoscopic, and radiographic findings are key elements to consider when answering this question. If the patient has minimal symptoms, the cancer can be traversed endoscopically, and there is no radiographic evidence of high-grade obstruction and many patients with partially obstructing colon and rectal cancers will tolerate aggressive chemotherapy.

• In those patients with partially obstructing rectal cancers, the addition of radiation therapy is also well tolerated and can be highly effective.

• Patients must be instructed to monitor their symptoms closely and to report any signs of worsening obstruction immediately.

• For patients with advanced obstruction, nonsurgical palliative options include laser therapy, fulguration, and colonic self-expanding metal stents. If less invasive endoluminal strategies are not successful in patients with nonresectable malignant obstruction of the colon and rectum, surgical creation of a palliative proximal diverting stoma or intestinal bypass should be performed.

Laser Therapy and Fulguration

• Laser therapy has been utilized for palliation of obstructing rectal cancers. The immediate success rate in treating obstructive symptoms is in the range of 80–90 %.

• However, laser therapy is practical only for treating cancers of the distal colon and rectum and is rarely used to treat proximal lesions. In addition, multiple sessions are often required in order to achieve lasting relief of symptoms.

• Serious complications like bleeding, perforation, and severe pain have been reported in 5–15 % of patients, especially those undergoing multiple treatment sessions.

Self-Expanding Metal Stents

• Since their introduction in 1991, colonic stents have become an effective method of palliation for obstruction in colorectal cancer patients, especially those with unresectable metastatic disease.

• Stents can be placed in patients using minimal sedation and allow endoscopic assessment of the proximal colon. Moreover, these stents can be placed across relatively long lesions by overlapping stents in a “stent-within-stent” fashion.

• A systematic review from 1990 to 2000 included 29 case series and evaluated technical and clinical success, complications, and reobstruction.

• Stent insertion was attempted in 598 cases and was technically feasible in 551 (92 %) cases and clinically successful in relieving obstruction in 525 (88 %) cases.

• Palliation of obstruction was achieved in 302 (90 %) of 336 cases. Stent placement as a “bridge to surgery” was successful in 223 (88 %) of 262 insertions of which 95 % had a one-stage surgical procedure.

• There were three deaths (1 %). Perforation occurred in 22 cases (4 %). Stent migration was reported in 54 (1 %) of the 551 technically successful cases. Stent reobstruction occurred in 52 (10 %) of the 525 clinically successful cases and trended toward a higher incidence of reobstruction in the palliative treatment group.

• There is limited data evaluating stent placement proximal to the splenic flexure. In a recent publication, colonic stenting was attempted in 97 patients with malignant large-bowel obstruction. Sixteen (17 %) patients had lesions proximal to the splenic flexure (eight ascending, eight transverse colon). Stenting was successful in relieving obstruction in 14 (88 %) of these patients.

• Complications reported in the literature for colonic and rectal stents include stent malpositioning, stent migration, tumor ingrowth (through the stent interstices), tumor overgrowth (beyond the ends of a stent), perforation, stool impaction, bleeding, tenesmus, and postprocedure pain. Stenting of cancers in the mid to low rectum may result in urgency, pain, and incontinence. While the complications associated with stents and other less invasive endoluminal strategies should not be taken lightly, one must keep in mind that emergency operations for malignant colon and rectal obstruction have a mortality rate of 15–34 % and a morbidity rate of 32–64 %.

Surgical Management of the Primary Cancer: To Resect or Not to Resect?

• The role of surgical resection of the primary colon or rectal cancer in patients with unresectable metastases is controversial, and no randomized controlled trials have demonstrated a survival benefit for bowel resection in stage IV patients.

• Randomized trials of 5FU-based chemotherapy vs. best supportive care, conducted in the 1990s, have shown that stage IV patients receiving systemic chemotherapy have increased length and quality of life.

• At this time, standard management for patients with unresectable metastatic colorectal cancer is systemic chemotherapy, at least initially.

• The proper use of elective colon and rectal resections in nonobstructed patients is a source of continuing debate. Loss of performance status, risk of surgical complications, and delay in chemotherapy are potential downsides to palliative surgical resection.

