大腸直腸癌微創手術在多科整合治療導向下之研發

Abstract

背景/目的 大腸直腸癌發病率位居臺灣十大癌症之首。癌症治療方法日新月異，近年來隨著醫學的進步和外科手術的發展，多科整合治療和微創手術是大腸直腸癌治療的主流。除手術外，大腸直腸癌的治療方法還包括化學治療、標靶治療、免疫治療和放射線治療，並朝著個人化醫療方向發展。然而，儘管大腸直腸癌有許多治療選擇，手術切除仍然是大腸直腸癌的主要治療方式。在過去20年來，腹腔鏡手術已經成為治療大腸直腸癌的黃金準則，而機械手臂輔助手術是另一種新的手術方式。臺大醫院於西元2012年引進機械手臂系統，而應用於治療大腸直腸癌的機械手臂相關手術方法也在陸續研發中。因此，本研究的目標是開發新的手術方法，希望在個人化、人性化精準醫療的架構下，為大腸直腸癌的外科腫瘤學樹立一個新的里程碑。 方法與結果 本文主要是陳述個人在博士班研讀期間，配合臺大醫院2012年開始引進機械手臂輔助手術及大腸直腸多科整合治療團隊的成立，在此架構下針對本院大腸直腸癌臨床病人治療方法的研發。本研究的成果分為三個部分： (一)成功研發先進的大腸直腸癌微創手術方法及提供足夠的臨床證據。分述於下： 1. 我們將微創的腹腔鏡手術和機械手臂輔助手術成功應用在局部侵犯晚期病人的多重器官切除及重建，另外這些病人若需要進行腹膜減積手術合併溫熱療法亦可同時進行，目前這些手術已經變成本科的臨床常規手術，使病人得到足夠的腫瘤廓清效果和快速的恢復。 2. 我們將微創的腹腔鏡手術和機械手臂輔助手術成功應用在晚期大腸直腸癌的廣泛淋巴腺廓清使此種手術變成臨床的常規，並促使病人得到延長存活和最佳的術後恢復。 3. 創立機器人手臂輔助下的括約肌間切除術，使罹患超低位直腸癌的病人肛門得以保留而提高生活品質。 4. 建立機器人手臂輔助下的自然孔道大腸直腸全切除手術合併迴腸直腸吻合；衡諸世界微創手術的領域這是相當新穎的術式。在此研究中，我們針對需進行全大腸切除的家族性腺瘤性息肉病及大腸無力症病人，進行機器手臂輔助經自然孔道取標本全大腸切除手術，手術結果顯示了此手術方式在技術上是可行的，同時可減少手術傷口，進而減少手術傷口相關併發症並達到更好傷口外觀，對於需要接受全大腸切除的病人來說是一個很好的選擇。 5. 我們證實機械手臂輔助手術的發展極大地影響了大腸直腸癌病人的預後，並提供了高等級的臨床證據。在此研究中我們針對接受過術前前導性化放療後進行機器手臂手術或腹腔鏡手術的直腸癌病人，根據傾向評分匹配分析比較了接受機器手臂手術或腹腔鏡手術病人的手術結果。研究結果顯示兩組之間的主要併發症發生率相似，無病生存率和總生存率沒有顯著差異。與腹腔鏡手術治療相比，機器手臂手術具有相似的安全性和腫瘤治療預後；對於需要微創手術的病人來說，機器手臂手術是一個可接受的選擇。 (二)確立在多科診療架構的臨床照護下，高危險群的病人手術治療亦能得到最佳的腫瘤治療效果和減少併發症。 此研究我們回溯性納入年齡≥90歲原發性大腸直腸癌病人，研究結果顯示接受腫瘤切除手術的病人比接受非手術治療的病人的癌症相關存活期更長。此研究顯示，在臨床實務過程中，我們不應拒絕≥90歲的大腸直腸癌病人進行手術治療。隨著目前微創手術的發展，相信對於90歲以上的大腸直腸癌病人的手術安全性將獲得改善，而微創手術是老年大腸直腸癌病人治療可發展之目標。估計在西元2025年台灣將邁入超高齡社會(65歲以上人口佔20%以上)；然而目前對於極端高齡大腸直腸癌病人的治療方針仍不明確。相信本研究成果能提供健保署作為參考，對國家健保政策的擬定提供建議並對國民健康有所貢獻。 (三)確認長期低劑量的節律化學治療對第二期大腸直腸癌病人具有減低復發率的效果，而腫瘤微環境因子的分析更能提高大腸直腸癌術後輔佐治療的適切性。 大腸直腸癌治療雖以手術治療為主，但惡性腫瘤都有一定的復發率。第二期大腸直腸癌預後相對較好，且接受輔助性治療有其副作用，因此化學治療並非常規用於所有第二期大腸直腸癌病人。在此研究中，我們評估第二期大腸直腸癌病人在根治性手術後使用輔助化療藥物與否的臨床結果和預後因素。研究結果顯示，對於第二期大腸直腸癌病人於術後接受長期低劑量節律替加氟尿嘧啶輔助性化學治療對減低腫瘤復發與延長存活有幫助。我們可以根據病人之風險因子，以決定是否要接受化學治療。此外，我們還比較了微衛星不穩定大腸直腸癌和微衛星穩定大腸直腸癌腫瘤微環境中各種免疫細胞的表現。我們的研究結果顯示，微衛星不穩定大腸直腸癌的免疫細胞浸潤密度高於微衛星穩定大腸直腸癌，但接下來仍需要進一步研究，以確定微環境因素對腫瘤預後之影響，期望根據不同的腫瘤微環境因素對於治療副作用及預後之影響，找到能夠指引大腸直腸癌治療的微環境生物標記。 結論 本研究證實機器手臂輔助手術改善腹腔鏡手術的諸多缺點。針對需要進行多臟器切除及重建、廣泛淋巴結廓清、超低位直腸癌的括約肌間切除術、腹膜減積手術合併溫熱療法的大腸直腸癌，目前機械手臂輔助手術已經研發成功而成為臨床的常規手術；另外，我們也證實大腸直腸癌病人進行機械手臂輔助手術，應用在前導性化學治療和放射線治療後需接受肛門保留手術的病人，顯示其手術之安全性及有效性；而以目前微創手術的進步，相信將來即使高危險的晚期大腸直腸癌或甚至極度年老病人亦能透過手術而得到最佳的存活和最快的恢復；而本研究也顯示隨著腫瘤微環境和生物標記的闡明，亦能使病人在精準醫療的架構下接受適切的輔佐性化學治療，而得到最大的腫瘤治療效果並減低副作用。我們深信以這些研究成果為基礎再進行大規模前瞻性研究，必能提供足夠的臨床證據嘉惠病人以及提供台灣健保署擬訂健保政策的參考。

Background/Aims Colorectal cancer ranks first among the top ten cancers in Taiwan. Recently, there has been rapid developments in cancer treatment. Multidisciplinary therapy and minimally invasive surgery have become mainstream treatments for colorectal cancer with the advancements in medicine and surgery. In addition to surgery, treatments for colorectal cancer include chemotherapy, targeted therapy, immunotherapy, and radiation therapy and these are now moving ahead towards personalized medicine. Despite the many treatment options available, surgical resection remains the mainstay of treatment for colorectal cancer. In the past 20 years, laparoscopic surgery has become the gold standard for the treatment of colorectal cancer, and robotic surgery is another emerging surgical approach. The National Taiwan University Hospital introduced a robotic system in 2012, and related surgical methods of the robotic system for the treatment of colorectal cancer are also being developed in this country. Therefore, the goal of this study was to develop innovative surgical methods with the aim of setting a new milestone in the surgical management of colorectal cancer under the framework of personalized precision medicine. Methods and Results The present dissertation mainly describes my personal research findings during the Ph.D. training