The effect of hyperthermic intraoperative intraperitoneal chemotherapy (HIPEC) as an adjuvant in patients with resectable pancreatic cancer

Background – aims: The long-term survival of pancreatic cancer is poor even after potentially curative resection. The incidence of local-regional failures is high. There is evidence that hyperthermic intraperitoneal intraoperative chemotherapy (HIPEC) is effective in controlling the local-regional failures. The purpose of the study is to identify the effect of HIPEC after surgical removal of pancreatic carcinoma.

Patients – Methods: Prospective study including 33 patients with resectable pancreatic carcinomas. All patients underwent surgical resection (R₀) and ΗIPEC as an adjuvant. Morbidity and hospital mortality were recorded. The patients were followed-up for 5 years. Survival was calculated. Recurrences and the sites of failure were recorded.

Results: The mean age of the patients was 67.8?±?11.1 years (38–86). The hospital mortality was 6.1% (2 patients) and the morbidity 24.2% (8 patients). The overall 5-year survival was 24%. The mean and median survival was 33 and 13 months, respectively. The median follow-up time was 11 months. The recurrence rate was 60.6% (20 patients). Three patients were recorded with local-regional failures (9.1%) and the others with liver metastases.

Conclusions: It appears that HIPEC as an adjuvant following potentially curative resection (R₀) of pancreatic carcinoma may effectively control the local-regional disease. Prospective randomised studies are required.     

Cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy (HIPEC) in patients with gastric cancer and peritoneal carcinomatosis

Background

Gastric Cancer (GC) with Peritoneal Carcinomatosis (PC) has long been regarded as a terminal disease. Over the past two decades, cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) has changed the traditional concept of peritoneal metastases from being a systemic disease, to being considered a locoregional dissemination.

The use of intraperitoneal chemotherapy for gastric malignancies

Introduction: Gastric cancer is the fourth/fifth most common malignancy worldwide, with only a quarter of patients achieving a 5-year survival rate. It has been estimated that 15–50% or more of patients have peritoneal disease upon surgical exploration. Until the early 1990s, peritoneal metastasis was considered as terminal stage of the disease; in the late 1990s, selected patients with peritoneal metastasis were recategorized as local disease. Over the past two decades, the treatment of peritoneal involvement has transformed, and cytoreductive surgery plus intraperitoneal therapy have drastically altered the natural course of several malignancies.

Areas covered: We performed a review of studies available on PubMed from 1 January 2014 to 31 July 2019 and the analysis of their reference citations. We describe the most current intraperitoneal chemotherapy opportunities in the treatment of gastric cancer: hyperthermic intraoperative intraperitoneal chemotherapy (HIPEC), laparoscopic hyperthermic intraperitoneal chemotherapy (LHIPEC), neoadjuvant intraperitoneal and systemic chemotherapy (NIPS), LHIPEC + NIPS, extensive intraoperative peritoneal lavage (EIPL), early postoperative intraperitoneal chemotherapy (EPIC), and pressurized intraperitoneal aerosol chemotherapy (PIPAC).

Expert opinion: Comprehensive treatment consisting of CRS combined with perioperative intraperitoneal/systemic chemotherapy can, today, be considered an effective strategy to improve the long-term survival of gastric cancer patients with peritoneal metastasis.     

Advanced gastric cancer with or without peritoneal carcinomatosis treated with hyperthermic intraperitoneal chemotherapy: A single western center experience

Introduction

The aim of this article was to evaluate the role of hyperthermic intraperitoneal chemotherapy (HIPEC), associated or not to cytoreductive surgery (CS) in the treatment of different stages of advanced gastric cancer (AGC).

Patients and methods

Thirty seven patients with AGC who underwent 43 HIPEC from June 1992 to February 2007 were included. HIPEC used Mitomycin-C and Cisplatin for 60–90 min at 41–43 °C intra-abdominal temperature. The main endpoints were long-term survivals, morbidity and mortality rates.

Results

Eleven patients had no demonstrable sign of PC and constituted the Prophylactic-group, while 26 patients had macroscopic PC (PC-group). Five patients were Gilly 1 or 2 (nodules <0.5 cm) and 21 Gilly 3 or 4 (nodules ≥0.5 cm). In the PC-group a complete curative CS was achieved before HIPEC in 8 (PC-curative subgroup) and a palliative HIPEC in 18 patients (PC-palliative subgroup). The overall 30-days mortality was 5% (2 patients). Two patients in the Prophylactic group died within 6 months after hospital discharge (overall mortality 11%). The estimated risk of death per procedure was 9%. Ten patients (27%) presented one or more complications. The median survival was 23.4 months in the Prophylactic group, and 6.6 months in the PC-group (p < 0.05). The median survival in the PC-curative subgroup was 15 vs 3.9 months in the PC-palliative subgroup (p = 0.007). The median survival according to Gilly classification was significantly different (Gilly 1&2 vs Gilly 3&4, 15 vs 4 months respectively, p = 0.014). The global recurrence rates between the Prophylactic group and the PC-curative subgroup at 2 years were 36% vs 50% respectively. The median delay to recurrence was 18.5 vs 9.7 months respectively.

