转移性结直肠癌

Colorectal Cancer: Metastatic (Palliation)转移性结直肠癌,Approximately 20% of patients with colorectal cancer present with established distant metastases.Despite considerable progress Stage IV patients arenot curable.5-yearsurvival rate for Stage IV patients diagnosed between 1991and 2000 was 8%.Systemic chemotherapy,endoscopic treatments to palliate obstruction, surgical diversion, and surgical resection all have important roles in treatment of Stage IV patients.,将近20%的结直肠癌患者都会发生远处转移尽管医疗技术有了很大进步，但IV期患者仍无法治愈1991-2000年IV期患者的5年生存率为8%系统的化疗，内镜治疗缓解梗阻，造瘘，手术切除都是治疗IV期患者的重要手段,For patients withgood performance status and minimal symptoms from theirprimary cancers, standard treatment is systemic chemotherapy, which is well documented to increase survival and quality of life.Surgical resection of the primary tumor and,when feasible, of the metastatic lesions can provide excellentpalliation and can, in some cases, provide lasting cure.In the past decade, there has been remarkable improvementin the efficacy of chemotherapy for colorectal cancer. FOLFOX or FOLFIRI. Median survival hasimproved from 1214 months to 21 months,对于一般情况好，原发肿瘤症状轻的患者，标准的治疗应为系统的化疗，可以有效的提高生存率和生活质量对于有转移患者的原发肿瘤切除，如果可以切除的话，有些情况下对病情有良好的缓解作用在过去的10年里，化疗的疗效有了显著的提高，FOLFOX、FOLFIRI方案的应用使转移癌患者的中位生存时间从12-14月提升至21个月,Biology of Metastatic Disease,The clinical presentation of Stage IV patients is variable. Mostpresent with symptoms referable to the primary tumor.Initial staging evaluation should include colonoscopy withbiopsy, and imaging of the primary tumor, liver, and lungs.Endorectal ultrasound or MRI is recommended for rectal cancers to documentthe initial T and N stage. CTscanning of the chest/abdomen/pelvis is a highly accurate andefficient method of detecting metastases. PET scanning detects occult disease not seen onCT scan in 20% of Stage IV patients.,Diagnosis/Staging,IV期肿瘤患者的临床表现是多种多样的。大部分与原发病灶有关。初始的评估手段应有：结肠镜（取活检），肿瘤、肝脏、肺部的影像学检查。经直肠腔内超声或MRI是指导临床TNM分期的重要手段。胸、腹、盆的CT检查是发现转移的准确有效的方法。PET可以发现CT发现不了的一些隐性疾病，检出率达20%。,诊断/分期,Once the extent of disease workup is complete and distantmetastases have been documented, the surgeon must makethree important judgments.First is whether the patient is fitfor aggressive treatment.Second is whether the primary tumor presentsa clinically significant risk of bowel obstruction.Thethird determination is whether the patients metastases can besurgically resected, and therefore treated with curative intent,当常规检查完善，并发现转移时，外科医生需要做3个判断。1 患者是否适合接受手术治疗。2 原发肿瘤是否有显著的梗阻风险。3 转移灶是否可以手术切除。以达到治愈的目的,Management of patients with advanced disease is often complex, and multidisciplinary evaluation can be helpful in determining initial therapy. The surgeon and medical oncologistshould evaluate the patient in consultation with a radiologistand gastroenterologist. The goals, priorities, and expectedcourse of treatment should be discussed. For rectal cancersthat are bulky or symptomatic, the advice of a radiation oncologist is often helpful.,Multidisciplinary Evaluation,晚期肿瘤病人的管理是复杂的。外科及肿瘤科医生应与放疗及消化科医生会诊。,多学科评估,Approximately 8%29% of patients with colorectal cancerinitially present with symptoms of partial or complete bowelobstruction.For patients with advanced obstruction,nonresective palliative options include laser therapy, fulguration, colonic self-expanding metal stents, and creation of adiverting stoma.,Palliative Management of the PrimaryCancerStents, Laser,将近8-29%结直肠癌患者以全或不全性肠梗阻为首发表现。对于晚期肿瘤梗阻患者，不可切除的姑息治疗包括：激光、电灼、肠内自扩张支架、造瘘。