结直肠癌伴腹膜转移治疗的研究进展

结直肠癌是全球第三大常见癌症，也是与癌症相关死亡的第四大常见原因。转移性疾病仍然是结直肠癌死亡的主要原因，除了淋巴和血源传播途径外，结直肠癌还会引起肿瘤细胞的腹腔传播，最终导致腹膜癌。随着各种治疗的进展，转移性结直肠癌患者的预后明显改善，但对伴有腹膜转移的患者疗效并不理想。最近越来越多的研究表明，肿瘤细胞减灭术(CRS)和腹腔热灌注化疗(HIPEC)可使结直肠癌伴腹膜转移患者受益，预后较好，腹腔内加压气溶胶化疗(PIPAC)、新辅助化疗、Radspherin短距离辐射等新型疗法也相继出现。本文就结直肠癌伴腹膜转移的治疗研究进展作一综述。     

结直肠癌腹膜转移伴卵巢转移的治疗现状与挑战

腹膜是结直肠癌转移的好发部位。出现腹膜转移的女性结直肠癌患者常伴有卵巢转移。通常认为出现腹膜转移和卵巢转移的女性结直肠癌进展迅速且预后极差,目前仍无有效的治疗手段。虽然结直肠癌患者接受化疗及靶向药物后可显著改善预后,但同时伴有腹膜转移和卵巢转移的女性结直肠癌患者却无法明显获益。许多研究证实肿瘤细胞减灭术（CRS） 联合腹腔内热灌注化疗（HIPEC）可延长这类患者的生存期,改善生活质量。本文综述了结直肠癌腹膜转移和卵巢转移患者的诊治现状和相关进展。     

结直肠癌腹膜转移的多学科综合治疗

腹膜转移是结直肠癌常见转移部位之一,传统观念认为其预后差,没有手术治疗的价值。近年来,随着外科技术、精确控温的腹腔热灌注化疗以及多学科综合治疗的进步,对结直肠癌腹膜转移的认识和治疗策略发生很大的变化,拟就这一问题进行综述。在预后方面,如果仅行姑息性化疗,结直肠癌腹膜转移的预后差于肝、肺等非腹膜部位的转移;但对于一部分合适的患者施行完全性腹膜减瘤术联合腹腔热灌注化疗,则可能使部分患者获得长期生存;腹膜转移癌的预后因素包括腹膜播散癌指数、减瘤术完全性程度、是否合并腹膜外转移(肝脏等)、腹膜表面疾病严重程度评分和日本腹膜分期等。在治疗方面,完全性腹膜减瘤术联合腹腔热灌注化疗以及全身治疗(化疗+靶向治疗),可能是最佳的多学科综合治疗策略。     

中国大陆腹腔热灌注化疗治疗胃肠癌腹膜转移癌的现状

对于胃、结直肠癌患者来说, 腹膜转移是肿瘤晚期的标志性事件。既往的全身化疗及姑息性手术治疗模式对其疗效很差, 细胞减灭术联合腹腔热灌注化疗可改善部分腹膜转移癌患者的生活质量、延长生存期, 已经成为结直肠癌腹膜转移的标准治疗策略。但是, 该方案在我国并未获得统一认识和广泛应用。本文在分析我国胃、结肠癌腹膜转移癌的诊治现状同时, 就我国未来开展胃肠癌腹膜转移瘤的规范治疗提出建议。      

细胞减灭术联合腹腔热灌注化疗治疗结直肠癌腹膜转移的临床应用与展望

结直肠癌为我国常见恶性肿瘤之一, 其发病率逐年上升。腹膜为结直肠癌第2常见转移部位, 早期诊断困难, 预后不良。既往多采取全身性系统静脉化疗作为腹膜转移的主要治疗策略, 其全身不良反应明显, 且不能有效控制肿瘤进展。近年来, 外科技术、理念、设备的不断发展以及新的化疗药物与靶向药物的出现改善了结直肠癌腹膜转移患者的生存质量及预后。细胞减灭术(CRS)联合腹腔热灌注化疗(HIPEC)可在有效清除腹腔内游离癌细胞与亚临床病灶的同时, 减轻化疗药物带来的全身不良反应, 最大程度上实现宏观与微观的肿瘤根治, 目前, CRS+HIPEC已被国内外作为结直肠癌腹膜转移的一线治疗方案。文章分析总结了CRS+HIPEC治疗结直肠癌腹膜转移的生存疗效、预后因素分析、化疗安全性等问题, 探讨了HIPEC治疗目前存在的问题与争议。     