Conclusion

HIPEC might be useful to improve the survival in selected patients with ACG only when a complete cytoreduction can be achieved. Despite encouraging data, prospective studies, based on larger cohorts of patients are required to assess the role of this procedure as a prophylactic treatment in patients with AGC.     

Adjuvant chemotherapy for high-grade appendiceal cancer after cytoreductive surgery with hyperthermic intraperitoneal chemotherapy

IntroductionThere are no available data on the efficacy of adjuvant chemotherapy (ACT) in stage IVA/B high-grade mucinous appendiceal cancer treated with CRS/HIPEC. We evaluated the association between ACT and survival in this cohort.Materials and methodsA single-institution retrospective cohort study using a prospective database was conducted. Stage IVA/B high-grade mucinous appendiceal cancer patients who underwent CRS/HIPEC with CC-0/1 were included. Survival was compared between ACT and no chemotherapy (NoCT) patients. Subgroup analysis was performed with adjustment for confounding variables.ResultsWe identified 180 patients: 77 ACT and 103 NoCT. ACT regimens included 5-FU/capecitabine (13%), oxaliplatin-based (63%), and irinotecan-based (21%), combined with bevacizumab in 27% of cases. Median number of cycles was 9 (IQR: 6–12). Median overall survival (OS) did not significantly differ between ACT and NoCT (53 vs 75 months, p = 0.566). Multivariable Cox regression showed no OS benefit for ACT vs NoCT in patients with neoadjuvant chemotherapy (HR 1.14; 95%CI: 0.38–3.39) or without it (HR 1.33; 95%CI: 0.69–2.57), with signet ring cell (HR 0.89; 95%CI: 0.38–2.06) or other histologies (HR 1.11; 95%CI: 0.50–2.46), positive lymph nodes (HR 1.60; 95%CI: 0.74–3.49), or peritoneal cancer index ≥20 (HR 1.08; 95%CI: 0.55–2.11) after adjusting for other factors.ConclusionsIn our cohort, colon-type ACT was not associated with better OS in stage IVA/B mucinous appendiceal cancer after CRS/HIPEC, even after adjusting for confounders. This may be due to different tumor biology than colon cancer or small sample size. Prospective collaborative studies are needed.     

Evolution and emerging future of cytoreducxtive surgery and hyperthermic intraperitoneal chemoperfusion in gastric cancer: From treating the incurable to preventing recurrence

The number of new gastric cancer (GC) cases is decreasing, and these patients have longer survival thanks to new oncological treatments. In advanced GC a common evolution of this neoplasm is peritoneal metastases (PM). In the past this finding meant no chance for cure. However, today, using high quality operations and HIPEC, we are able to increase the number of patients treated with curative intention. New options in the diagnosis of PM, tumour susceptibility for different drugs, importance of quality of life, usage in ascites treatment, diagnostic tools in image-guided surgery, new targeted therapies and analysis of currently ongoing trials are presented together with today’s knowledge of HIPEC efficacy in order to evaluate gastric PM. HIPEC is an effective tool in the treatment of selected patients with PM from GC. Together with new diagnostic options such as targeted therapies, HIPEC may improve the prognosis of these patients, not only by treating clinically manifest carcinomatosis, but also in the prophylactic setting, addressing occult peritoneal seeding.     

Preoperative intraperitoneal chemotherapy for patients with serosa-infiltrating gastric cancer