• On the other hand, elective operations have a far lower morbidity than emergency surgery. In addition, there are increased risks and potential complications associated with operations performed on patients who develop large-bowel obstruction while receiving chemotherapy or who present with more advanced disease after multiple cycles of ineffective chemotherapy.

• From the limited data in the literature, it is clear that initial colon resection is frequently practiced, particularly for patients with colon primaries and with less extensive metastatic disease. However, it is difficult to assess the impact of colon and rectal resection on symptom control, tolerance to subsequent chemotherapy, quality of life, or survival from these studies.

• A recent meta-analysis evaluating patients with stage IV colorectal cancer treated with chemotherapy combined with and without surgical resection revealed prolonged survival in patients undergoing palliative surgical resection and chemotherapy when compared to chemotherapy alone. Chemotherapy regimens included 5-flourouracil, oxaliplatin, and irinotecan.

• Eight retrospective studies with a sum total of 1,062 patients met the inclusion criteria for this study. The median survival for palliative surgical resection combined with chemotherapy ranged from 14 to 22 months (data extracted from studies with 100 % patient participation in systemic chemotherapy). The median survival for chemotherapy alone was 6–15 months.

• The estimated standardized median difference in survival was 6.0 months in favor of palliative surgical resection (standardized difference 0.55; 95 % CI 0.29, 0.82; p < 0.001). In addition, patients managed with chemotherapy alone were more likely to experience a complication related to the primary tumor (95 % CI 1.7, 34.4; p = 0.008). There was no difference in the incidence of metastatic disease tumor burden becoming more favorable and amenable to curative resection after systemic chemotherapy in either group (0.85; 95 % CI 0.40, 1.8; p = 0.662).

• There are obvious limitations of this meta-analysis given the retrospective nature of the studies available for review as well as the chemotherapy regimens utilized in these studies not being equivalent to current regimens.

• There is little published data evaluating the effectiveness of radiotherapy in palliative management of stage IV rectal cancer. Crane and colleagues reported 55 patients who received chemoradiotherapy and 25 patients who received chemoradiotherapy followed by surgery. The majority of both groups received systemic therapy (78 % of patients).

• Pelvic symptom control was high (81 %) in the chemoradiotherapy group but not as high as in the chemoradiotherapy combined with surgical resection group (91 %). There was limited data on the durability of symptom control over time.

• To summarize the treatment options for stage IV patients with unresectable metastases, treatment algorithms are shown for patients with stage IV colon cancer (Fig. 47.2) and stage IV rectal cancer (Fig. 47.3). The algorithms show multiple treatment options, reflecting the heterogeneity of disease presentation. The major variables to consider are location of the primary tumor, degree of colon and/or rectal obstruction, extent of metastatic disease, and fitness of the patient for surgery.

  Fig. 47.2

  

  Treatment algorithm for patients with stage IV colon cancer: use of palliative colon resection

  Fig. 47.3

  

  Treatment algorithm for patients with stage IV rectal cancer: use of palliative rectal resection

Liver Metastasis

• Overall, it is been estimated that about 10 % of all patients with colorectal liver metastases are candidates for potentially curative hepatic surgery (with 5-year survival ranging from 28 to 45 %). The remaining majority of patients receive palliative therapy.

• This underscores the importance of patient selection in determining optimal treatment and highlights the fact that the majority of patients with liver metastases have unresectable disease.

• With improvements in chemotherapy, surgical technique, and ablative techniques, the number of patients eligible for hepatic surgery is on the rise.

Natural History of Untreated Liver Metastases

• To understand the impact of therapy, the natural history of untreated disease must be reviewed.

• Hepatic metastases left untreated result in median survivals of 5–10 months; long-term survival was rarely seen.

• Patients with limited metastases isolated to the liver, who would otherwise be potential candidates for surgery, had 3-year survival of 14–23 % and 5-year survival of 2–8 %.

Diagnosis

• After a diagnosis of hepatic metastases is made, careful evaluation accurately stages the patient. Complete cross-sectional imaging of the abdomen and pelvis with triple-phase CT and/or MRI is essential to rule out extrahepatic disease.

• The additional advantage of routine chest CT is low compared to that of a plain chest X-ray but should be considered. F-FDG positron emission tomography (PET) scanning is routinely performed because of prospective data documenting its utility (changes management decisions in patients with recurrent colorectal carcinoma 20–50 % of the time).