结直肠癌术后腹腔免疫化疗的疗效观察

目的　观察腹腔免疫化疗在结直肠癌术后应用的疗效。方法　对 4 6例结直肠癌术后患者(DukesC期、D期 )行腹腔免疫化疗 ,评价患者生活质量、免疫指标改善 ,近期复发转移情况。结果　结直肠癌术后应用腹腔免疫化疗 ,患者免疫指标改善 ,副反应轻 ,术后肿瘤复发 ,转移率下降。结论　腹腔免疫化疗对防治结直肠癌术后复发 ,转移是一种安全、方便有价值的方法     

结直肠癌术后腹腔免疫化疗的疗效观察

目的：观察腹腔免疫化疗在结直肠癌术后应用的疗效。方法：对46例结直肠癌术后患（DukesC期、D期）行腹腔免疫化疗，评价患生活质量、免疫指标改善，近期复发转移情况。结果：结直肠癌术后应用腹腔免疫化疗，患免疫指标改善，副反应轻，术后肿瘤复发，转移率下降。结论：腹腔免疫化疗对防治结直肠癌术后复发，转移是一种安全、方便有价值的方法。     

腹腔热灌注化疗在胃癌腹膜转移治疗中的作用

胃癌发生腹膜转移预后极差,中位生存期小于6个月.全身化疗并没有明显增加这些患者的生存期.腹腔热灌注化疗是目前常用的治疗腹膜转移的方法.全文系统回顾分析了腹腔热灌注化疗在胃癌腹膜转移治疗、进展期胃癌术后辅助治疗以及术前新辅助治疗的疗效.     

肿瘤细胞减灭术联合腹腔热灌注化疗治疗结直肠癌腹膜转移癌

结直肠癌(colorectal cancer,CRC)发病率呈上升趋势,虽然诊疗技术不断进步,仍有较多患者确诊时已经出现腹腔种植转移或根治性切除术后很快出现腹膜转移癌(peritoneal carcinomatosis,PC)。目前针对这种情况的治疗方法,主要有全身化疗、肿瘤细胞减灭术(cytoredu:tive surgery,CRS)联合全身化疗、CRS联合腹腔热灌注化疗(hyperthermie intraperitonealchemotherapy,HIPEC)等,其中CRS+HIPEC被认为是目前治疗CRC腹膜种植转移的有效方法。本文综述了该技术的治疗进展。1 HIPEC防治CRC PC的理论基础HIPEC是将大量含化疗药物的灌注液体持续、循环、充盈患者腹腔,预防和治疗PC。1980年Spratt等     

腹腔化疗在结直肠癌治疗中的应用

术后早期腹腔化疗对结直肠癌术后腹膜种植和肝转移的防治具有重要意义。腹腔化疗联合细胞减负荷手术已经应用于结直肠癌伴腹膜癌病的治疗并取得了较好疗效。本文拟就结直肠癌腹腔化疗的理论基础，临床应用现状及进展作一综述。     

Targeting Hyaluronic Acid and Peritoneal Dissemination in Colorectal Cancer

Peritoneal metastasis (PM) from colorectal cancer (CRC) carries a significant mortality rate for patients and treatment is challenging. The development of PM is a multistep process involving detachment, adhesion, invasion and colonization of the peritoneal cavity. Cytoreductive surgery and HIPEC (hyperthermic intraperitoneal chemotherapy) for PM from CRC has some benefit but overall survival is poor and recurrence rates are high. Treatments to prevent the development of peritoneal metastasis could have the potential to improve CRC survival and disease-free outcomes.The ability of cancer cells to invade the peritoneum and become established as metastatic tumors is influenced by a multifactorial process. Hyaluronic acid (HA) has been shown to coat the mesothelial cells of the peritoneum and has been demonstrated to be utilized in various malignancies as part of the metastatic process in peritoneal dissemination. CD44, RHAMM (CD168) and ICAM-1 have all been shown to be binding partners for HA. Targeting HA-mediated binding may prevent adhesion to distant sites within the peritoneum through suppression of interaction of these molecules. Here we review the current literature and discuss key molecules involved with PM dissemination, with the potential to target these mechanisms in the delivery of future treatments.     

Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for colorectal cancer: survival outcomes and patient selection

Background

Chemotherapy hyperthermic intraperitoneal chemotherapy (HIPEC) is playing an ever increasing role in the management of colorectal cancer (CRC) with peritoneal metastases (PM) as results approach those of surgical resection of liver metastases. Selection criteria for treatment type, sequence and timing of currently available therapies remain ill-defined.

Methods

We review the current published literature analyzing outcomes by treatments with surgery, systemic chemotherapy, cytoreductive surgery (CRS) and HIPEC, and ongoing clinical trials. A clinical pathway that incorporates all currently available therapies, determining the timing and sequence of such therapies was constructed.

