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      Cytoreduction for colorectal metastases: liver, lung, peritoneum, lymph nodes, bone, brain. When does it palliate, prolong survival, and potentially cure?

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      Current Problems in Surgery

      Elsevier BV

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          Abstract

          <p class="first" id="P1">Colorectal cancer commonly metastasizes. The liver is the most frequent site of metastases and dominates the length of survival for this disease. As surgical and systemic therapies have become accepted and now are proven to be potentially curative, other sites of metastases have become more clinically relevant in terms of clinical symptoms and influence on survival. Treatment of extrahepatic metastases by surgical and ablative procedures is increasingly accepted and is proving to be effective at palliating symptoms, as well as life prolonging. In this review, we will first summarize key issues with metastatic colorectal cancer to the liver and available treatments. We will then discuss surgical and ablative treatments of other sites of disease including lung, lymph nodes, peritoneum, bone, and brain. Best available evidence for treatment strategies will be presented as well as potential new directions. </p><p id="P2">Colorectal cancer commonly metastasizes. Most commonly this occurs by five means: direct extension, lymphatic spread, portal venous spread to liver, peritoneal dissemination, and vascular spread to distant organs including lung, bone, and brain. The liver is the most frequent site of metastases and dominates the length of survival for this disease. Nearly one-half of patients diagnosed with colorectal cancer will be found to have liver metastases at some point during their disease. When untreated, patients with liver metastases have a median survival of 6–9 months. Even with the best chemotherapy, median survival of unresectable disease is 13–18 months. In the last three decades, treatment of extrahepatic metastases by surgical and ablative procedures has proven to be effective. It is increasingly accepted and is effective at palliating symptoms, prolongs life, and can be potentially curative. The fact that liver resection is affecting outcome is also highlighted by the fact that over 70% of patients with unresectable liver metastases die of their liver metastases. In patients treated by hepatectomy, approximately 30% ultimately die of liver metastases. </p><p id="P3">The median survival of patients after hepatectomy for stage IV metastatic colorectal cancer in the liver is over forty months. Consequently, other sites of metastases are not only more likely to become apparent, but also more likely to cause symptoms and influence survival. Thus, management of liver metastases has made enough progress so that other sites of metastases have become more clinically relevant. In this review, we will first summarize the natural history of colorectal cancer metastases. We then will address key issues with metastatic colorectal cancer to the liver and available treatments. This is followed by a discussion of surgical and ablative treatments of other sites of disease including lung, peritoneum, bone, lymph nodes and brain. Best available evidence for treatment strategies will be presented as well as potential new directions. </p><p id="P4">At presentation, 20–25% of patients will have distant metastases, most to the liver. Another 20–25% will later develop liver metastases. Of patients who succumb to the disease, 49% will have liver dominant disease, and 83% will have some liver involvement. Disease specific survival is also significantly shorter for those who die of liver metastasis, compared to patients who die from other metastatic sites. Thus, addressing liver metastases initially is the most clinically relevant, since this is the most life limiting. Currently, patients who do not undergo surgical treatment of liver metastases typically live less than 18 months, with no 5-year survivors. By comparison, those who are resected but recur have a median survival of 40 months, and have a 17% 5-year survival. As such, liver directed therapies shift the cause of death to other sites at a later time point. For this reason, having metastases at other sites does not change survival for patients with liver metastases, as long as they are candidates for surgery. Understanding patient prognosis after treatment of liver metastases goes beyond American Joint Committee on Cancer (AJCC) staging due to patient heterogeneity. Clinical risk scores have been developed to facilitate this, and show that survival is based on primary cancer metastases to lymph nodes, length of disease free interval (if liver disease was not identified at diagnosis), number of metastases within the liver, and serum carcinoembryonic antigen level. </p><p id="P5">Most major centers report operative mortality of &lt;5% for those undergoing hepatectomy for colorectal cancer liver metastases. Indications for surgery are expanding, which is no longer limited to younger patients without comorbidities. Number of liver metastases is less important for determining resectability than is the existence of adequate vascular inflow and outflow of the remaining liver remnant. Smaller lesions within the planned liver remnant can be treated with microwave ablation or irreversible electroporation. The post-operative functional liver remnant must, however, be 20–40% of the pre-operative liver volume depending on hepatocyte functionality. This is dependent on exposure to previous chemotherapy and pre-existing cirrhosis. If the functional liver remnant is insufficient at presentation, it can be