• The major strength of PET scanning appears to be the detection of occult extrahepatic disease. PET/CT provides more accurate tumor localization.

• Once the issue of extrahepatic disease has been addressed, high-quality imaging of the liver is essential in determining bulk of disease and resectability.

• CT scans are the most common modality used to address liver disease, and with modern dynamic helical scanning techniques, this remains the mainstay of hepatic imaging.

• Routine CT scans can now evaluate the liver in combination with CT angiography or triphasic imaging of the parenchyma through various phases of intravenous contrast circulation.

• Ultrasound is excellent at distinguishing neoplastic tumors from benign lesions such as cysts, focal nodular hyperplasia, or hemangiomata; can evaluate the relationship of specific lesions to major vascular structures and the biliary tree; and is useful when performing intraoperative ablative procedures.

• MRI is an excellent method for characterizing liver multiple hepatic lesions; distinguishing malignant lesions from cysts, hemangiomata, and other benign lesions; and evaluating relationships of tumor to the biliary tree (via magnetic resonance cholangiopancreatography – MRCP) and to hepatic vasculature. High-quality MRI and triple-phase CT are probably equivalent for evaluating extent of liver disease and as aids in surgical planning.

Treatment Options

• In the patient who presents with liver metastases, the first consideration must be whether the liver disease is curable. The second consideration is whether the patient’s disease if initially unresectable can be made amenable to surgery or ablative procedures with the addition of systemic chemotherapy.

Chemotherapy

• With the development of irinotecan, oxaliplatin, hepatic arterial infusional chemotherapy with FUDR, and newer molecular-based therapies, there are now more effective chemotherapeutic options for these patients.

• Irinotecan (CPT-11) in conjunction with 5FU/LV (FOLFIRI) is more effective than 5FU/LV alone for treatment of metastatic colorectal cancer response rates of 40 % and modestly improved survival (median 15–17 months vs. 12–14 months).

• Oxaliplatin/5FU/LV (FOLFOX) produced response rates in excess of 50 % (compared to 22 % for 5FU/LV). Early analyses of comparisons of irinotecan/5FU/LV to FOLFOX have so far shown FOLFOX to yield superior response rates.

Biomarker Targeted Therapy

• Epidermal growth factor receptor is a member of the tyrosine kinase family, and its activation stimulates many cancer-related processes such as proliferation, angiogenesis, invasion, and metastasis.

• Monoclonal antibodies that target epidermal growth factor receptor (EGFR) have increased the treatment options for patients with metastatic colorectal cancer.

• Several studies have found an association between a KRAS mutation and a lack of response to EGFR-directed therapy. The importance of defining the KRAS status of the primary tumor has provided oncologists with important information about response to treatment.

• The addition of cetuximab to FOLFIRI, in patients with metastatic colorectal cancer, improved overall survival (OS) by 3.5 months in KRAS wild-type patients. We are now seeing median survivals in excess of 20 months.

Hepatic Arterial Infusion

• Hepatic metastases derive their blood supply largely from the hepatic arterial branches. Thus hepatic artery infusional chemotherapy (HAI) has an advantage over systemically delivered chemotherapy as the drugs used in HAI have a higher therapeutic index due to high first-pass hepatic extraction and high systemic clearance and fewer systemic side effects.

• The most commonly used agent for HAI is fluorodeoxyuridine (FUDR), which has a 90 % hepatic extraction ratio, while this is beneficial for isolated hepatic disease, it limits treatment of occult extrahepatic disease. This can be addressed by giving additional systemic agents or by using 5FU via the hepatic artery with a higher “spillover” effect into the systemic circulation.

• Two meta-analyses of the first seven trials confirmed the increased response rates, and both showed a modest survival benefit.

• Finally, a meta-analysis of FUDR-HAI vs. systemic chemotherapy for unresectable liver metastases from colorectal cancer that included results from ten RCT has shown a greater tumor response rate with FUDR-HAI when compared with systemic therapy; however, this did not translate to a survival advantage over 5FU-based systemic therapy.

• One explanation for the lack of survival advantage is while control of hepatic disease was excellent with HAI, there was significant extrahepatic failure. FUDR while an effective agent for treating liver metastases can have liver-related complications including biliary sclerosis (18–29 %). Finally, the placement of the HAI catheter is an invasive procedure, and technical complications include primary catheter failure, catheter-related thrombosis, and infection.