program, which is in line with the introduction of robotic surgery and establishment of a multidisciplinary team for colorectal cancer in the National Taiwan University Hospital since 2012, when the treatment methods for patients with colorectal cancer were developed under the framework of precision medicine. The major study results were divided into the following three parts: 1. Successful development of several innovative minimally invasive surgical methods for the treatment of colorectal cancer with adequate clinical evidence, including (1) Successful application of minimally invasive laparoscopic surgery and robotic surgery for multiple organ resection and reconstruction in patients with locally advanced colorectal cancer. In addition, cytoreductive surgery followed by hyperthermic intraperitoneal chemotherapy can be performed with minimal invasiveness in patients with peritoneal carcinomatosis from colorectal cancer. At present, these operations have become routine practices in our institution, with adequate tumor clearance and rapid recovery. (2) Successful application of the robot-assisted approach to extensive lymph node dissection, a requisite for radical surgery in advanced colorectal cancer. This surgery has become part of our routine practice and has promoted prolonged survival and optimal postoperative recovery. (3) The implementation of robotic intersphincteric resection to preserve the anus and improve the quality of life of patients with ultralow rectal cancer within the anal canal. (4) The establishment of robotic natural orifice specimen extraction (NOSE) total colectomy and ileorectal anastomosis is a novel procedure in the field of minimally invasive surgery. In this study, we performed NOSE total colectomy and ileorectal anastomosis in patients with familial adenomatous polyposis and colonic inertia who required total colectomy. We have demonstrated that this surgical approach is technically feasible with a reduction in surgical wounds and wound-related complications, thus facilitating better cosmesis and quality of life. Overall, this is a novel option for patients who require total colectomy with ileorectal anastomosis. (5) Based on high-level clinical evidence, we confirmed that robotic surgery profoundly affects the prognosis of patients with colorectal cancer. In this study, we compared the surgical outcomes of patients who underwent either robotic or laparoscopic surgery using propensity score matching analysis in a cohort of patients with rectal cancer undergoing neoadjuvant chemoradiotherapy. The study indicated a similar major complication rate and no significant differences in disease-free survival and overall survival between the two patient groups. Thus, robotic surgery is safe with oncologic outcomes similar to those of traditional laparoscopic surgery. Therefore, it is an acceptable option for patients requiring minimally invasive surgery. 2. Under the framework of a multidisciplinary team approach for the treatment of colorectal cancer, surgery remains the main treatment modality in the context of optimal oncologic efficacy, even in high-risk patients. We retrospectively reviewed the clinicopathologic features of patients aged ≥90 years with primary colorectal adenocarcinoma and found that patients who underwent tumor resection had longer survival than those who underwent non-operative treatments. This study concluded that surgical treatment should not be denied to patients aged ≥90 years with primary colorectal cancer. With the current development of minimally invasive surgery, it is believed that the surgical safety for nonagenarian patients with colorectal cancer has significantly improved, and minimally invasive surgery is indicated for elderly patients with colorectal cancer. It is estimated that, in 2025, Taiwan will become a super-aged society (people aged ≥65 years will account for >20% of the population); however, the current treatment guidelines for extremely elderly patients with colorectal cancer remain unclear. The results of the present study on extremely old patients with colorectal cancer can be referenced by the National Health Insurance Bureau in Taiwan to formulate a national healthcare policy. 