,原发肿瘤的姑息治疗-支架，激光,Laser therapy has been used for palliation of obstructingrectal cancers for the past two decades.However,laser therapy is only for distal colon and rectum, and is rarely used to treat proximallesions.Complicationssuch as bleeding, perforation, and severe pain have beenreported in 5%15% of patients.,过去20年，激光治疗用于缓解直肠癌所致的梗阻症状。激光治疗仅适用于末端结肠和直肠，几乎不用于近端结肠并发症主要有：出血、穿孔、剧痛。报道的发生率为5-15%。,Surgical fulguration of rectal cancers is another method ofopening the rectal lumen.Fulguration, in combinationwith endoluminal debulking, can remove a large volume oftumor; however, unlike laser therapy, this procedure requireshospital admission and regional or general anesthesia.,电灼疗法是另一种打通直肠腔的方法。电灼结合经直肠腔内减瘤，可以去除大块的肿瘤组织。需要住院，麻醉支持。,In 1991, colonic stents havebecome an important method of palliation for obstruction incolorectal cancer patients, especially those with unresectable metastatic disease.These self-expanding metallicstents can potentially dilate the lumen to a near-normaldiameter, providing quick relief of symptoms and, in somecases, allowing endoscopic assessment of the proximalcolon.Complications included stent migration resulting in expulsion,reobstruction, and intractable tenesmus. Stenting of cancers inthe mid and low rectum may result inincontinence.Complications on colonic stentsinclude stent malpositioning, migration, tumor ingrowth, tumor overgrowth, perforation, stool impaction, bleeding, tenesmus, and postprocedure pain.,结肠支架自1991年出现以来，已成为晚期结直肠癌梗阻患者姑息治疗的重要方法，特别是那些转移灶无法切除的患者。自我扩张的金属支架可以扩张肠腔近乎正常直径，快速的缓解梗阻，甚至有些患者还可容结肠镜通过，以完善近端结肠的检查。并发症主要有移位、脱出、再次梗阻、里急后重感、肿瘤向支架网内生长、肿瘤生长超过了支架的覆盖、穿孔、出血、便嵌塞。,The role of bowel resection in patients with unresectablemetastases is controversial.No randomized data demonstrating a survival benefit for bowel resection in Stage IV patients.However, palliative resection of the primary tumor does provide durable localcontrol, is generally well tolerated, and can benefit manyStage IV patients.Its shown that Stage IVpatients receiving systemic chemotherapy have increasedlength and quality of life. With modern multidrugregimens, the beneficial impact of chemotherapy continues toincrease.Thus, standard management for patients withunresectable metastatic colorectal cancer is systemicchemotherapy.,Surgical Management of the PrimaryCancerResection,对转移灶无法切除的患者行肠切除的作用仍存争议没有数据表明手术对IV期患者的生存率有更多益处然而，切除原发肿瘤对局部控制的益处确实惠及很多IV期患者。有数据支持系统化疗可以延长生存期提高生活质量，而且现代药物的进步以及多药物联合化疗确实使疗效得到了提高。所以对于转移灶不可切除的结直肠癌标准的治疗方案应该选择系统化疗。,原发肿瘤的外科治疗-切除术,The proper use of elective colon/rectal resection in nonobstructed patients is a source of continuingdebate.Oncologists properly cite loss of performance status,risk of surgical complications, and delay in chemotherapy asmajor downsides to palliative resection. Surgeons, however,understand that elective operations have a far lower morbiditythan emergency surgery and fear having to operate on patientswho obstruct while receiving chemotherapy or who presentwith more advanced disease after multiple cycles of ineffective chemotherapy.,对未梗阻的患者选择性的行结、直肠切除术是否恰当仍是争论的源泉。内科医生担心患者一般情况变糟、术后并发症的风险、以及因为手术所耽误的化疗时间。外科医生的理由是择期手术比急症手术解决梗阻的并发症发病率更低，尤其是经过数个周期化疗之后，以及肿瘤恶化使手术难度加大。,Studies document that surgical resection can achieve excellentpalliation of local symptoms.For patients with nonobstructing primary tumors,upfront treatment with chemotherapy is favored because, inthis era of increasingly effective chemotherapyIt should be remembered that thegoal of therapy is effective palliation, and surgical resectionremains the most effective and durable local treatmentoption.,一些研究得出的结论手术干预可以很好的缓解局部症状。对于尚无梗阻迹象的原发肿瘤，化疗更受青睐，这也得益于化疗药物的发展和效果的提高。需要记得的是，对于晚期肿瘤患者的治疗目的是有效的缓解症状，所以手术切除仍是对局部症状最有效持久控制的选择。