Chinese expert consensus on cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for peritoneal malignancies

Locoregional spread of abdominopelvic malignant tumors frequently results in peritoneal carcinomatosis(PC). The prognosis of PC patients treated by conventional systemic chemotherapy is poor, with a median survival of 6 mo. However, over the past three decades, an integrated treatment strategy of cytoreductive surgery(CRS) + hyperthermic intraperitoneal chemotherapy(HIPEC) has been developed by the pioneering oncologists, with proved efficacy and safety in selected patients. Supported by several lines of clinical evidence from phases Ⅰ, Ⅱ and Ⅲ clinical trials, CRS + HIPEC has been regarded as the standard treatment for selected patients with PC in many established cancer centers worldwide. In China, an expert consensus on CRS + HIPEC has been reached by the leading surgical and medical oncologists, under the framework of the China Anti-Cancer Association. This expert consensus has summarized the progress in PC clinical studies and systematically evaluated the CRS + HIPEC procedures in China as well as across the world, so as to lay the foundation for formulating PC treatment guidelines specific to the national conditions of China.     

Cytoreductive surgery and intraperitoneal chemotherapy for colorectal peritoneal metastases

AIM: To systematically review the available evidence regarding cytoreductive surgery (CRS) and intraperitoneal chemotherapy (IPC) for colorectal peritoneal metastases (CPM).METHODS: An electronic literature search was carried out to identify publications reporting oncological outcome data (overall survival and/or disease free survival and/or recurrence rates) following CRS and IPC for treatment of CPM. Studies reporting outcomes following CRS and IPC for cancer subtypes other than colorectal were only included if data were reported independently for colorectal cancer-associated cases; in addition studies reporting outcomes for peritoneal carcinomatosis of appendiceal origin were excluded.RESULTS: Twenty seven studies, published between 1999 and 2013 with a combined population of 2838 patients met the predefined inclusion criteria. Included studies comprised 21 case series, 5 case-control studies and 1 randomised controlled trial. Four studies provided comparative oncological outcome data for patients undergoing CRS in combination with IPC vs systemic chemotherapy alone. The primary indication for treatment was CPM in 96% of cases (2714/2838) and recurrent CPM (rCPM) in the remaining 4% (124/2838). In the majority of included studies (20/27) CRS was combined with hyperthermic intraperitoneal chemotherapy (HIPEC). In 3 studies HIPEC was used in combination with early post-operative intraperitoneal chemotherapy (EPIC), and 2 studies used EPIC only, following CRS. Two studies evaluated comparative outcomes with CRS + HIPEC vs CRS + EPIC for treatment of CPM. The delivery of IPC was performed using an “open” or “closed” abdomen approach in the included studies.CONCLUSION: The available evidence presented in this review indicates that enhanced survival times can be achieved for CPM after combined treatment with CRS and IPC.     

Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy in gastric cancer

Gastric cancer associated peritoneal carcinomatosis(GCPC) has a poor prognosis with a median survival of less than one year. Systemic chemotherapy including targeted agents has not been found to significantly increase the survival in GCPC. Since recurrent gastric cancer remains confined to the abdominal cavity in many patients, regional therapies like aggressive cytoreductive surgery( CRS) and hyperthermic intraperitoneal chemotherapy(HIPEC) have been investigated for GCPC. HIPEC has been used for three indications in GC- as an adjuvant therapy after a curative surgery, HIPEC has been shown to improve survival and reduce peritoneal recurrences in many randomised trials in Asian countries; as a definitive treatment in established PC, HIPEC along with CRS is the only therapeutic modality that has resulted in longterm survival in select groups of patients; as a palliative treatment in advanced PC with intractable ascites, HIPEC has been shown to control ascites and reduce the need for frequent paracentesis. While the results of randomised trials of adjuvant HIPEC from western centres are awaited, the role of HIPEC in the treatment of GCPC is still evolving and needs larger studies before it is accepted as a standard of care.     

Second-look surgery plus hyperthermic intraperitoneal chemotherapy for patients with colorectal cancer at high risk of peritoneal carcinomatosis: Does it really save lives?

