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 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.     

Peritoneal carcinomatosis cytoreductive surgery and HIPEC: a ray of hope for cure

This article offers a review on the use of cytoreductive surgery (CS) plus hyperthermic intraperitoneal chemotherapy (HIPEC) for the treatment of peritoneal carcinomatosis (PC). Traditionally, PC was treated with systemic chemotherapy alone with very poor response and a median survival of 6 months or less. In this review article, preoperative workup, surgical procedures, morbidity and mortality rates, oncological outcomes and quality of live after CS and HIPEC are reported regarding the different tumor entities. This combined treatment for selected patients was found to improve survival. The extent of intraperitoneal tumor and the completeness of surgery are the most important factors of postoperative outcome. On the other hand, the need of phase III studies, explains a consensus among many surgical oncology experts throughout the world about the use of this new treatment strategy as a standard of care.     

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.     

Colorectal peritoneal metastases: Optimal management review

The peritoneum is a common site of dissemination for colorrectal cancer, with a poorer prognosis than other sites of metastases. In the last two decades, it has been considered as a locoregional disease progression and treated as such with curative intention treatments. Cytoreductive surgery(CRS) and hyperthermic intraperitoneal chemotherapy(HIPEC) is the actual reference treatment for these patients as better survival results have been reached as compared to systemic chemotherapy alone, but its therapeutic efficacy is still under debate. Actual guidelines recommend that the management of colorectal cancer with peritoneal metastases should be led by a multidisciplinary team carried out in experienced centers and consider CRS + HIPEC for selected patients. Accumulative evidence in the last three years suggests that this is a curative treatment that may improve patients disease-free survival, decrease the risk of recurrence, and does not increase the risk of treatment-related mortality. In this review we aim to gather the latest results from referral centers and opinions from experts about the effectiveness and feasibility of CRS + HIPEC for treating peritoneal disease from colorectal malignancies.     

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.     

Peritoneal carcinomatosis of colorectal origin: Incidence, prognosis and treatment options

Peritoneal carcinomatosis (PC) is one manifestation of metastatic colorectal cancer (CRC). Tumor growth on intestinal surfaces and associated fluid accumulation eventually result in bowel obstruction and incapacitating levels of ascites, which profoundly affect the quality of life for affected patients. PC appears resistant to traditional 5-fluorouracil-based chemotherapy, and surgery was formerly reserved for palliative purposes only. In the absence of effective treatment, the historical prognosis for these patients was extremely poor, with an invariably fatal outcome. These poor outcomes likely explain why PC secondary to CRC has received little attention from oncologic researchers. Thus, data are lacking regarding incidence, clinical disease course, and accurate treatment evaluation for patients with PC. Recently, population-based studies have revealed that PC occurs relatively frequently among patients with CRC. Risk factors for developing PC have been identified: right-sided tumor, advanced T-stage, advanced N-stage, poor differentiation grade, and younger age at diagnosis. During the past decade, both chemotherapeutical and surgical treatments have achieved promising results in these patients. A chance for long-term survival or even cure may now be offered to selected patients by combining radical surgical resection with intraperitoneal instillation of heated chemotherapy. This combined procedure has become known as hyperthermic intraperitoneal chemotherapy. This editorial outlines recent advancements in the medical and surgical treatment of PC and reviews the most recent information on incidence and prognosis of this disease. Given recent progress, treatment should now be considered in every patient presenting with PC.     

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 ...     

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。     

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.     

Management of peritoneal carcinomatosis from colorectal cancer: review of the literature

Background

Today, we do not have a universally accepted evidence on how to treat peritoneal carcinomatosis (PC) from colorectal cancer (CRC) in international guidelines.

Methods

The present study is a review of the literature investigating current strategies to treat CRC PC.