augmented by pre-operative portal venous embolization. Expanding on this concept, some surgeons perform a two-staged procedure that begins with liver partition and portal vein ligation to promote growth of the functional liver remnant, which can initially be as small as a single liver segment. If metastatic disease is limited to the liver, but is too extensive to resect, a hepatic artery infusion pump that delivers floxuridine directly and only to the liver may also be considered. Patients who are not considered operative candidates up front can be converted to resectable with neoadjuvant chemotherapy. It should be noted that 70% of patients who receive neoadjuvant chemotherapy and have so called “disappearing liver metastases” will have microscopic residual foci of disease in the liver, which is the site of local recurrence in 59% of these patients. </p><p id="P6">Surgical treatment of liver metastases can be performed synchronous with resection of the primary disease, or at different times. If resectability of the colorectal disease is in question, this should be performed first to ensure an R0 resection prior to addressing the metastatic disease. If the colorectal disease is clearly resectable, then the liver should be approached first to ensure low central venous pressure during this portion of the procedure without compromising blood flow to an intestinal anastomosis. A minimally invasive approach may be appropriate depending on the location of planned resections. Given the number of variables that go into determining optimal treatment of colorectal cancer liver metastases, decisions must be made in a multidisciplinary environment that includes team members with expertise in radiology, interventional radiology, chemotherapy, and surgery. Currently, there are wide discrepancies in referral of patients for surgical intervention versus patients who are considered resectable by liver surgeons, reinforcing that multidisciplinary care is of utmost importance. </p><p id="P7">Lung metastases are the second most common site of colorectal cancer metastases, but are rarely (&lt;10%) found in isolation. Five-year survival is best for patients who have lung metastases resected, compared to patients where the lung disease is left in situ and only liver disease is removed (13% vs. 57%). Existing data, however, are largely retrospective. A randomized phase III trial to examine the effect of concurrent lung metastasectomy (PulMiCC trial) is currently underway. Similar to liver disease, criteria for resectability have expanded in the last few decades. It is currently considered acceptable to treat colorectal cancer lung metastases if there is complete treatment of the primary tumor as well as complete resection of all pulmonary metastases while maintaining adequate pulmonary function. Pre-operative lung function tests are used to assess anticipated post-operative pulmonary function and need for supplemental oxygen. Treatment consists of removal of the minimum amount of lung necessary to completely remove the metastatic deposit. Some consider thoracotomy superior to video assisted thoracoscopic surgery due to the ability to palpate the lung for additional deposits. No studies, however, show a survival advantage with an open compared to a thoracoscopic approach. Propensity score matched retrospective studies in fact suggest the opposite. Methylene blue staining of nodules via CT guidance or navigational bronchoscopy can also be used to assist with intraoperative tumor identification. Approach to thoracic lymph nodes is variable and of uncertain survival benefit. Positive lymph nodes do indicate significantly poorer prognosis. For this reason, lymph node examination is generally recommended for completing staging and to help determine prognosis, which may guide further therapies. Patients who have unresectable disease can alternatively be treated with radiofrequency, microwave, or cryoablation, or stereotactic radiation. </p><p id="P8">Of patients who die of metastatic colorectal disease, it is believed that 25% have peritoneal carcinomatosis. Treatment of peritoneal carcinomatosis by cytoreduction and hyperthermic intraperitoneal chemotherapy (HIPEC) is of particular interest because progression leads to patient suffering from malignant bowel obstruction, weight loss, and symptomatic ascites. This can result in chemotherapy interruptions and repeated hospitalizations. Peritoneal carcinomatosis occurs more often in patients with right sided colon cancers, T3 tumors, involved mesenteric lymph nodes, and those who developed obstruction or perforation. Identification of peritoneal disease is variable because it is difficult to assess by existing imaging modalities, but is suggested by omental caking, scalloping of the diaphragm, peritoneal nodules, and ascites. [18F]-Fluoro-deoxyglucose positron emission tomography (FDG-PET) can be used to confirm inconclusive imaging findings, but the gold standard of assessment is operative exploration. A study of high risk patients with negative imaging identified peritoneal carcinomatosis in 68%. Diagnostic laparoscopy may be used to avoid exploration in patients without carcinomatosis, or with too extensive carcinomatosis to treat surgically (often because of disease within the mesentery and porta hepatis). Two prospective systematic second look operations studies (CEA Second Look and PROPHYLOCHIP) failed, however, to show a survival advantage. A randomized trial of cytoreduction and HIPEC versus systemic chemotherapy alone showed near doubling of survival in the cytoreduction and HIPEC group. This study was published prior to the widespread use of oxaliplatin and irinotecan though, limiting its applicability to our current patient population. A