Results

Most of the literature on outcome data comes from studies reporting the results of CRS and HIPEC with large series showing a median survival of 32-47 months. Meanwhile, the vast majority of patients, over 90% in the United States, are being treated with palliative systemic therapies following the NCCN guidelines.

Conclusions

Cooperation between medical and surgical oncologists represents an unmet need in oncology when it comes to patients with CRC with PM. The presented clinical pathway constitutes a feasible and much needed first step to start this cooperation.     

Oxaliplatin-based hyperthermic intraperitoneal chemotherapy with single drug versus multiple drug treatment for colorectal cancer with peritoneal metastases: an observational cohort study

BackgroundLong-term survival for selected patients with peritoneal metastases (PM) from colorectal cancer (CRC) is possible when treated with cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). The objective of this study was to compare three different oxaliplatin-based (OX)-HIPEC regimens. Primary end-point was disease-free survival (DFS), and secondary endpoints, morbidity and overall survival (OS).MethodsThis is a retrospective study of all patients with colorectal PM treated with CRS and HIPEC between 2004 and 2015 from the prospectively maintained Uppsala HIPEC database. One hundred and thirty-three patients were identified. Three HIPEC regimens were included: OX-HIPEC, OX-HIPEC + post-operative intraperitoneal chemotherapy (EPIC) with 5-fluorouracil (5-FU), and oxaliplatin-irinotecan-based (OXIRI)-HIPEC. Multivariable Cox regression for DFS was performed.ResultsSixty-one patients received OX-HIPEC, 24 patients received OX-HIPEC + 5-FU EPIC, and 48 patients received OXIRI-HIPEC. The DFS for the OX-HIPEC group was 10.5 months, OX-HIPEC + EPIC 11.9 months, and OXIRI-HIPEC 13.4 months (OX-HIPEC vs. OXIRI HIPEC, P=0.049). The morbidity and OS did not differ between the groups. In the multivariable analysis, low peritoneal cancer index (PCI), absence of liver metastases, low completeness of cytoreduction (CC) score, and multiple drug (EPIC or OXIRI) HIPEC regimen were independent prognostic factors for DFS.ConclusionsThis study showed improved DFS with an intensification of HIPEC by adding irinotecan or EPIC compared to oxaliplatin alone without an increase in morbidity or mortality.     

Role of novel targeted agents in the treatment of metastatic colorectal cancer

Modern chemotherapy regimens, combining bolus or infused schedules of 5‐fluorouracil (5‐FU) with irinotecan or oxaliplatin, have significantly improved the treatment outcomes of patients with metastatic colorectal cancer (CRC). The addition of novel targeted agents to chemotherapy has the potential to increase the median survival of patients with metastatic CRC beyond 2 years. Bevacizumab, a monoclonal antibody (mAb) to vascular endothelial growth factor, has an established role in first‐line treatment in combination with either 5‐FU/leucovorin or irinotecan/5‐FU/leucovorin regimens, while cetuximab, a mAb to epidermal growth factor receptor, in combination with irinotecan is more suitable for the treatment of refractory metastatic CRC. The use of bevacizumab in later stages of the disease and cetuximab in chemotherapy‐naive patients as well as concurrent treatment with both agents is still under investigation. The landmark studies leading to the approval of these agents in the treatment of metastatic CRC as well as associated toxicity profiles and detailed treatment recommendations are discussed in this review.     

Chemotherapy for colorectal cancer liver metastases

Colorectal cancer (CRC) is a highly prevalent malignant disease in industrialized nations. The annual incidence of invasive CRC in the U.S. is among the highest in the world, and the liver is the only metastatic site in approximately one third of patients. Without treatment, patients with metastatic disease have a poor prognosis; however, long-term survival benefits and even cure have been reported in patients undergoing surgical resection of metastases. In addition, advances in chemotherapy, imaging, and surgical techniques have increased the proportion of patients who are eligible for resection. Combination therapy with fluorouracil and leucovorin has been the mainstay of treatment for metastatic CRC; however, the introduction of newer agents, such as oxaliplatin and irinotecan, and targeted agents, such as cetuximab and bevacizumab, has yielded improvements in response rates (RRs) and survival. Maximizing the exposure of hepatic metastases to high target concentrations of cytotoxic drugs using hepatic arterial infusion (HAI) increases RRs further than with systemic chemotherapy; however, the impact of HAI on survival is unclear. As the goals of chemotherapeutic treatment for metastatic CRC increasingly shift from palliation to prolongation of survival, improvement in RRs, and downsizing of tumors in order to enable or optimize resection, treatment in a multidisciplinary environment involving a medical oncologist, radiologist, and surgical oncologist with hepatobiliary expertise will become central to deciding the best course of therapy and timing of surgery.     