Results

Despite the progresses of systemic chemotherapy, the presence of PC among patients with metastatic CRC reduces the overall survival to 30 %, and only 4 % of patients with PC from CRC treated are alive for 5 years. Many trials evaluate the combined treatment of cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) for CRC PC, suggesting a survival benefit in highly selected patients. Only one trial is randomized and presents some biases. The two main prognostic factors are Peritoneal Cancer Index (PCI) and completeness of cytoreduction score (CC score). There is no universal agreement on how to approach the synchronous presence of PC and liver metastasis with a curative intent during the same procedure. A growing interest among the scientific community has arisen about systematic second-look surgery and HIPEC treatment in high-risk patients.

Conclusion

Current evidences suggest that CRS and HIPEC might be beneficial in highly selected patients affected with PC from CRC. Anyway, today, there is a shortage of well-designed phase 3 trials.     

Improved prognosis of pancreatic cancer patients with peritoneal metastasis

BackgroundPeritoneal metastasis is one of the most important poor prognostic factors in advanced pancreatic cancer (PC). Whether the prognosis of PC with peritoneal metastasis has improved with the advent of gemcitabine plus nab-paclitaxel (GnP) and modified FOLFIRINOX (mFFX) is uncertain. The aim of this study was to evaluate the improvements in treatment outcomes of PC with peritoneal metastasis.MethodsWe retrospectively investigated consecutive PC patients with peritoneal metastasis treated with chemotherapy at our institution between 2010 and 2019. We compared the clinical characteristics and survival outcomes according to the period of diagnosis (group A, 2010–2014; group B, 2015–2019) and chemotherapy regimen. We also examined the prognostic factors for overall survival (OS).ResultsAmong 180 patients included (GnP 88; mFFX 14; other regimens 78), distant metastasis was confined to the peritoneum in 89 patients. Although group B had a worse performance status compared to group A, median OS was significantly longer in group B. GnP and mFFX showed a significantly higher objective response rate and disease control rate in addition to longer progression free survival and OS compared to other regimens. The administration of GnP or mFFX, performance status, and neutrophil to lymphocyte ratio ≥5 were identified as independent prognostic factors for OS. Furthermore, the amount of ascites and extent of peritoneal metastasis were significantly associated with OS in patients with distant metastasis confined to the peritoneum.ConclusionsThe prognosis of PC with peritoneal metastasis has significantly improved over time with the advent of GnP and mFFX.     

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.     

Guidelines for chemotherapy of biliary tract and ampullary carcinomas

Few randomized controlled trials (RCTs) with large numbers of patients have been conducted to date in patients with biliary tract cancer, and standard chemotherapy has not been established yet. In this article we review previous studies and clinical trials regarding chemotherapy for unresectable biliary tract cancer, and we present guidelines for the appropriate use of chemotherapy in patients with biliary tract cancer. According to an RCT comparing chemotherapy and best supportive care for these patients, survival was significantly longer and quality of life was significantly better in the chemotherapy group than in the control group. Thus, chemotherapy for patients with biliary tract cancer seems to be a significant treatment of choice. However, chemotherapy for patients with biliary tract cancer should be indicated for those with unresectable, locally advanced disease or distant metastasis, or for those with recurrence after resection. That is why making the diagnosis of unresectable disease should be done with greatest care. As a rule, pathological diagnosis, including cytology or histopathological diagnosis, is preferable. Chemotherapy is recommended in patients with a good general condition, because in patients with general deterioration, such as those with a performance status of 2 or 3 or those with insufficient biliary decompression, the benefit of chemotherapy is limited. As chemotherapy for unresectable biliary tract cancer, the use of gemcitabine or tegafur/gimeracil/oteracil potassium is recommended. As postoperative adjuvant chemotherapy, no effective adjuvant therapy has been established at the present time. It is recommended that further clinical trials, especially large multi-institutional RCTs (phase III studies) using novel agents such as gemcitabine should be performed as soon as possible in order to establish a standard treatment.     