BACKGROUND AND OBJECTIVES: Serosa-infiltrating gastric cancer poses a high risk for peritoneal recurrence. This study examined the feasibility and efficacy of preoperative intraperitoneal (i.p.) chemotherapy for such cancer. METHODS: Patients with serosa-infiltrating tumors, diagnosed by conventional examinations as well as by staging laparoscopy, were enrolled in this study. Those with unresectable T4 tumors, visible peritoneal metastasis or distant organ metastasis were excluded. Twenty-five eligible patients received preoperative i.p. chemotherapy, which consisted of i.p. injection of 20 mg of mitomycin C on day 1 and 10 mg of cisplatin for 5 days, followed by surgery. RESULTS: Of the 25 patients, 24 underwent gastrectomy with lymph node dissection and 1 underwent palliative gastrojejunostomy. The curability of the surgery was curability A in 6, B in 16, and C in 3. Preoperative T stages (T3 in 21 and T4 in 4) were downstaged postoperatively (T1 in 1, T2 in 10, T3 in 11, and T4 in 3). The 1- and 2-year overall survival was 83.3 and 51.3%, respectively. The median survival time was 24.4 months. The toxicity of the preoperative treatment was tolerable and no serious postoperative complication was seen. CONCLUSIONS: Preoperative i.p. chemotherapy seems to be a safe and effective therapy for serosa-infiltrating gastric cancer. Randomized clinical trials comparing preoperative i.p. chemotherapy followed by surgery and surgery alone are needed.     

Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for treatment of ovarian cancer

Hyperthermic intraperitoneal chemotherapy (HIPEC), a strategy combining maximal cytoreductive surgery and maximal regional chemotherapy, has been applied to treat ovarian cancer resulting in long-term survival rates in selected patients. However, the status of HIPEC in ovarian cancer remains an experimental procedure, given the many variables among the data and trials reviewed, to enable us to derive strong conclusions about its role from this overview. In this review we discuss treatment with HIPEC in patients with ovarian cancer and future prospective of its use in clinical setting. HIPEC is an effective tool in the treatment of selected patients with peritoneal carcinomatosis from ovarian cancer. Unfortunately, due to the lack of randomised trials, the evidence of HIPEC is very limited. Future randomised studies are awaited to define the role and clinical impact of HIPEC in ovarian cancer.     

Prophylactic hyperthermic intraperitoneal chemotherapy in patients with epithelial appendiceal neoplasms

Background Prophylactic hyperthermic intraperitoneal chemotherapy (HIPEC) is a promising approach for preventing peritoneal carcinomatosis in high-risk patients. We report our initial experience with prophylactic HIPEC in a series of patients with appendiceal neoplasms. Methods We retrospectively reviewed our prospectively maintained database to identify patients who underwent HIPEC in the absence of peritoneal disease. Patients with previously documented peritoneal surface disease were excluded. Data regarding clinical, operative and pathological features were analysed. Results Out of 322 HIPEC procedures performed between March 2007and August 2015, we identified 16 patients who underwent surgery with prophylactic intent. Primary diagnoses included high-grade and low-grade appendiceal neoplasms. Most patients presented originally with appendiceal perforation; all patients underwent initial surgery during which the appendix or right colon were resected. Following a median time interval of 2.2 months, a second surgery performed at our institution consisted of completion of omentectomy, partial colectomy and oophorectomy, with administration of prophylactic HIPEC (using mitomycin C). A totally laparoscopic approach was attempted and achieved in 11 patients in whom the median duration of surgery, estimated intraoperative blood loss and length of hospitalisation were 251?min, 100?cm³ and 4 days, respectively. There were no cases of major perioperative morbidity or mortality. Conclusions Prophylactic HIPEC for appendiceal neoplasms is feasible, safe and may be performed laparoscopically. Larger studies with long-term follow-up are needed to determine whether a survival benefit is associated with this treatment.     

Postprogression survival for first-line chemotherapy in patients with advanced gastric cancer

BackgroundWith the increasing availability of active agents, the importance of postprogression survival (PPS) has been recognised for several malignancies. However, little is known of PPS in advanced gastric cancer.Patients and methodsA literature search identified 43 randomised trials in chemotherapy-naive patients with advanced gastric cancer. We partitioned overall survival (OS) into progression-free survival (PFS) and PPS, and then examined the correlation between median OS and either median PFS or median PPS. The correlation between differences in OS (ΔOS) and those in PFS (ΔPFS) between trial arms was also investigated.ResultsThe average median OS was significantly longer in recent (2006 and later) trials than in older (2005 and earlier) trials (10.60 versus 8.64 months, P < 0.001), as was the average median PPS (5.34 versus 3.74 months, P = 0.001). Median PPS was correlated with median OS for all trials (r = 0.732), and this correlation was more pronounced in recent trials (r = 0.850). By contrast, the correlation between median PFS and median OS was less pronounced in recent trials (r = 0.282), as was that between ΔPFS and ΔOS (r = 0.365).ConclusionAn increase in median PPS was found in accordance with an increase in median OS in recent trials compared with older trials for patients with advanced gastric cancer.     