The treatment of peritoneal carcinomatosis (PC) of colorectal origin with cytoreductive surgery(CRS) plus hyperthermic intraperitoneal chemotherapy (HIPEC) has a 5-year recurrence-free or cure rate of at least 16%, so it is no longer labeled as a fatal disease, and offers prolonged survival for patients with a low peritoneal carcinomatosis index. Metachronous PC of colorectal origin is so predictable that there is a model which has been used to successfully determine the individual risk of each patient. Patients at risk are clearly identified; those with the highest risk have small peritoneal nodules present in the first surgery (70% probability of developing PC), ovarian metastases(60%), perforated tumor onset or intraoperative tumor rupture(50%). Current clinical, biological and imaging techniques still lack sufficient sensitivity to diagnose PC in its initial stages, when CRS plus HIPEC has a greater impact and a higher cure rate. Second-look surgery with HIPEC or prophylactic HIPEC at the time of the first intervention have been proposed as means of preventing and/or anticipating clinical or radiological relapse in at-risk patients. Both techniques have shown a significant decrease in peritoneal relapses and should be considered essential weapons in the management of colorectal cancer.     

Therapeutic options for peritoneal metastasis arising from colorectal cancer

Peritoneal metastasis is a common sign of advanced tumor stage, tumor progression or tumor recurrence in patients with colorectal cancer. Due to the improvement of systemic chemotherapy, the development of targeted therapy and the introduction of additive treatment options such as cytoreductive surgery(CRS) and hyperthermic intraperitoneal chemotherapy(HIPEC), the therapeutic approach to peritoneal metastatic colorectal cancer(pm CRC) has changed over recent decades, and patient survival has improved. Moreover, in contrast to palliative systemic chemotherapy or best supportive care, the inclusion of CRS and HIPEC as inherent components of a multidisciplinary treatment regimen provides a therapeutic approach with curative intent. Although CRS and HIPEC are increasingly accepted as the standard of care for selected patients and have become part of numerous national and international guidelines, the individual role, optimal timing and ideal sequence of the different systemic, local and surgical treatment options remains a matter of debate. Ongoing and future randomized controlled clinical trials may help clarify the impact of the different components, allow for further improvement of patient selection and support the standar-dization of oncologic treatment regimens for pm CRC. The addition of further therapeutic options such as neo-adjuvant intraperitoneal chemotherapy or pressurized intraperitoneal aerosol chemotherapy, should be investig-ated to optimize therapeutic regimens and further improve the oncological outcome.     

肿瘤细胞减灭术联合腹腔热灌注化疗（CRS/HIPEC）治疗结直肠癌腹膜转移的现状和进展

腹膜是结直肠癌转移的好发部位。结直肠癌发生腹膜转移长期以来被认为预后很差,主要采用姑息性手段治疗。尽管化疗及靶向治疗在结直肠癌治疗上有很大进展,但对于腹膜转移的结直肠癌疗效并不理想。最近越来越多的证据表明,肿瘤细胞减灭术(CRS)联合腹腔内热灌注化疗(HIPEC)的治疗方法能给这部分患者带来较大的生存获益。本文综述了结直肠癌腹膜转移的诊治现状和相关进展。目前认为CRS联合HIPEC对选择的结直肠癌腹膜转移患者是一种安全有效的治疗模式,但HIPEC能否预防进展期结直肠癌发生腹膜转移,还有待进一步的临床试验研究。     

腹膜转移的结肠癌患者MDT诊治二例

本文描述了2例异时性腹膜转移的结肠癌病例的多学科诊治过程。1例多发转移,1例单发转移。这两例患者经MDT讨论后都首先采用了肿瘤减灭术联合腹腔热灌注化疗的治疗模式（cytoreductive surgery,CRS/hyperthermic intraperitoneal peroperative chemotherapy,HIPEC）,单发转移的患者目前获得了12个月的无病生存期（disease-free survival,DFS）,而多发转移的患者也获得了12个多月的总生存期（overall survival,OS）。目前发现与结直肠癌腹膜转移患者OS相关的因素包括肿瘤减灭术（CRS）完全程度和肿瘤累及的范围（腹膜转移癌指数）等。因此,对于结直肠癌的腹膜转移患者,评估病变范围极其重要,对于较局限的腹膜转移,多学科的综合诊治和积极的治疗手段能改善这部分患者的生存时间和生存质量。     

肿瘤细胞减灭术及腹腔热灌注化疗联合肝切除治疗结直肠癌腹膜转移合并肝转移的临床疗效

目的探讨肿瘤细胞减灭术（CRS）及腹腔热灌注化疗（HIPEC）联合肝切除治疗结直肠癌腹膜转移（CRPM）合并肝转移（LM）的安全性及有效性。 方法回顾性收集中国医学科学院肿瘤医院结直肠外科自2017年6月至2019年6月采用CRS+HIPEC联合肝切除治疗的16例CRPM合并孤立LM患者的临床病理资料。 结果男性6例,女性10例,中位年龄62岁。全组患者接受CRS+HIPEC联合同步肝切除,肝脏转移瘤均获得完整切除。中位总生存期25个月,中位无病生存期9个月。1年及3年总生存率分别为75.0%及37.0%,1年及3年无病生存率分别为50.0%及9.4%。6例（37.5%）出现轻度并发症（Clavien-Dindo Ⅰ~Ⅱ）,4例（25.0%）出现严重并发症（Ⅲ~Ⅳ）。 结论CRPM合并孤立的、能完整切除的LM的患者接受CRS+HIPEC联合同期肝切除是安全可行的,同时可为患者带来一定生存获益。     