more recent randomized trial of systemic chemotherapy with cytoreduction with or without HIPEC failed to show a survival advantage in the HIPEC group, but showed a remarkable median survival of 41 months without HIPEC. Of note, no randomized trial to date shows the additive benefit of cytoreductive surgery to modern chemotherapy. Cytoreduction and HIPEC for peritoneal disease remains a popular strategy in select centers because of acceptable morbidity and mortality, along with reported 5-year survival of 27%. </p><p id="P9">Bone metastases are important to address due to the pain they cause impacting patient quality of life. Tumor related factors not only affect the bone where they are deposited, but also can make adjacent nerves more sensitive to painful stimuli. Further, local therapy can be used in situations where most of the patient’s disease is controlled with systemic therapy, but bone lesions progress. External beam radiation therapy (EBRT) is first line because it is non-invasive and operator independent, but can only be used in patients who can tolerate long periods of immobility while the therapy is being delivered. Pain relief is experienced by 60–80% of patients after EBRT, but can take up to 6 weeks for full effect, and recurs in 50% of patients by 18 weeks. Radiofrequency and microwave ablation can be used for local bone metastases when EBRT is not possible or fails, and improve symptoms in 90% of patients. Radiofrequency ablation has several limitations including dependence on tissue conductivity and predisposition to heat loss from adjacent blood vessels. Microwave ablation can achieve higher temperatures and generate larger ablation zones, however prospective data comparing radiofrequency to microwave ablation for this purpose are lacking. Cryoablation alternatively can be used to freeze tumor tissue. Advantages with cryoablation include a readily visible ablation zone, with less procedurally related pain compared to hyperthermic techniques. Disadvantages include absence of vessel coagulation that can lead to bleeding, and longer procedural time needed for repeat freeze-thaw cycles that are required. High intensity focused ultrasound (HIFU) is a newer technology that uses targeted high energy ultrasound waves on a focused point to induce thermal injury. It is non-invasive and is performed under magnetic resonance imaging (MRI) guidance allowing for real time assessment of thermal ablation. Its use is limited in locations that abut critical organs that could be affected by patient motion during treatment, and can only treat small tissue volumes at a time. </p><p id="P10">Data is also accumulating that selective resection of distant lymph node metastases may have therapeutic benefit. Patients found to have positive peri-hepatic lymph nodes have lower 3-year overall survival compared to those with negative peri-hepatic lymph nodes (25 vs. 75%). Para-aortic lymph nodes exist between the left renal vein and aortic bifurcation; clearance is associated with a survival advantage in retrospective series. They are positive in 38% of patients with suspicious pre-operative imaging, and when positive are associated with survival similar to that of distant metastatic disease. Similar findings have been reported for lateral pelvic lymph node resections in rectal cancer. While there is no survival difference between patients with and without a lateral pelvic lymph node dissection, there is decreased survival for those who have positive lateral pelvic lymph nodes. Existing data on extended lymphadenectomy is mostly from Eastern countries, and thus may not be well applied to Western populations. As such, current recommendations are to perform extended lymph node clearance only in select patients for prognostic purposes. </p><p id="P11">Colorectal cancer brain metastases are rarely (&lt;1%) the first metastatic site. Brain metastases are most often identified in patients with metastases to 3 or more other sites, with an average interval from diagnosis of colorectal cancer to detection of 20–40 months. One-year survival after diagnosis is 30%. Patients often present with headache and gait changes; fewer (24%) present with seizure. Contrast enhanced MRI is the diagnostic modality of choice. Treatment begins with management of seizures and cerebral edema if present, but should not be prophylactic. Reviews of patients treated for colorectal cancer brain metastases consistently show that treatment lengthens life. This is most true for patients with good performance status; those with no impairment of performance status have a median survival of 13.5 months. Treatment with surgical resection via craniotomy is used for more superficial tumors that are larger, and when tissue is needed to confirm the diagnosis. Stereotactic radiosurgery alternatively can be used for smaller tumors that are located more deeply in the brain, and can be used in combination with surgical resection when needed. Whole brain radiation has been used after open surgery and stereotactic radiosurgery for metastases in the past, but a recent randomized trial showed no difference in survival with this additional treatment. In this study, 22% of each group were alive and functionally independent at 2 years. </p><p id="P12">To conclude, there are now many accepted effective ways to treat colorectal cancer metastases to the liver, lung, peritoneum, bone, distant lymph nodes, and brain. These treatments can be used to palliate symptoms and also to prolong life. Due to the complexity and multifactorial nature of the decision making that goes into optimal patient care, treatment of colorectal cancer metastases should routinely be performed in a multidisciplinary environment to maximize patient benefit. </p>