• Many phase I and II trials are now evaluating combinations of HAI FUDR or oxaliplatin with systemically administrated 5FU/LV with irinotecan and/or oxaliplatin. Even in pretreated patients, impressive response rates in excess of 80 % are being seen.

• The combination of HAI and systemic 5FU/LV has further improved transformation rates of previously isolated unresectable colorectal liver metastasis into resectable lesions in as many as 26 % of cases.

Resection

• With effective systemic therapies, ablative techniques and treatment modalities aimed at “downstaging” the liver disease, more patients can be made amenable to resection.

• Mortality rates for hepatectomy for metastatic colorectal cancer are uniformly 5 % or less (Table 47.1).

  Table 47.1 Outcome of patients undergoing pulmonary metastasectomy for colorectal cancer

• Morbidity has been reported between 20 and 50 %.

• Liver failure and significant hemorrhage are now distinctly uncommon. In a review of more than 1,800 liver resections (57 % of a lobe or greater) over the last decade, the median hospital stay was 8 days, morbidity was 45 %, and mortality was 3 %.

• Major institutional and multi-institutional reviews have now clearly documented the 5-year survival of patients undergoing hepatectomy for metastatic colorectal cancer ranges from 25 to 40 %, 10-year survival ranges from 20 to 26 %, and median survivals range from 24 to 46 months.

• These results obviously compare favorably to the results of no treatment (median survival 5–10 months) and to those of chemotherapy (median survival 10–14 months).

• True long-term cure from chemotherapy is extraordinarily rare, while at least half of the long-term survivors after liver resection are disease-free and presumably cured. For these reasons, no trial has ever compared hepatectomy to no treatment or chemotherapy alone. Liver resection for resectable hepatic colorectal metastases is the treatment of choice.

Patient Selection

• Many studies of patients undergoing liver resection for isolated hepatic metastases have evaluated prognostic factors to help select those patients most likely to benefit from hepatectomy and, conversely, to identify those unlikely to benefit.

• The two most consistent negative prognostic factors are the presence of extrahepatic disease and the inability to resect all tumor; these two factors remain contraindications to hepatectomy. The exception to this rule is the patient with limited pulmonary metastases or colonic anastomotic recurrence, who may undergo combined resections with some success.

• A list of other poor prognostic factors exist; these include lymph nodes involved by the primary colorectal tumor, synchronous presentation (or shorter disease-free interval), larger number of tumors, bilobar involvement, CEA elevation greater than 200 ng/ml, and involved histologic margins.

• While it appears to be true that the stage of the primary tumor, the interval in which metastatic disease has developed, and the bulk of tumor in the liver (measured by size, number, and/or CEA level) can provide prognostic information on outcome after hepatectomy, none of these findings in and of themselves preclude the potential for long-term survival.

Margin Status

• The importance of obtaining negative margins with hepatectomy has been demonstrated in multiple studies showing improved disease-free and overall survival.

• Wide resection margins with >1 cm clearance is desirable; however, a consensus statement from the Society of Surgical Oncology concluded that while wide margins of >1 cm are desirable and should be sought, anticipation of a close margin should not preclude a resection.

• As a result, a more recent study examined the difference in outcomes between those patients with R0 resections vs. R1 resections. When coupled with SCT, the R1 resection group has similar 5-year overall survival rates to the R0 resection group (57 % vs. 60 %, p = 0.12). Intrahepatic recurrence demonstrated a higher recurrence of 28 % for the R1 resection group vs. 17 % for the R0 resection (p = 0.004) group.

Recurrence

• Recurrence following hepatectomy for colorectal metastases is common, occurring two-thirds of patients.

• In patients who do recur, the liver is the most common site of recurrence and is involved approximately 45 % of the time. Most of these recurrences are isolated to the liver. Other common sites are lung, bone, and various intra-abdominal sites.

• Currently, at least 14 series reporting on more than 700 patients have documented that repeat hepatectomy for metastatic colorectal cancer is safe and effective in well-selected patients. Mortality is less than 5 %, median survival from the time of the second liver resection ranges from 23 to 46 months, and 5-year survival ranges from 30 to 41 %.