腹膜转移癌诊疗决策中评分系统的研究进展

腹膜转移是肿瘤的晚期阶段，预后较差。肿瘤细胞减灭术联合腹腔热灌注化疗（CRS+HIPEC）可以显著改善患者预后。患者的预后往往和腹膜疾病的严重程度和CRS肿瘤细胞减灭的程度相关。在术前和术中有各种评分系统合理评估患者腹膜肿瘤负荷，本文对腹膜转移癌诊疗决策中评分系统展开综述。     

Benefit of cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy in patients with isolated peritoneal metastases from colorectal cancer

Background

Ever since Sugarbaker has established the cytoreductive surgery (CRS) in combination with intraoperative hyperthermic intraperitoneal chemotherapy (HIPEC), there is a chance of cure for selected patients with peritoneal metastases from colorectal cancer. Objective of this study was to investigate the benefit of CRS and HIPEC compared to other therapy options in patients with isolated synchronous and metachronous peritoneal metastases of colorectal origin in terms of long-term overall survival.

Methods

A retrospective population-based cohort study, including 370 patients diagnosed with isolated synchronous and metachronous peritoneal metastases of colorectal origin, was carried out. Therefore, data were acquired from the cancer registry at the Regensburg Tumor Center in Bavaria, Germany. Patients’ overall survival (OAS) according to their therapy received was analyzed by means of Kaplan-Meier method and multivariable Cox regression.

Results

Overall median survival was 41.6 months for patients treated with CRS and HIPEC, compared with surgery and chemotherapy (24.0 months, log-rank p?=?0.015), chemotherapy only (14.1 months, p?<?0.001), surgery only (11.4 months, p?<?0.001), and best supportive care (7.9 months, p?<?0.001). This benefit persisted after adjustment for further risk factors in multivariable analysis.

Conclusion

The effect of CRS and HIPEC stands out significantly in comparison to all other therapies. The multimodality approach should be a regular option for patients with isolated peritoneal metastases.

     

Multimodality treatment of peritoneal carcinomatosis from colorectal cancer: first results of a new German centre for peritoneal surface malignancies

Background The presence of peritoneal carcinomatosis arising from colorectal cancer is associated with a poor prognosis. It was the purpose of this study to analyze morbidity, mortality, and survival after major cytoreductive surgery and intraperitoneal chemotherapy. Materials and methods Thirty-two patients with peritoneal carcinomatosis were operated between April 2004 and June 2006 with the aim of complete macroscopical cytoreduction. All had a primary colorectal carcinoma. Surgery in these patients was followed by hyperthermic intraperitoneal chemotherapy (HIPEC) consisting of mitomycin C and doxorubicin. Data were analyzed retrospectively. Results Of all patients, 16 had appendix and 16 non-appendiceal colorectal carcinoma. A macroscopically complete cytoreduction was achieved in 24 patients by parietal and visceral peritonectomy procedures. All resections were combined with HIPEC. Overall morbidity was 34%. Most frequent surgical complications were intestinal obstruction (4/32), enteric fistula (2/32), pancreatitis (2/32), and bile leakage (2/32). One patient presented grade 4 renal toxicity. There was no hospital mortality. The median follow-up was 12 months. The 1-year overall survival rate is 96%. All patients after complete cytoreduction are still alive. Conclusions Cytoreductive surgery combined with HIPEC is associated with an acceptable morbidity and low mortality. Complete cytoreduction may improve survival, particularly in well-selected patients having a low tumor volume and no extra-abdominal metastases.     

Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy: Where are we?