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          Most cited references 280

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          Cancer Statistics, 2017.

          Each year, the American Cancer Society estimates the numbers of new cancer cases and deaths that will occur in the United States in the current year and compiles the most recent data on cancer incidence, mortality, and survival. Incidence data were collected by the Surveillance, Epidemiology, and End Results Program; the National Program of Cancer Registries; and the North American Association of Central Cancer Registries. Mortality data were collected by the National Center for Health Statistics. In 2017, 1,688,780 new cancer cases and 600,920 cancer deaths are projected to occur in the United States. For all sites combined, the cancer incidence rate is 20% higher in men than in women, while the cancer death rate is 40% higher. However, sex disparities vary by cancer type. For example, thyroid cancer incidence rates are 3-fold higher in women than in men (21 vs 7 per 100,000 population), despite equivalent death rates (0.5 per 100,000 population), largely reflecting sex differences in the "epidemic of diagnosis." Over the past decade of available data, the overall cancer incidence rate (2004-2013) was stable in women and declined by approximately 2% annually in men, while the cancer death rate (2005-2014) declined by about 1.5% annually in both men and women. From 1991 to 2014, the overall cancer death rate dropped 25%, translating to approximately 2,143,200 fewer cancer deaths than would have been expected if death rates had remained at their peak. Although the cancer death rate was 15% higher in blacks than in whites in 2014, increasing access to care as a result of the Patient Protection and Affordable Care Act may expedite the narrowing racial gap; from 2010 to 2015, the proportion of blacks who were uninsured halved, from 21% to 11%, as it did for Hispanics (31% to 16%). Gains in coverage for traditionally underserved Americans will facilitate the broader application of existing cancer control knowledge across every segment of the population. CA Cancer J Clin 2017;67:7-30. © 2017 American Cancer Society.
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            ESMO consensus guidelines for the management of patients with metastatic colorectal cancer.

