Systemic chemotherapy using FLOT – regimen combined with cytoreductive surgery plus HIPEC for treatment of peritoneal metastasized gastric cancer

Müller H; Hotopp Th; Tofeili A; Wutke K;

Dept. of visceral surgery, DRK Manniske Hospital, Bad Frankenhausen, Germany

Author address

Dr. Herwart Müller

An der Wipper 2

06567 Bad Frankenhausen

Germany

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Abstract

Background. The aim was to evaluate the feasibility and the effectiveness of neoadjuvant systemic chemotherapy using FLOT - protocol followed by cytoreductive surgery (CRS), hyperthermic intraperitoneal chemotherapy (HIPEC) followed by systemic chemotherapyand in patients with peritoneal carcinomatosis (PC) from gastric cancer.

Material and methods. Twentysix (median age 53 years, range 39 – 71) were scheduled for three cycles of neoadjuvant systemic chemotherapy using bi-weekly FLOT – protocol followed by CRS + HIPEC. Thereafter 3 additional cycles of FLOT were given. During HIPEC in Colliseum technique Oxaliplatin was given in a dosage of 200 mg/m² and Docetaxel in a dosage of 80 mg/m².

Results. All patients underwent cytoreductive surgery plus HIPEC. Peritoneal Cancer index was > 15 in 3 cases only. Complete resection could be carried out in all cases (CC-O 18, CC-1 8). Postoperative complication rate was 23% with no mortality within 30 days. Anastomotic leakage rate was 3.2 %. Overall survival was 19.0 months with a 2-year survival rate 38 %. Regression analysis demonstrated a Peritoneal Cancer Index PCI > 12 as negative factor for survival.

Discussion. Neoadjuvant chemotherapy using FLOT – protocol followed by CRS + HIPEC seems to be associated with prolonged OS in patients with peritoneal carcinomatosis from gastric cancer. This treatment is not recommended for patients with extensive peritoneal involvement and PCI > 12.

Introduction

In gastric cancer (GC) peritoneal seeding is a characteristic feature of cancer spread. Peritoneal Carcinosis (PC) from GC is characterized by the presence of tumor nodules of various size, number and distribution on parietal and visceral peritoneal surfaces, with very poor prognosis and a median survival of less than 6 months (1,2). As PC is currently regarded as a variant of systemic spread of disease, treatments for such patients are palliative systemic chemotherapy and best support care, with limited efficacy (3,4,5). These nihilistic treatment approaches are ill conceived, as data supporting systemic therapy for secondary PC is derived from clinical trials reporting the results of treatment of distinctively different tumor biology-visceral metastasis of hematogenous origin, not PC (6,7).

To tackle this problem, a more aggressive treatment strategy called cytoreductive surgery (CRS) plus hyperthermic intraperitoneal chemotherapy (HIPEC) has been developed over the past 3 decades, taking advantages of surgery to reduce visible tumor burden, and regional hyperthermic chemotherapy to eradicate micro-metastases, expanding cancer surgery from resection of primary tumor to surgical management of metastatic diseases (8,9)

Cohort studies suggested CRS plus HIPEC could improve outcome of patients with PC from GC (10,11,12). Non-randomized comparative studies suggested the superior efficacy of CRS + HIPEC over CRS alone for the treatment of gastric PC (13,14,15). Only a few of previous published studies documented the effect of combination of a distinctive systemic chemotherapy and CRS plus HIPEC (16). This study was undertaken to evaluate the efficacy of CRS plus HIPEC combined with Oxaliplatin, and Taxotere – based systemic chemotherapy.

Patients and Methods

Patients

Twenty six patients with documented gastric cancer spreading to peritoneum, including 12 men and 14 women, aged 39 - 71 years (median 53 years) have been treated at DRK Manniske Hospital, Bad Frankenhausen between August 2008 and April 2013. Routine preoperative studies included thorough physical examination, blood test, serum biochemistry and electrolytes, liver and renal function evaluation and coagulation studies. Other examinations included chest x-ray, contrast-enhanced three-dimensional abdominal-pelvic computed tomography, and cardiac function assessments. Patient inclusion criteria were: age 18–75 years old; Karnofsky performance status of >70; life expectancy of >8 weeks; normal peripheral blood white blood cells count ?3500/mm³ and platelet count ?80,000/mm³; acceptable liver function with bilirubin no greater than 2 times the upper limit of normal (ULN), and aspartic aminotransferase and alanine aminotransferase no greater than 2 ULN; acceptable renal function, with serum creatinine no greater than 1.5 mg/dl; and cardiovascular pulmonary and other major organ functions can stand major operation. Exclusion criteria were metastases in other organs like liver or lung.