Peritoneal surface malignancies are generally associated with poor prognosis. In daily clinical routine, systemic chemotherapy is still considered the only reasonable therapy despite of encouraging results of cytoreductive surgery (CRS) along with intraperitoneal hyperthermic chemotherapy (HIPEC). The Achilles heel of CRS and HIPEC is appropriate patient selection and precise surgical technique preventing patients from excessive morbidity and mortality. Given these findings, new concepts of second look surgery for high risk patients allow detection of peritoneal spread ahead of clinical symptoms or presence of peritoneal masses reducing perioperative morbidity. In addition, personalized intraperitoneal chemotherapy might further improve outcome by appreciating individual tumor biology. These days, every physician should be aware of CRS and HIPEC for treatment of peritoneal surface malignancies. Since there is now sufficient data for the superiority of CRS and HIPEC to systemic chemotherapy in selected patients, our next goal should be providing this strategy with minimal morbidity and mortality even in the presence of higher tumor load.     

肿瘤细胞减灭术加腹腔热灌注化疗治疗结直肠癌腹膜转移癌的临床研究

目的：探讨肿瘤细胞减灭术（CRS）加腹腔热灌注化疗（HIPEC）治疗结直肠癌腹膜转移癌（ CRC PC）的疗效及安全性。方法选取结直肠癌腹膜转移癌（ CRC PC）患者67例,随机分为治疗组（ CRS＋HIPEC）38例,对照组（CRS＋静脉辅助化疗）29例,比较两组的生存期、生存率、术后并发症及化疗毒副作用。结果治疗组中位生存期23.0个月,显著长于对照组的11.0个月（ P＜0.01）,治疗组1、2、3年生存率分别为70.9％、45.7％、8.2％,分别优于对照组的68.8％、21.2％、0％。术后并发症发生率两组相似（ P＞0.05）。化疗毒副作用：对照组恶心呕吐、白细胞减少、血小板减少发生率较治疗组高（P＜0.01）,而治疗组腹胀、腹泻发生率较对照组高（ P＜0.01或P＜0.05）;两组其他毒副作用相似（ P＞0.05）。结论 CRS＋HIPEC治疗CRC PC能明显延长患者生存期,并发症和化疗毒副作用并没有明显增加。     

Hyperthermic intraperitoneal chemotherapy for gastric and colorectal cancer in Mainland China

AIM:To investigate the current status of peritoneal carcinomatosis(PC) management,as well as the usage of cytoreductive surgery(CRS) and hyperthermic intraperitoneal chemotherapy(HIPEC) in mainland China.METHODS:A potentially curative therapeutic strategy for selecting patients with PC,known as Techniques,consists of CRS in combination with HIPEC.A systemic search of published works and clinical trials was performed.Additional papers were retrieved by crosschecking references and obtaining information from ...     

Role of CRS and HIPEC in appendiceal and colorectal malignancies: Indian experience

Background

Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy are recently being considered as standard of treatment for patients with peritoneal carcinomatosis of appendiceal or colorectal origin. It is an extensive procedure with high morbidity. Being a newer treatment modality, not much experience has been published from an Indian center about it.

Methods

All patients of colorectal and appendiceal cancer with peritoneal metastasis from January 2012 to March 2015 who were planned for cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC) were analyzed with respect to morbidity, mortality, and survival.

Results

Thirty-three patients were planned for cytoreductive surgery (CRS)+HIPEC for peritoneal carcinomatosis of colorectal or appendiceal origin. There were 18 males and 15 females and mean age was 48.2 years (21–75 years). Of these, 14 had disease from appendiceal origin and 19 of colorectal origin. Cytoreductive surgery was performed 29 times in 27 patients and was abandoned in 6 patients. Overall morbidity was 55.17% with hematological toxicity being the most common (46.1%) and mortality being 3.4%. Four-year actuarial survival of patients undergoing CRS and HIPEC was 58.39% and 33.33% for patients undergoing CRS alone (p=0.302). Appendiceal primary neoplasms had better overall survival compared to colorectal primary (63.64% vs. 50.68% 4-year actuarial survival).

Conclusions

CRS and HIPEC can be performed with acceptable morbidity and mortality in selected patients of colorectal and appendiceal malignancies with peritoneal carcinomatosis. In addition, it is associated with better overall survival. Morbidity profile of Indian subcontinent patients is different from that of western population with hematological toxicity being the most common.

     

Surgical management of patients with peritoneal carcinomatosis of gastrointestinal origin

Peritoneal carcinomatosis is found in approximately 15 % of patients with colorectal cancer during the course of their disease, and is associated with a poor prognosis. Even more patients with gastric cancer develop peritoneal seeding. Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC) have been introduced in the past decade and have led to 5-year survival rates of 30 to 40 % for selected patients with colorectal cancer and peritoneal carcinomatosis. These numbers have been demonstrated by many retrospective analyses and by prospective Phase II studies. The clinical assessment to select patients who will benefit from the combined therapy and achievement of complete macroscopic cytoreduction both play a crucial role. Less favourabale results have been achieved for patients suffering from stage IV gastric cancer with peritoneal seeding. Promising results were demonstrated for postoperative intraperitoneal chemotherapy following curative gastrectomy. Patients with hepatic, biliary and pancreatic cancers and peritoneal carcinomatosis do not benefit from cytoreductive surgery. There is a need for further multicentre, prospective trials analysing the use of hyperthermic intraperitoneal chemotherapy. They should be conducted in the specialised centres by interdisciplinary teams.     