            Colorectal cancer (CRC) is one of the most common malignancies in Western countries. Over the last 20 years, and the last decade in particular, the clinical outcome for patients with metastatic CRC (mCRC) has improved greatly due not only to an increase in the number of patients being referred for and undergoing surgical resection of their localised metastatic disease but also to a more strategic approach to the delivery of systemic therapy and an expansion in the use of ablative techniques. This reflects the increase in the number of patients that are being managed within a multidisciplinary team environment and specialist cancer centres, and the emergence over the same time period not only of improved imaging techniques but also prognostic and predictive molecular markers. Treatment decisions for patients with mCRC must be evidence-based. Thus, these ESMO consensus guidelines have been developed based on the current available evidence to provide a series of evidence-based recommendations to assist in the treatment and management of patients with mCRC in this rapidly evolving treatment setting.
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              Perioperative chemotherapy with FOLFOX4 and surgery versus surgery alone for resectable liver metastases from colorectal cancer (EORTC Intergroup trial 40983): a randomised controlled trial

              Summary Background Surgical resection alone is regarded as the standard of care for patients with liver metastases from colorectal cancer, but relapse is common. We assessed the combination of perioperative chemotherapy and surgery compared with surgery alone for patients with initially resectable liver metastases from colorectal cancer. Methods This parallel-group study reports the trial's final data for progression-free survival for a protocol unspecified interim time-point, while overall survival is still being monitored. 364 patients with histologically proven colorectal cancer and up to four liver metastases were randomly assigned to either six cycles of FOLFOX4 before and six cycles after surgery or to surgery alone (182 in perioperative chemotherapy group vs 182 in surgery group). Patients were centrally randomised by minimisation, adjusting for centre and risk score. The primary objective was to detect a hazard ratio (HR) of 0·71 or less for progression-free survival. Primary analysis was by intention to treat. Analyses were repeated for all eligible (171 vs 171) and resected patients (151 vs 152). This trial is registered with ClinicalTrials.gov, number NCT00006479. Findings In the perioperative chemotherapy group, 151 (83%) patients were resected after a median of six (range 1–6) preoperative cycles and 115 (63%) patients received a median six (1–8) postoperative cycles. 152 (84%) patients were resected in the surgery group. The absolute increase in rate of progression-free survival at 3 years was 7·3% (from 28·1% [95·66% CI 21·3–35·5] to 35·4% [28·1–42·7]; HR 0·79 [0·62–1·02]; p=0·058) in randomised patients; 8·1% (from 28·1% [21·2–36·6] to 36·2% [28·7–43·8]; HR 0·77 [0·60–1·00]; p=0·041) in eligible patients; and 9·2% (from 33·2% [25·3–41·2] to 42·4% [34·0–50·5]; HR 0·73 [0·55–0·97]; p=0·025) in patients undergoing resection. 139 patients died (64 in perioperative chemotherapy group vs 75 in surgery group). Reversible postoperative complications occurred more often after chemotherapy than after surgery (40/159 [25%] vs 27/170 [16%]; p=0·04). After surgery we recorded two deaths in the surgery alone group and one in the perioperative chemotherapy group. Interpretation Perioperative chemotherapy with FOLFOX4 is compatible with major liver surgery and reduces the risk of events of progression-free survival in eligible and resected patients. Funding Swedish Cancer Society, Cancer Research UK, Ligue Nationale Contre le Cancer, US National Cancer Institute, Sanofi-Aventis.
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                Author and article information

                Contributors
                (View ORCID Profile)
                Journal
                Current Problems in Surgery
                Current Problems in Surgery
                Elsevier BV
                00113840
                September 2018
                September 2018
                : 55
                : 9
                : 330-379
                Article
                10.1067/j.cpsurg.2018.08.004
                6422355
                30526930
                © 2018

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