Laparoscopic distal gastrectomy and hyperthermic intraperitoneal chemotherapy in the treatment of advanced gastric cancer: a retrospective case-matched study on perioperative outcomes

BackgroundThis study aimed to assess the safety and efficacy of laparoscopic distal gastrectomy (LDG) with intraoperative hyperthermic intraperitoneal chemotherapy (HIPEC) for advanced gastric cancer (AGC).MethodsIn this case-matched study, we retrospectively reviewed the database of 223 patients with AGC who underwent LDG in Tangdu Hospital from April 2016 to February 2019. Among all participants, 177 patients underwent LDG alone and 46 underwent LDG with HIPEC. We matched total of 138 (1:2) patients from the LDG + HIPEC group (n 46) and the LDG group (n 92) for gender, age, date of operation, and tumor-node-metastasis (TNM) stage of tumor.ResultsThere was no significant difference in the Clavien-Dindo classification of complications between LDG alone and LDG + HIPEC patients. Further analysis showed the morbidity of gastroparesis to be significantly increased in LDG + HIPEC patients. At the same time, we found that the operation time, the time to 1st flatus, and hospital stay were longer in LDG + HIPEC patients and the incidence of abdominal recurrence 2 years after operation was significantly higher in the LDG group than the LDG + HIPEC group.ConclusionsThe combination of LDG with intraoperative HIPEC is a safe and feasible method for AGC and HIPEC will limit the recovery of gastrointestinal functions. In addition, during the follow-up of our study, although there was no statistical difference between the two groups in abdominal recurrence at 2 years after surgery, a decreasing trend of abdominal recurrence in LDG + HIPEC patients could be seen in comparison to LDG patients.     

完全肿瘤细胞减灭术加腹腔热灌注化疗治疗胃癌腹膜转移的病例筛选策略

目的:构建肿瘤细胞减灭程度(completeness of cytoreduction,CC)预测模型,为肿瘤细胞减灭术(cytoreductive surgery,CRS)加腹腔热灌注化疗(hyperthermic intraperitoneal chemotherapy,HIPEC)治疗胃癌腹膜转移(gastric cancer with peritoneal metastasis,GCPM)提供病例筛选方法。方法:比较完全CRS(complete CRS,CCRS)组和不完全CRS(incomplete CRS,ICRS)组患者基本临床病理特征和治疗参数,通过逻辑回归模型筛选CC独立预测因子,精准预测CCRS可能性。结果:125例患者纳入本研究,其中CC0组52例(41.6%),中位总生存期为30.0(95%CI:16.8～43.3)个月;CC1-3组73例,中位总生存期7.3(95%CI:5.7～8.8)个月,差异有统计学意义(P<0.001),而CC1、CC2和CC3组间中位总生存期差异无统计学意义(P>0.05)。因此,CC0定义为CCRS组,CC1-3定义为I...     

Cytoreductive surgery combined with hyperthermic intraperitoneal chemoperfusion for the treatment of gastric cancer: A single-centre retrospective study

Aim: Cytoreductive surgery (CRS) combined with hyperthermic intraperitoneal chemoperfusion (HIPEC) is the treatment regime most likely to achieve prolonged survival in patients with peritoneal carcinomatosis from gastroenteric cancer. To date, few publications have focused on the treatment of patients with gastric cancer alone. Several controversies remain unsolved, including the safety and effectiveness of the CRS–HIPEC combination regime, particularly in cases where HIPEC is used as adjuvant treatment after CRS. Therefore, in the current study, we aimed to evaluate the safety and effectiveness of CRS combined with HIPEC in patients with gastric cancer.

Method: Data from 231 patients with a median age of 55.1 years treated with the CRS–HIPEC combination regime between January 2009 and December 2014 were retrospectively reviewed. All patients underwent the combination therapy (mean of 2.4 cycles per patient, range, 1 to 4 cycles).

Results: Median overall survival was 37.0 months, with 1-, 2- and 3-year survival rates recorded as 83.4%, 68.5%, and 38.7%, respectively. The serum levels of carcinoembryonic antigen (CEA) and carbohydrate antigen 199 (CA199) were significantly decreased after combination therapy in the completeness of cytoreduction (CCR)-0 and CCR-1 groups, while no significant changes observed in marker levels were observed in the CC ≥2 group. The post-operative morbidity and mortality rates were 6.9% and 0.9%, respectively. Multivariate analysis revealed low TNM tumour stage, ascites condition and CCR score as independent predictors for better survival.

Conclusion: In view of the acceptable morbidity and mortality rates we propose that CRS combined with HIPEC presents an effective and safe treatment modality for patients with gastric cancer, especially in cases where optimal cytoreduction is achieved before the HIPEC procedure.     