,Of the 150,000 new cases of primary colorectal cancer diagnosed in the United States each year, approximately 60% ofthese patients will develop liver metastases and about one-third will have disease limited to the liver.Of those able to undergo complete hepatic resection, 25%35% achieve long-term survival.Therefore, onlya small percentage of the overall number of patients withmetastatic colorectal cancer are cured by liver surgeryIt should be noted, however, that withimprovements in chemotherapy, surgical technique, and ablative techniques, the number of patients eligible for hepaticsurgery is on the rise.,Liver Metastasis,美国每年新增原发结直肠癌约15万，将近60%的患者会发生肿瘤转移，其中大约1/3为肝转移。对于能够接受肝切除的患者，25-35%能延长生命。所以只有很少一部分人能够被肝手术治愈。值得注意的是，随着化疗药物、外科技术和消融技术的进步，越来越多的患者可以接受肝切除。,肝转移,Before the 1980s, most hepatic metastases were leftuntreated. Several investigators have retrospectively studieduntreated patients, documenting median survivals of 510months; long-term survival was rarely seen.Nonetheless, some investigators retrospectively identified patients with isolated, potentiallyresectable hepatic metastases who were left untreated. Inthese patients with limited metastases isolated to the liver,who would otherwise be potential candidates for surgery, 3-year survival was 14%23% and 5-year survival was2%8%.even in the best of circumstances, 5-year survival of patients with untreated livermetastases is distinctly uncommon.,Natural History of Untreated Liver Metastases,在19世纪80年代之前，大部分肝转移是不治疗的。回顾性研究指出如果肝转移癌不予治疗，中位生存时间是5-10个月，长生存期极为罕见。一些研究回顾了转移灶孤立有切除可能却没有切除的患者，3年生存率14-23%，5年生存率2-8%即便在最佳的条件下，不治疗肝转移的话，患者活过5年的极为罕见。,未治疗的肝转移癌的自然病程,A careful extent of disease workup should beinitiated. First, a complete evaluation of the colon viacolonoscopy should be performed within a year of presentation; this addresses the issue of synchronous and metachronous colonic neoplasms, as well as the issue of localrecurrence (especially in rectal cancers).Complete crosssectional imaging of the abdomen and pelvis with high-qualityCT is also essential, to rule out extrahepatic disease. PET scanning isroutinely performed because of early prospective data documenting its utility. The information obtained from PET scanning changes management decisions in patients with recurrentcolorectal carcinoma 20%50% of the time. The majorstrength of PET scanning seems to be the detection of occultextrahepatic disease.,Diagnosis and Patient Evaluation,1. 1年内结肠镜检查，判断是否有同时或异时原发癌，以及是否有局部复发，尤其是直肠癌患者。2. 腹+盆高分辨CT平扫，判断是否有肝外转移。3.PET应该作为常规。因为能发现20-50%的复发，从而影响治疗策略。PET的优势就在于能够发现隐匿的肝外病变。,诊断及患者的评估,CEA level should also be drawn, and serves as a baseline tofollow after the conclusion of therapeutic interventions.High-quality imaging of the liver is essential in determiningbulk of disease and resectability. CT scan.Routine CT scans can now evaluatethe liver in combination with CT angiography or triphasicimaging of the parenchyma through various phases of intravenous contrast circulation. The most sensitive CT techniqueis CT portography, which is a CT scan performed after injection of contrast into the superior mesenteric artery. When injected contrast enters the portal circulation,metastases appear like filling defects. evaluating thenumber of hepatic tumors, it often fails to define the anatomicrelationships of tumor to hepatic vasculature, it requires aninvasive procedure, and it is costly.,4. 检测CEA水平的变化。5. 肝脏的高清影像，如CT。现在对肝脏的评估常采用常规CT联合CT血管造影以及注射对比剂之后的三相摄片。敏感度最高的是CT门静脉造影，向肠系膜上动脉内注射对比剂，当对比剂经过门脉循环时转移灶会呈现充盈缺损。缺点是难以分辨肿瘤与肝脏血管的解剖关系、有创、价格高昂。