• Because of the potential for further effective therapeutic interventions after primary liver resection, patients eligible for such treatment should be followed with serial CEA and imaging studies to detect recurrences at an early and potentially treatable phase.

• Since recurrence after hepatectomy for metastatic colorectal cancer is common, there is a sound rationale for use of adjuvant therapy.

• A 2008 EORTC trial showed significant benefit to perioperative FOLFOX therapy.

• Because the large majority of patients with hepatic colorectal metastases are technically unresectable, the development of more effective chemotherapy has inspired many oncologists to employ a “neoadjuvant” chemotherapy strategy in an attempt to render patients resectable.

• In a series from France, 701 patients with unresectable liver metastases received chronomodulated 5FU/LV and oxaliplatin. Ninety-five (14 %) of these patients became resectable, secondary to chemotherapeutic response, and underwent staged resection. The resections employed techniques such as portal vein embolization and intraoperative ablation to extirpate all tumors and achieved an actuarial 5-year survival rate of 35 %.

Ablative Procedures

• Other methods of tumor destruction utilizing thermal ablation techniques have also been developed to treat and palliate those tumors that are not amenable to resection.

• Cryotherapy has been used for decades and employs the use of probes to freeze tumors and surrounding normal hepatic parenchyma. Cryotherapy generally requires a laparotomy, and complications such as bleeding, liver cracking, and a cryoshock phenomena characterized by thrombocytopenia and disseminated intravascular coagulation can occur.

• Radiofrequency ablation (RFA) and microwave ablation (MWA) probes have been developed that can heat liver tumors and a surrounding margin of tissue to create coagulation necrosis. RFA and MWA can be employed percutaneously, laparoscopically, and at laparotomy under ultrasound, CT, or MRI guidance. Furthermore, RFA has low morbidity that generally ranges around 10 % and is rarely serious.

• RFA can be used near blood vessels, but major bile ducts can be seriously injured, limiting the use of RFA in central tumors situated near major bile ducts.

• Local recurrence following RFA is a significant problem and appears to be strongly correlated with tumor size. Generally, recurrence is more common in tumors greater than 4 or 5 cm in diameter and in tumors abutting major blood vessels.

• Perhaps the greatest application of ablative techniques will be in their use as additions to resection in patients with multiple bilobar tumors.

• Yttrium-90 microspheres is a way of delivering a pure beta-emitting form of radiation to an unresectable liver lesion without suffering the locoregional side effects of external beam radiation. The microspheres are most often administered via an angiographic-guided catheter placement. The procedure first requires accessible feeding vessels that allow for treatment of the lesions, but it is imperative that healthy liver and lungs are excluded and therefore appropriate treatment dosing is critical.

• The first study to combine radioembolization (REB) with systemic chemotherapy (SCT) randomly assigned patients to either treatment with SCT or with REB plus SCT. The overall median survival was 29.4 months in the study arm vs. 12.8 months in the SCT alone arm. This trial and others show promising results in patients with metastatic colorectal cancer.

Lung Metastasis

• Approximately 10 % of patients with colorectal cancer develop pulmonary metastasis. The vast majority of patients with metastatic colorectal cancer to the lung have advanced disease and are therefore treated with systemic chemotherapy or best supportive care.

• Approximately 11 % of these individuals will have isolated pulmonary metastases. Patients with isolated or limited pulmonary may be considered candidates for pulmonary metastasectomy.

• Modern series of lung resection for metastatic colorectal cancer report operative mortalities of less than 2 %. Five-year survival rates range from 16 to 64 % but generally cluster around 30–40 %.

• Most studies evaluate factors associated with outcome; however, given the limited number of cases, the statistical power of these studies to detect significant factors is limited.

• The most commonly cited significant factors associated with adverse outcomes include the number and size of pulmonary metastasis, short disease-free interval (DFI), elevated CEA, and incomplete resection.

• The use of video-assisted thoracoscopic surgery (VATS) has increased significantly and is often used in metastasectomy when a minimal parenchymal resection is necessary.

• Radiation therapy for colorectal cancer pulmonary metastasis has been of limited utility in the past due to radiation-induced pneumonitis, rib and spinal fractures, and skin toxicities.