Systemic chemotherapy

Patients received oxaliplatin 85 mg/m2, leucovorin 200 mg/m2, and docetaxel 50 mg/m2, each as a 1- to 2-h i.v. infusion followed by FU 2600 mg/m2 as a 24-h continuous infusion. The drugs were given on day one of two weekly cycles. Antiemetic prophylaxis was given according to local protocols. Prophylactic dexamethasone 8 mg was administered orally (days 0 to 3) to prevent fluid retention and allergic reactions. The dose of FU and docetaxel was reduced by 25% for diarrhea or mucositis exceeding NCI-CTC grade 2. In cases of paresthesia or dysesthesia persisting between cycles, oxaliplatin was reduced by 25%. In cases of paresthesia or dysesthesia accompanied by pain or functional impairment, oxaliplatin was reduced by 50% (if lasting between 7 and 14 days) or omitted in further cycles until recovery (if persisting between cycles).

Treatment was continued for three cycles before cytoreductive surgery and another three cycles thereafter. Treatment free interval between chemotherapy and surgery was a minimum of 3 weeks.

Cytoreductive surgery and hyperthermic peritoneal perfusion (HIPEC)

All CRS and HIPEC procedures were performed by the same team of surgical oncologists, anesthesiologist and operating room staff at DRK Manniske Hospital. The abdominal exploration was performed under general anesthesia and hemodynamic monitoring, through a midline xiphoid-pubic incision. Once the abdominal wall was open, detailed evaluation of peritoneal carcinomatosis index (PCI) was conducted, taking into consideration the size and distribution, according to the principle of Sugarbaker. The characteristics of ascites were also recorded. After evaluation, maximal CRS was performed, including the resection of the primary tumor with acceptable margins, any involved adjacent structures, D 2 -lymphadenectomy, peritoneotomies where peritoneal surfaces were involved by tumor, according to the peritonectomy procedure developed by Sugarbaker.

After surgery, HIPEC was performed before closure of abdominal cavity, as this open technique is believed to provide optimal thermal homogeneity and spatial diffusion, with 80 mg/m² Oxaliplatin and 200 mg/m² Taxotere each dissolved 3000 – 4000 ml of heated saline depending to volume of abdominal cavity. The heated perfusion solution was infused into the peritoneal cavity at a rate of 1500 ml/min through the inflow tube introduced from an automatic hyperthermia chemotherapy perfusion device (Skala medical, Prag). The skin of the abdomen is attached to a retractor ring and a plastic sheet covered the open wound to keep the temperature stable. The perfusion in the peritoneal cavity was stirred manually with care not to infuse directly on the bowel surface. The temperature of the perfusion solution in peritoneal space was kept at 41.5 ± 0.5°C and monitored with a thermometer on real time. The total HIPEC time was 45 min, after which the perfusion solution in the abdominal cavity was removed through the suction tube, and drainage tubes were placed at appropriate sites depending on the type of primary operation. The wound was closed with relaxing suture, and patient was delivered to the intensive care unit for recovery. When the condition stabilized, the patients were transferred to the surgical oncology ward.

The extent of CRS was determined by Sugarbaker’s criteria on the completeness of cytoreduction (CC). A score of CC-0 indicates no residual peritoneal disease after CRS; CC-1, less than 2.5 mm of residual disease; CC-2, residual tumor between 2.5 mm and 2.5 cm; and CC-3, more than 2.5 cm of residual tumor or the presence of a sheet of unresectable tumor nodules.

Statistical Analysis

All patients were regularly followed up for detailed monitoring of disease status. Data were obtained from a database of clinical records, surgical reports, medical imaging reports, laboratory and pathology reports, and follow-up records. Patients alive at the time of analysis were censored at the last follow-up. OS was estimated by the Kaplan–Meier method, stratified by PCI and CC, and tested with the log-rank test.

Results

Baseline Data and Surgical Intervention

A total of twenty six patients have been treated by systemic chemotherapy and underwent cytoreductive surgery plus HIPEC. Clinical characteristics are listed in Table 1.

Table 1: Clinicopathological characteristics of 26 patients with peritoneal carcinomatosis

Chemotherapy

Pre-operative induction chemotherapy for three cycles of FLOT - regimen was given as intended dosage in 25 of 26 patients corresponding to a completeness rate of 96.2 %. Reduced general condition was the reason in most cases not to complete intended chemotherapy postoperatively. Only 19 of 26 patients have been treated by chemotherapy corresponding to an application rate of 73.1 %.

surgical interventions

Intend of cytoreduction was to eliminate all visible tumor formations regardless of extent of intervention and regardless of how many organs have to be resected. Surgical procedures are listed in Table 2.

Table 2: surgical procedures

Survival Analysis

At the time of this writing, the median follow-up was 14.7 months (4.0 – 40.7 months). The median survival was 19 months. The 1- and 2-year survival rates were 72 % and 37 % shown in Table 3.