“En bloc ” caudate lobe and inferior vena cava resection following cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for peritoneal and liver metastasis of colorectal cancer

There are diverse protocols to manage patients with recurrent disease after primary cytoreductive surgery(CRS) with hyperthermic intraperitoneal chemotherapy(HIPEC) for peritoneal carcinomatosis. We describe a case of metachronous liver metastasis after CRS and HIPEC for colorectal cancer, successfully treated with a selective metastectomy and partial graft of the inferior vena cava. A 35-year-old female presented with a large tumour in the cecum and consequent colonic stenosis. After an emergency right colectomy, the patient received adjuvant chemotherapy. One year later she was diagnosed with peritoneal carcinomatosis, and it was decided to carry out a CRS/HIPEC. After 2 years of total remission, an isolated metachronous liver metastasis was detected by magnetic resonance imaging surveillance. The patient underwent a third procedure including a caudate lobe and partial inferior vena cava resection with a prosthetic graft interposition, achieving an R0 situation. The postoperative course was uneventful and the patient was discharged on postoperative day 17 after the liver resection. At 18-mo follow-up after the liver resection the patient remained free of recurrence. In selected patients, the option of re-operation due to recurrent disease should be discussed. Even liver resection of a metachronous metastasis and an extended vascular resection are acceptable after CRS/HIPEC and can be considered as a potential treatment option to remove all macroscopic lesions.     

&ldquo;En bloc&rdquo; caudate lobe and inferior vena cava resection following cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for peritoneal and liver metastasis of colorectal cancer

There are diverse protocols to manage patients with recurrent disease after primary cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) for peritoneal carcinomatosis. We describe a case of metachronous liver metastasis after CRS and HIPEC for colorectal cancer, successfully treated with a selective metastectomy and partial graft of the inferior vena cava. A 35-year-old female presented with a large tumour in the cecum and consequent colonic stenosis. After an emergency right colectomy, the patient received adjuvant chemotherapy. One year later she was diagnosed with peritoneal carcinomatosis, and it was decided to carry out a CRS/HIPEC. After 2 years of total remission, an isolated metachronous liver metastasis was detected by magnetic resonance imaging surveillance. The patient underwent a third procedure including a caudate lobe and partial inferior vena cava resection with a prosthetic graft interposition, achieving an R0 situation. The postoperative course was uneventful and the patient was discharged on postoperative day 17 after the liver resection. At 18-mo follow-up after the liver resection the patient remained free of recurrence. In selected patients, the option of re-operation due to recurrent disease should be discussed. Even liver resection of a metachronous metastasis and an extended vascular resection are acceptable after CRS/HIPEC and can be considered as a potential treatment option to remove all macroscopic lesions.     

Long-term results after proactive management for locoregional control in patients with colonic cancer at high risk of peritoneal metastases

Purpose

A major problem in treating patients with peritoneal spread from colorectal cancer is that at diagnosis wide peritoneal involvement often precludes all curative attempts. A possible solution is to identify those patients at risk for peritoneal metastases and intervene early to prevent locoregional disease spread before it develops and, thus, to improve outcome.

Methods

We analyzed long-term results from a previous study and compared outcomes in 25 patients with advanced colon cancer considered at high risk for peritoneal spread (pT3/pT4 and mucinous or signet ring cell histology) prospectively included and managed with a proactive surgical approach including target organ resection for peritoneal spread plus hyperthermic intraperitoneal chemotherapy (HIPEC) and in 50 retrospectively well-matched controls who underwent standard surgical resection during the same period and in the same hospital by different surgical teams.

Results

At 48 months after the study closed, peritoneal metastases and local recurrence developed significantly less often in proactively managed patients than in controls (4 vs 28 %) (p?p?<0.04).

Conclusions

In patients with advanced colon cancer at risk for peritoneal recurrence, the proactive surgical approach plus HIPEC seems to achieve good locoregional control preventing peritoneal spread thus improving outcome without increasing morbidity. These advantages merit investigation in a multicentric randomized trial.