,Ultrasound and MRI are additional imaging techniques thatcan be useful in specific circumstances. Ultrasound is not anaccurate method for addressing extrahepatic disease, often cannot visualize the entire liver. Distinguishingneoplastic tumors from benign lesions such as cysts, focalnodular hyperplasia, or hemangiomata. Additionally, ultrasound can specifically evaluate the relationship of specificlesions to major vascular structures and the biliary tree.MRIis an excellent method for characterizing liver lesions.Particularly if there are multiple hepatic lesions. MRI is also an excellent modality forevaluating relationships of tumor to the biliary tree (via magnetic resonance cholangiopancreatographyMRCP) and tohepatic vasculature. High-quality MRI and CT are probablyequivalent.,6. 超声和MRI腹部超声对肝外病变的确定稍差，而且常常不能检查到整个肝脏。但是能用于鉴别肿瘤与良性疾病，如囊肿、局部增生结节、肝血管瘤等。另外还有助于确定肿瘤与肝血管及胆管结构的关系。MRI可以很好的明确肝转移。尤其是肝内多处转移灶，以及转移灶与血管、胆管的关系。,In any patient being considered forhepatic resection, a complete medical workup should be performed to assess the patients fitness for undergoing a majorabdominal operation. Any potential for liver dysfunction; Pulmonary function; Cardiac disease.,所有需要行开腹肝切除的患者都应完善上述检查，并评估是否适合手术。除此之外，还应考虑患者的全身情况，是否存在肝功能不全，肺功能障碍及心脏疾患。,Until recently, chemotherapy was considered largely ineffective as treatment of unresectable metastatic colorectal cancer.However, with the development of irinotecan, oxaliplatin,hepatic arterial infusional chemotherapy with fluorodeoxyuridine (FUDR), and newer molecular-based therapies, there arenow more effective chemotherapeutic options for thesepatients.Irinotecan (CPT-11) in conjunction with 5-FU/LV has beenrecently shown to be more effective than 5-FU/LV alone fortreatment of metastatic colorectal cancer.Theaddition of oxaliplatin has been particularly exciting becauseof the in vitro sensitivity seen in cisplatin-resistant cell lines,as well as its synergy with 5-FU.,Treatment OptionsChemotherapy,截至近期，对于不可切除的转移性结直肠癌，化疗是无效的。但是随着伊立替康、奥沙利铂、肝血管灌注脱氧氟脲苷化疗以及靶向治疗的发展，提供了更有效的化疗方案。伊立替康联合5-FU/LV比单纯5-FU/LV有更好的疗效。奥沙利铂对顺铂耐药的细胞有效，而且与5-FU有协同作用。,治疗选择 化疗,As these trials mature, and modern systemic chemotherapy regimens are refined, we are now seeingmedian survivals in excess of 20 months.,随着现代化疗方案的改善，结直肠癌肝转移患者的中位生存时间已经超过20个月。,Regional hepatic therapy via hepatic artery infusional(HAI) chemotherapy has been studied since the 1970s. Thistreatment takes advantage of the fact that hepatic metastasesderive their blood supply from hepatic arterial branches.Additionally, only a small proportion of systemically administered chemotherapy reaches the liver. The most frequentlyused agent for HAI is FUDR, which has a 90% hepatic extraction ratio. This permits maximal treatment of liver metastasesand minimization of systemic side effects.However, HAIwith FUDR limits treatment of occult extrahepatic disease.This can be addressed by giving additional systemic agents,or by using 5-FU via the hepatic artery with a higher ”spillover” effect into the systemic circulation.,对于肝脏血管内灌注化疗的研究始于19世纪70年代。肝脏转移灶的血供来源于肝脏血管是该治疗手段的依据。另外，全身性化疗中只有一小部分化疗药物能够到达肝脏。HAI最常用的药物是FUDR脱氧氟脲苷，在肝脏中吸收率达90%，使对转移灶的治疗最大化，全身的副反应最小化。然而HAI对肝脏外病变作用有限，这可以通过额外的全身性化疗解决，或使用5-FU灌注，通过肝动脉与更多的“外溢”到全身血液循环的效果。,The development of targetedmolecular-based therapy provides even greater hope for moreeffective systemic treatments. Anti-angiogenic therapy withanti-vascular endothelial growth factor antibodies (bevacizumab) are also currently being evaluated. Inhibitors of thereceptor for epidermal growth factor, a tyrosine kinase receptor, has also shown promising results, and drugs such ascetuximab (C225), ZD1839 (Iressa), and OSI774 (Tarceva)are actively being studied. Results of current clinical trials areanxiously awaited to see where these molecular-based targeted therapies will ultimately fit in among the armamentarium of systemic therapy for colorectal cancer.,分子靶向治疗的发展提供了更有效的治疗手段，前景被业界看好。