• However, these toxicities can be minimized with the advent of robotic-assisted Gamma Knife radiotherapy or “CyberKnife.” Initial reports appear to have minimal toxicity associated with single-session lung radiotherapy using robotic image-guided real-time respiratory and tumor tracking. This is an exciting field of research and may become an additional therapeutic modality in the future. However, the outcome and efficacy data is limited at this time, and the associated cost of robotic image-guided radiotherapy will be a limiting factor in widespread availability.

Peritoneal Metastasis

• Peritoneal carcinomatosis represents one of the most challenging presentations of metastatic colorectal cancer. The peritoneal surface is involved in approximately 10–15 % of colorectal cancer patients at time of initial presentation (synchronous metastases) and in 20–50 % of patients who develop recurrence (metachronous metastases).

• As a site of colorectal cancer metastasis, the peritoneal surface ranks second only to the liver. It is characterized by intraperitoneal spread of metastatic nodules. Peritoneal metastasis occurs by direct implantation of cancer cells via one of the four mechanisms: (1) spontaneous intraperitoneal seeding from a T4 colorectal cancer that has penetrated the serosal surface of the colon, (2) extravasation of tumor cells at the time of colon perforation from an obstructing cancer, (3) iatrogenic tumor perforation through an area of serosal injury or enterotomy at the time of colon resection, and (4) leakage of tumor cells from transected lymphatics or veins at the time of colon resection.

• The risk of peritoneal metastasis is therefore highest in the setting of locally advanced cancers.

• Peritoneal metastases are clinically important because of their frequent progression to malignant ascites and/or malignant bowel obstruction.

• Preoperative detection of peritoneal metastases is not reliable. Noninvasive imaging frequently misses small peritoneal lesions, even when these are widely disseminated. The sensitivity of CT scanning for lesions smaller than 5 mm is only 28 %, as compared to 70 % for lesions 2 cm or greater. Thus, indirect signs such as bulky primary tumor, ascites, or bowel obstruction are important clues.

• The utility of MRI in diagnosis of peritoneal carcinomatosis beyond that of CT is largely unknown, and PET scans are of limited value.

• Unfortunately, in the majority of cases, diagnosis is made at the time of primary resection.

• The extent of carcinomatosis is a major prognostic factor and is best assessed by either laparoscopic or open exploration. Two different peritoneal carcinomatosis staging systems (Gilly’s classification and Peritoneal Cancer Index of Sugarbaker) can be used to assess the extent of carcinomatosis.

• Standard management of patients known to have peritoneal metastases at initial presentation is systemic chemotherapy. Colon resection plays an important role for patients with obstructing primary cancers and also for patients with occult metastases that are first detected in the operating room.

• Patient survival is highly variable, depending on the extent of metastatic disease and response to chemotherapy. Contemporary combination chemotherapy regimens have significantly greater efficacy and can produce long periods of disease control in certain patients.

• Despite the grim prognosis for patients with peritoneal carcinomatosis from colorectal cancer, a subset of patients once thought unsalvageable are now being considered for surgery with curative intent. Pioneered by Sugarbaker, the goal of cytoreductive surgery and intraperitoneal (IP) chemotherapy is to remove all macroscopic disease with peritonectomy procedures and visceral resections followed by perioperative IP chemotherapy to destroy residual microscopic disease. IP delivery offers a pharmacokinetic advantage over standard intravenous delivery by producing high regional concentrations of drug while simultaneously minimizing systemic toxicities.

• The most widely reported method of IP chemotherapy is intraoperative delivery of mitomycin in a hyperthermic (41C) circuit for 90 min (HIPEC – heated intraperitoneal chemotherapy).

• In carefully selected cases, there appears to be a survival benefit. Multiple phase II and one phase III study establish superiority over conventional palliative surgery or systemic chemotherapy. Several phase II studies show 5-year survival rates ranging between 19 and 28 %.

• The most consistent and important prognostic factor in these studies is the ability to achieve complete resection of all gross disease. Five-year survival rates reported for patients with completely resected disease range from 27 to 54 %.

Ovarian Metastasis

• Approximately 4–30 % of ovarian neoplasms are metastatic cancers, the most common being colorectal and breast cancer. Between 6 and 14 % of all women dying with colorectal cancer are found to have ovarian metastases at the time of autopsy.