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。     

Lessons from the comparison of two randomized clinical trials using gemcitabine and cisplatin for advanced biliary tract cancer

There had been no standard chemotherapy established for advanced biliary tract cancer (BTC) until 2009, when the combination of cisplatin and gemcitabine (GC) was adopted as a first line standard chemotherapy option based on the results from two randomized studies: ABC-02, a UK investigator-initiated trial and the largest randomized phase III study in this tumor type with 410 patients; and BT22, a Japanese, industry-sponsored, randomized phase II study with 83 patients. In this review, investigators from both studies collaborated to compare protocols, patient characteristics, and outcomes of both studies including sub-analyses of study results. Although both studies showed GC combination therapy to be more effective than monotherapy, a detailed comparison revealed disparities between efficacy and safety end-points between the studies, which did not necessarily arise from different populations but from differences in protocol design. This review provides clinicians with insights for advanced BTC clinical study design and interpretation of historical studies.     

Evaluation and treatment of malignant ascites secondary to gastric cancer

Malignant ascites affects approximately 10% of patients with gastric cancer(gC), and poses significant difficulties for both patients and clinicians. In addition to the dismal general condition of affected patients and the diversity of associated complications such as jaundice and ileus, problems in assessing scattered tumors have hampered the expansion of clinical trials for this condition. However, the accumulation of reported studies is starting to indicate that the weak response to treatment in g C patients with malignant ascites is more relevant to their poor prognosis rather than to the ascites volume at diagnosis. Therefore, precise assessment of initial state of ascites, repetitive evaluation of treatment efficacy, selection of suitable treatment, and swift transition to other treatment options as needed are paramount to maximizing patient benefit. Accurately determining ascites volume is the crucial first step in clinically treating a patient with malignant ascites. Ultrasonography is commonly used to identify the existence of ascites, and several methods have been proposed to estimate ascites volume. Reportedly, the sum of the depth of ascites at five points(named "five-point method") on three panels of computed tomography images is well correlated to the actual ascites volume and/or abdominal girth. This method is already suited to repetitive assessment due to its convenience compared to the conventional volume rendering method. Meanwhile, a new concept, "Clinical Benefit Response in g C(CBR-GC)", was recently introduced to measure the efficacy of chemotherapy for malignant ascites of g C. CBR-GC is a simple and reliable patient-oriented evaluation system based on changes in performance status and ascites, and is expected to become an important clinical endpoint in future clinical trials. The principal of treatment for g C patients with ascites is palliation and prevention of ascites-related symptoms. The treatment options are various, including a standard treatment based on the available guidelines, cytoreductive surgery with hyperthermic intraperitoneal chemotherapy(HIPEC), laparoscopic HIPEC alone, intravenous chemotherapy, intraperitoneal chemotherapy, and molecular targetingtherapy. Although each treatment option is valid,further research is imperative to establish the optima choice for each patient.     

Current treatment options for colon cancer peritoneal carcinomatosis

Peritoneal carcinomatosis (PC), the dissemination of cancer cells throughout the lining of the abdominal cavity, is the second most common presentation of colon cancer distant metastasis. Despite remarkable advances in cytotoxic chemotherapy and targeted therapy for colon cancer over the last 15 years, it has been repeatedly shown that these therapies remain ineffective for colon cancer PC. Recently, there has been a rapid accumulation of reports that cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy (CRS-HIPEC) prolongs the life of colon cancer PC patients. Here, we will review the clinical presentation, the mechanisms of disease progression, and current treatment options for colon cancer PC, with a focus on the benefits and limitations of CRS-HIPEC.     

Evolution of clinical trials in head and neck cancer

The treatment paradigm for locally advanced head and neck cancers has evolved over the past two decades as the role of chemotherapy has been substantiated by clinical trials. Presently, concurrent chemoradiation is considered a standard treatment option for patients with resectable head and neck tumors desiring an organ preservation approach, as well as for patients with locally advanced nasopharyngeal cancers and patients in the postoperative setting who are at high risk for recurrence. The addition of a taxane to induction chemotherapy appears to improve efficacy over cisplatin and 5-FU. Targeted biologic therapies such as the monoclonal antibody Cetuximab has demonstrated efficacy with radiation that appear comparable to chemoradiation combinations and has a favorable toxicity profile. This review will discuss key clinical trials supporting the current standard of care. Emerging new technologies such as intensity modulated radiation therapy (IMRT) and image-guided radiation therapy (IGRT) will also be reviewed. Functional assessments and quality of life issues will be addressed.