抗血管内皮生长因子抗体（贝伐单抗），酪氨酸激酶受体，表皮生长因子受体抑制剂，也有着可喜的进展，以及药物，如西妥昔单抗（C225），ZD1839（易瑞沙），OSI774（特罗凯）正在积极研究。大家都在焦急的等待这些临床研究的结果，期待最终能有效治疗大肠癌。,Althoughresponse rates to chemotherapeutic regimens are improving,the only therapy ever shown to be potentially curative forhepatic colorectal metastases is complete resection.Liver resection performed in the 1970s and1980s was associated with high morbidity and mortality, making its role in the treatment of advanced cancer suspect at thattime.Over the last 20 years, large series havedemonstrated that liver surgery can now be practiced withacceptable safety, and that patients with isolated and resectablehepatic metastases have the potential for long-term survival.In modern series, mortality rates for hepatectomy formetastatic colorectal cancer are uniformly 5% or less.,Resection,虽然化疗的反应率在提高，但是对于结直肠癌肝转移的患者唯一可能达到治愈目的的手段就是手术切除。在19世纪70-80年代，肝切除有着高并发症率及死亡率，使其治疗作用遭到质疑。在过去的20年中，大宗的研究表明随着手术技术的进步肝脏手术已经安全许多，并使孤立的（转移灶）和可切除肝转移患者有了长期生存的可能性。研究显示肝转移癌肝叶切除术的死亡率为5%或更低。,切除,Morbidity for these operations remainssubstantial, and is usually reported between 20% and 50%.The most ominous complications,such as liver failure and significant hemorrhage, are now distinctly uncommon, thanks to better surgical technique andpostoperative care. in the 1970s, the first time,documented 5-year survival rates of 25%. Major institutionaland multi-institutional reviews of patients undergoing hepatectomy for metastatic colorectal cancer have now clearly documented that, in well-selected patients, 5-year survival rangesfrom 25% to 40%, 10-year survival ranges from 20% to 26%,and median survivals range from 24 to 46 months,肝切除的并发症发病率在20-50%最恶性的并发症如肝衰竭及严重出血现在已非常罕见，这也得益于手术技术的进步和术后护理的发展。19世纪70年代研究中首次发表的5年生存率为25%。现如今，大量单中心及多中心研究，病例选择恰当的条件下，5年生存率在25-40%，10年生存率在20-26%，中位生存时间在24-46个月。,Despiterecent improvements in chemotherapy resulting in median survivals as high as 20 months, complete resectionstill provides the best outcomes. True long-term cure fromchemotherapy is extraordinarily rare, whereas at least half ofthe long-term survivors after liver resection are disease-freeand presumably cured.For these reasons, no trial has evercompared hepatectomy to no treatment or chemotherapyalone.Liver resection for resectable hepatic colorectalmetastases is the treatment of choice.The two most consistent negative prognostic factors are thepresence of extrahepatic disease and the inability to resect alltumor; these two factors remain contraindications to hepatectomy.,虽然接受化疗中位生存时间达到20个月，但是要想达到最佳的预后还是需要完整的切除。经过化疗治愈的患者极为罕见，而接受肝切除术的患者中至少有一半能长期生存，并且无瘤生存。所以没有研究去对比肝切除和不治疗以及仅化疗的疗效。两个预后不良的因素：肝外病变和不能切除全部转移灶。这两点也是肝切除的禁忌症。,Although there are many inconsistencies in the majorreported series, a list of other poor prognostic factors exist;these include lymph nodes involved by the primary colorectaltumor, synchronous presentation or shorter disease-freeinterval (DFI), larger number of tumors, bilobar involvement, CEA elevation greater than 200ng/mL, and involved histologic margins.noneof these findings in and of themselves preclude the potentialfor long-term survival.,研究发现影响预后不良的因素还有：原发灶的淋巴结转移，同时性或异时性的多个肿瘤，肝脏多叶累犯，CEA高于200ng/mL。但这些研究结果本身并没有排除长期生存的可能性。,Recurrence after hepatectomy for colorectal metastases iscommon, occurring in more than two-thirds of patients. Infact, long-term survival does not necessarily imply that therehas been no recurrence.In patients who do recur, theliver is the most common site of recurrence and is involvedapproximately 45% of the time. Most of these recurrences areisolated to the liver. Other common sit