Morbidity and mortality outcomes of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy in patients with primary and recurrent advanced ovarian cancer

Background

The aim of this study is to report the perioperative outcomes of CRS and HIPEC from a single institution and review those factors that are associated with a poor perioperative outcome in patients with peritoneal dissemination from primary or recurrent ovarian cancer.

Patients and method

A retrospective cohort study setting was conducted in a third level hospital peritoneal surface malignancy program. Ninety one patients diagnosed with ovarian peritoneal carcinomatosis, primary and recurrent without extraperitoneal metastasis were included for cytoreductive surgery and HIPEC with paclitaxel. We analyzed the postoperative morbidity rates and a univariate and multivariate analysis of factors associated with overall (grade I–IV) and major (grade III–IV) postoperative morbidity were performed.

Results

Peritoneal Cancer Index (PCI) upper than 12 (OR = 2.942 95%: 1.892–9.594 p = 0.044) was an independent factor associated with the occurrence of I–IV postoperative morbidity. Regarding major complications (grade III–IV), on multivariate analysis, in addition to PCI >12 (OR = 6.692, 95% CI: 1974–45, 674, p = 0.032), the need to carry out intestinal resection (OR = 4.987, 95% CI: 1350–27, 620, p = 0.046) was an independent factor related with major morbidity (grade III–IV).

Conclusions

The use of HIPEC after aggressive cytoreductive surgery in patients with ovarian cancer with peritoneal dissemination can be performed with acceptable postoperative morbidity rates. Knowledge of the factors associated with the onset of these postoperative adverse events allows better management of the same and offers the patient a safe procedure.     

Clinical efficacy of cytoreductive surgery and hyperthermic chemotherapy in peritoneal carcinomatosis from gastric cancer

Evaluation of: Yang XJ, Huang CQ, Suo T et al. Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy improves survival of patients with peritoneal carcinomatosis from gastric cancer: final results of a Phase III randomized clinical trial. Ann. Surg. Oncol. 18(6), 1575–15781 (2011).

Peritoneal carcinomatosis (PC) is the most common pattern of metastasis and recurrence in patients with gastric cancer and is associated with poor clinical outcome and survival. Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC) was recently established as a new treatment option for PC of gastrointestinal cancer. However, the role of cytoreductive surgery in gastric cancer and the intrinsic role of HIPEC remains unclear. The evaluated article presented a single center Phase III study, randomizing 68 patients with PC from gastric cancer to surgical cytoreduction only (CRS; n = 34) versus cytoreduction plus HIPEC with cisplatin and mitomycin (CRS+HIPEC; n = 34). Median overall was 6.5 months in the CRS group and 11.0 months in the CRS+HIPEC group (p = 0.046). Serious adverse events were acceptable in both groups. Multivariate analysis found CRS+HIPEC, synchronous PC, complete cytoreduction, systemic chemotherapy >6 cycles and no incidence of severe adverse events independent predictive factors for survival. This was the first study to show the positive effects of HIPEC in addition to CRS in PC independently of the tumor entity. In patients with gastric cancer, multimodal treatment concepts combining surgical cytoreduction and HIPEC may provide a new option in carefully selected patients.     

Hyperthermic intraperitoneal chemotherapy in serosa-invasive gastric cancer patients

BackgroundEvaluation of hyperthermic intraperitoneal chemotherapy (HIPEC) in reducing metachronous peritoneal metastases (MPM) risks in patients with resectable serosa-invasive gastric cancer.Materials & methodsBetween 2008 and 2016, 154 patients with gastric cancer (stage IIB-IIIC) were randomly assigned to two groups: 76 patients underwent HIPEC (cisplatin 50 mg/m² + doxorubicin 50 mg/m², 42 °C, 1 h) combined with radical surgery (HIPEC group) and 78 patients underwent only radical surgery (control group).ResultsEvaluation of HIPEC toxicity showed neither toxic complications of IV-V degree nor haematological toxicity (according to CTCAE v. 4.03). There was no significant difference in the rate of complications between the two groups (p = 0.254). There was a more frequent disease progression in the control group than in the HIPEC group: 42/55 patients (76.4%) vs. 36/68 patients (52.9%), respectively (p = 0.009). At the same time a significant decrease in the rate of MPM was observed after HIPEC administration as compared with surgery alone – 16/68 (12.8%) vs. 39/55 (27.6%) (p < 0.001). 3-year progression-free survival was 47% (95% CI 36–61)) in the HIPEC group and 27% (95% CI 17–43) in the control group – p = 0.0024.The N-stage, HIPEC procedure, type of surgery and interaction between HIPEC treatment and age were independent prognostic factors.ConclusionsHIPEC appears to be helpful in improving treatment results in radically operated gastric cancer patients.