• The risk of developing ovarian metastasis is substantially higher in woman with stage IV disease and approaches 90 % in women with established peritoneal metastases. Thus, in a woman with recent diagnosis of advanced colorectal cancer, any ovarian mass should be considered a metastasis from colorectal cancer until proven otherwise.

• The pathogenesis of colorectal cancer ovarian metastasis is variable. Metastatic spread occurs primarily through the peritoneum but can also occur via the blood stream, through lymphatic vessels, or by direct extension. Careful intraoperative assessment of the ovaries at the time of colon cancer surgery is essential.

• Synchronous metastases occur in 0–8.6 % of patients in various clinical studies, while metachronous metastases develop in 1.4–6.8 % of colorectal cancer cases, usually within 2 years after the primary resection.

• Most often these metastatic lesions are large, and at least half of the cases have bilateral ovarian involvement.

• Distinguishing a metastatic colorectal cancer from primary ovarian tumor is difficult by gross assessment alone, but a correct diagnosis can generally be determined through integration of clinicopathologic, immunohistochemical, and cytogenetic features.

• Primary en bloc resection of CRC with direct extension to the ovary (T4) or resection of macroscopic metastatic disease to the ovary with prophylactic bilateral resection has been suggested to offer survival benefit and should be performed with curative intent in the absence of other significant metastatic disease.

• However, the removal of macroscopically normal ovaries, prophylactic oophorectomy, in women with colorectal cancer is the subject of much debate.

• Clinical studies attempting to document the benefit of ovarian metastasectomy in patients with colorectal cancer are small and retrospective. The majority of studies to date, however, fail to show any survival benefit for prophylactic oophorectomy, and most studies demonstrate that when ovarian metastasis is present, it is a poor prognostic sign.

• Based on the available data, it is reasonable to offer prophylactic oophorectomy to all postmenopausal patients, in particular to those women who have undergone pelvic radiation as part of their treatment for rectal cancer.

• For premenopausal patients, only those with established peritoneal metastases, those with a clearly increased risk of developing ovarian carcinoma [strong family history, known carriers of breast cancer (BRCA), or hereditary nonpolyposis colorectal cancer (HNPCC) mutation], or those who have already completed their families should be considered for prophylactic oophorectomy.

• Reoperation for metachronous metastases should be considered in selected patients with good performance status and limited tumor burden elsewhere. The survival benefit of removing ovarian metastases has never been well documented, although complete metastasectomy is associated with significantly better outcome when compared to palliative debulking, especially in the setting of metastatic disease confined to the pelvis.

• The median postresection survival for women with isolated ovarian metastases is 18 months. Five-year survival after resection of established ovarian metastases is rare. In these cases, systemic chemotherapy should be strongly considered, particularly when residual disease is present. With the availability of stronger chemotherapeutic regimens containing oxaliplatin, irinotecan, and/or bevacizumab, better survival can be expected.

Bone and Brain Metastases

• Bone metastases from colorectal cancer reportedly occur in 7–9 % of cases and most often present in the context of widespread metastatic disease.

• Routine diagnostic bone imaging is not indicated in colorectal cancer patients, however, unless there are specific bone-related symptoms.

• There are no curative modalities, but palliation of pain, fractures, or spinal cord involvement are important issues for these patients. Symptomatic relief from bony metastases can usually be accomplished with radiation and medical therapy.

• Cerebral metastases from colorectal cancer are uncommon, occurring in 1–4 % of colorectal cancer cases. Colorectal tumors account for approximately 3 % of all metastatic brain tumors. These are generally found in the context of widespread metastases to multiple organ sites but on rare occasion can present as an isolated brain metastasis.

• Once brain metastases occur, symptoms are common; palliative therapies include steroids to decrease swelling and anticonvulsants to control seizures. Definitive therapy of colorectal brain metastases usually involves surgery, radiation, or a combination of the two. For isolated, single brain metastases, resection can result in survival beyond 1–2 years.

• As with pulmonary metastasis, there is increasing interest and data in the literature regarding Gamma Knife and CyberKnife radiotherapy for bone and brain metastasis. The outcome and efficacy data is limited at this time, and the associated cost of robotic real-time image-guided radiotherapy may be a limiting factor in widespread applicability.