晚期结直肠癌内科治疗进展

晚期转移性结直肠癌的5年生存率低于10％。5-FU／LV方案治疗的中位生存期大约12个月。最近化疗方案的更新延长了患者的中位生存期。研究发现奥沙利铂、伊立替康联合5-FU／LV或者卡培他滨等化疗方案使中位生存期延长到20个月。奥沙利铂，伊立替康联合5-FU／LV比传统的单药5-FU／LV使生活质量改善时间延长。目前转移性结直肠癌标准的一线治疗方案为FOLFOX和FOLFIRI。正在进行的研究关注新的分子靶向药物（molecular targeted therapy）联合化疗治疗转移性结直肠癌，且部分试验取得了较好的疗效。本文将对5-FU、新一代化疗药物以及分子靶向药物在转移性结肠癌治疗的演进及新进展作一综述。     

Intraperitoneal chemotherapy and its evolving role in management of gastric cancer with peritoneal metastases简

Advanced gastric cancer （GC） has been recognized as lethal disease when peritoneal metastases （PM） occurred.There is no standard treatment for advanced GC with PM.Until 1980s,the therapeutic arena for these patients had remained stagnant,with no therapeutic approach having shown a survival gain in GC with PM.However,cytoreductive surgery （CRS） with peritonectomy procedures and intraperitoneal chemotherapy （IPC） promising new combined therapeutic approach to achieve disease control for GC with PM.The recent publications changed the GC with PM treatment landscape by providing an evidence that CRS and IPC led to prolongation in overall survival （OS）.This review will provide an overview of the evolving role of CRS and IPC in the management of advanced GC with PM in the current era.     

The contemporary management of peritoneal metastasis: A journey from the cold past of treatment futility to a warm present and a bright future

Peritoneal metastasis (PM) is often regarded as a less frequent pattern of spread; however, collectively across all spectra of primary tumors, the consequences of PM impact a large population of patients annually. Unlike other modes of metastasis, symptoms at presentation or during the treatment course are common, representing an additional challenge in the management of PM. Early efforts with chemotherapy and incomplete surgical interventions transiently improved symptoms, but durable symptom control and survival extension were rare, which established a perspective of treatment futility for PM through most of the 20th century. Notably, the continued development of better systemic therapy combinations, optimization of cytoreductive surgery (CRS), and rigorous investigation of combining regional therapy—specifically hyperthermic intraperitoneal chemotherapy—with CRS, have resulted in more effective multimodal treatment options for patients with PM. In this article, the authors provide a comprehensive review of the data establishing the contemporary approach for tumors with a high frequency of PM, including appendix, colorectal, mesothelioma, and gastric cancers. The authors also explore the emerging role of adding hyperthermic intraperitoneal chemotherapy to the well established paradigm of CRS and systemic therapy for advanced ovarian cancer, as well as the recent clinical trials identifying the efficacy of poly(adenosine diphosphate ribose) polymerase maintenance therapy. Finally, recent data are included that explore the role of precision medicine technology in PM management that, in the future, may help further improve patient selection, identify the best systemic therapy regimens, detect actionable mutations, and identify new targets for drug development.     

Chemotherapy for intraperitoneal use: a review of hyperthermic intraperitoneal chemotherapy and early post-operative intraperitoneal chemotherapy

Peritoneal spread of tumors is a major problem in cancer management. Patients develop a marked deterioration in quality of life and shortened survival. This is in part due to bowel obstructions, marked ascites, and overall increase debilitation. Standard medical management has shown to be inadequate for the treatment of these problems. Surgery can palliate symptoms, however, it is unable to be complete at the microscopic level by a significant spillage of tumor cells throughout the abdomen. Chemotherapy can have some improvement in symptoms however it is short lived due to poor penetration into the peritoneal cavity. The role of intraperitoneal chemotherapy is to maximize tumor penetration and optimize cell death while minimizing systemic toxicity. Hyperthermic intraperitoneal chemotherapy (HIPEC) and early post-operative intraperitoneal chemotherapy (EPIC) are two treatment methods that serve this role and have been shown to improve survival. This review will discuss different chemotherapies used for both of these treatment options.     

腹膜转移癌内科治疗新进展

腹膜转移癌因发现较晚且预后差,目前正成为研究热点。随着细胞减灭术及腹腔热灌注治疗的推广,部分经选择的患者获益。针对不同肿瘤的不同时期,大量的临床研究显示,用药选择、用药时机、用药方法方面均取得进展,尤其是加压腹腔内气溶胶化疗的使用减轻了治疗相关不良反应,并提高了疗效。本文就近年来腹膜转移癌的内科治疗进展进行阐述。