Table 3: survival curve of all patients treated by FLOT chemotherapy combined with CRS plus HIPEC

Simple regression analysis documented a linear correlation between extent of peritoneal involvement measured as Peritoneal Carcinosis Index (PCI) and risk for complication as documented in Table

Table 4: regression analysis documenting the linear correlation between PCI and complication rate

Extent of peritoneal involvement correlates to more aggressive surgical intervention and more resected abdominal organs. This improves the risk for severe and possibly life threatening complications. Univariate analysis on factors influencing survival detected extent of peritoneal involvement with a PCI > 12 as predictive (log rank test p= 0.052)(Table 4). In contrast to this presence of ascites (p = 0,159) and completeness of resection (p = 0.20) was not a predictive factor.

Table 5 survival curve dependent to peritoneal carcinosis index PCI >12, Log Rank – Test p = 0,052

Adverse Events

SAE grad 3 and 4 classified dependent to Clavien – Dindo scaling system had occurred in 6/ 26 patients (23 %) SAE included deep infection in 3 and anastomotic leckage in 3 (Table 4). Leakage rate of 93 performed anastomosis was 3.2%. There was no postoperative death within 30 days after surgery.

Table 4: SAE grad 3 and 4 classified dependent to Clavien – Dindo scaling system

Discussion

Gastric cancer is one of the major causes of cancer-related mortality worldwide. Its prognosis is poor and surgery offers the only realistic chance of cure. In case of inoperable tumors there is a need for effective induction treatment leading to inactivation of tumor cells and regression. Here we present data of a retrospective study about the combination of inductive chemotherapy followed by aggressive surgery for the treatment of peritoneal metastasized gastric cancer.

There is a rationale for combining docetaxel and oxaliplatin based on the activity of both agents in gastric cancer and in combination with infusional 5-FU, and their distinct and complementary mechanisms of action, lack of cross-resistance, and different toxicity profiles (17,18). The combination of docetaxel and oxaliplatin has been investigated in several recent phase 3 studies demonstrating a response rate of about 55 – 60 % combined with acceptable toxicity. Therefore we used the by Al Batran and co-workers in 2007 established FLOT – regimen as induction chemotherapy before performing cytoreductive surgery plus hyperthermic peritoneal perfusion (19).

Rationale behind cytoreductive surgery for peritoneal metastasized cancer is to reach a situation macroscopicly free of tumor. To reach this goal it is necessary to perform total gastrectomy, D2 – lymphnode dissection, resection of infiltrated organs and areal peritonectomy of affected peritoneum. At the end of surgery hyperthermic peritoneal perfusion (HIPEC) with Oxaliplatin and Doxetaxel was carried out using an open colliseum technique. Direct application of chemotherapeutic agents to the peritoneal surfaces in combination with hyperthermia allows for direct tissue penetration of the chemotherapy with limited systemic side effects. This technique has been evolved in last three decades leading to high rate of complete resections on one hand and an acceptable rate of complications on the other hand.

Interesting point in this study was the integration of aggressive surgery into a standard protocol of systemic chemotherapy. Drugs used for systemic chemotherapy – here Oxaliplatin and Docetaxel –were applicated during HIPEC to reach maximal efficacy of these cytostatics. This study should address the question of feasibility induced by a negative interference between chemotherapy and surgery on one hand and a possible positive effect of this combination in respect to survival.

With an over-all complication rate of 23 % and a leakage rate of 3.2 % this retrospective evaluation did not demonstrate a negative effect on complications due to previously given chemotherapy compared to recent publications in the literature (19,20). As an example Glehen et al. reported in a prospective study about peritonectomy plus HIPEC in the treatment of peritoneally metastasized gastric cancer a complication rate of 27 %. Complication rates in other trials are in the same range (19)

Combination of FLOT – regimen and cytoreductive surgery plus HIPEC resulted in a median survival rate of 19.0 months with 38 % of our patients living after 2 years. Compared to the publications given by Glehen (10.3 months), Yonemura (15.3 months), Hultman (14.3 months) and Yang (11.0 months) survival rate in our study seems to be somewhat higher (3,16,19,21). Hultman et al. presented data about a similar study with induction chemotherapy followed by cytoreductive surgery, HIPEC plus early postoperative intra-peritoneal chemotherapy. Postoperative complication rate was 62.5 % with a 90-day mortality rate of 10 %. Due to the exceedingly high complication rate median survival was 14.3 months only. We can confirm the statement given by Hultman and co-workers that aggressive surgery after inductive chemotherapy is not recommended in case of far advanced peritoneal carcinomatosis from gastric cancer. Using the data of our own study we have been able define the upper limit of effectiveness more precisely. For patients with a Peritoneal Cancer Index of 12 and more such aggressive treatment is not combined with prolongation in survival.

Our study has some limitations specifically in respect to the retrospective character of this evaluation. Here we cannot eliminate the possibility of a positive selection bias leading to higher rate of complete resections, lower complication rate and a somewhat positive influence on survival. Nevertheless the data presented in this study should be the basis for further evaluation.

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