3. Long-term low-dose metronomic chemotherapy reduces the recurrence rate of stage II colorectal cancer, and analysis of tumor microenvironmental factors can improve the adequacy of postoperative adjuvant therapy for colorectal cancer. Surgery is the mainstay treatment for colorectal cancer. However, a subset of patients still experiences tumor recurrence, even after radical surgery for colorectal cancer. As stage II colorectal cancer has a relatively good prognosis and adjuvant therapy has side effects, chemotherapy is not routinely used in all patients with stage II colorectal cancer. In this study, we aimed to evaluate the clinical outcomes and prognostic factors of patients with stage II colorectal cancer with or without adjuvant chemotherapy after radical surgery. The results of this study showed that postoperative adjuvant chemotherapy with tegafur-uracil for patients with stage II colorectal cancer is beneficial in preventing tumor recurrence and improving survival. The administration of chemotherapy can be individualized based on patient risk factors. In addition, we compared the presentation of various immune cells in the tumor microenvironment of microsatellite-unstable colorectal cancer and microsatellite-stable colorectal cancer. Our results showed that the density of immune cell infiltration was greater in microsatellite-unstable colorectal cancer than in microsatellite-stable colorectal cancer. Therefore, further research is needed to determine the influence of microenvironmental factors on tumor prognosis. The effects of environmental factors on treatment side effects and prognosis have the potential to be used as therapeutic indicators and they can serve as biomarkers to guide colorectal cancer treatment accordingly. Conclusions This study confirmed that robotic surgery has several shortcomings in laparoscopic surgery. The robot-assisted approach has been successfully developed and has become a routine procedure at our institution for advanced colorectal cancer requiring multiple organ resection and reconstruction, extensive lymph node dissection, intersphincteric resection for sphincter preservation, or cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy. Additionally, we confirmed the safety and effectiveness of robotic surgery in patients with rectal cancer after neoadjuvant chemoradiotherapy. Remarkably, with the progress of minimally invasive surgery, we believe that even patients with high-risk comorbidities, such as extremely old patients, can achieve improved survival and rapid recovery from surgery. Furthermore, this study indicated that by clarifying the tumor microenvironment and biomarkers, patients can undergo more appropriate adjuvant chemotherapy within the framework of precision medicine to obtain maximal oncologic efficacy and minimal side effects. We believe that the afore-mentioned findings would facilitate a further large-scale prospective study to provide more solid clinical evidence for the innovation of patient care, and even act as a useful reference for the National Health Insurance Bureau to enact healthcare policies accordingly.