Surgery Today

, Volume 46, Issue 8, pp 979–984 | Cite as

Cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (HIPEC) delivered via a modified perfusion system for peritoneal carcinomatosis of colorectal origin

  • Adrian Cravioto-Villanueva
  • Magdalena Cavazos
  • Pedro Luna-Perez
  • Hector Martinez-Gomez
  • María Lourdes Ramirez
  • Juan Solorzano
  • Hermelindo Montiel
  • Jesus Esquivel
Original Article
  • 321 Downloads

Abstract

Background and purpose

The long-term survival of patients with peritoneal carcinomatosis of colorectal origin has been achieved with cytoreductive surgery, which removes all macroscopic implants, combined with hyperthermic intraperitoneal chemotherapy (HIPEC). The current technology for administering intraperitoneal heated chemotherapy is expensive and, for some institutions, unaffordable. We conducted this study to assess the temperature stability provided by a modified, inexpensive system, to offer a simple and low cost alternative to the standard HIPEC delivery equipment.

Methods

Ten patients with histologically diagnosed peritoneal metastases of adenocarcinoma or pseudomyxoma peritonei underwent cytoreductive surgery and received HIPEC with 5-fluorouracil for 90 min, delivered via our modified system. The temperature was recorded from two probes: one in the inflow catheter and one in the outflow catheter. The intra-abdominal temperature was monitored meticulously to maintain it at between 41 and 42 °C.

Results

All patients underwent cytoreductive surgery and HIPEC using our modified delivery system. Temperature stability was achieved in all patients, with a mean of 41.4°. There were no thermal injuries associated with any of the ten perfusions. The mean hospital stay was 15 days and the median survival was 30 months.

Conclusion

Analysis of this data demonstrates that the uniform delivery of HIPEC at 41° with this modified system is feasible and safe. The outcome of the patients treated with cytoreductive surgery and HIPEC with this modified system compares favorably to other published series. Its low cost and simple design will give more patients with peritoneal carcinomatosis access to this treatment.

Keywords

Peritonectomy Cytoreduction Intraperitoneal hyperthermic chemotherapy Peritoneal carcinomatosis colorectal cancer 

Introduction

Involvement of the peritoneal surface is present in 10–15 % of colon cancer patients at the time of diagnosis [1, 2]. It is the second-most frequent cause of death from colorectal cancer after liver metastasis, occurring in as many as 50 % of patients. [3, 4] In an estimated 25 % of the patients, no other tumor locations can be found, even when a detailed diagnostic work-up is performed [5, 6, 7].

Peritoneal carcinomatosis from colorectal cancer has long been considered a terminal condition with no curative treatment options. The median survival has been reported as 5–7 months after treatment with fluorouracil and leucovorin [2, 8, 9] Despite new combinations of chemotherapeutic agents, such as irinotecan and oxaliplatin, the results of systemic chemotherapy treatment continue to show only mild benefit [10, 11, 12]. It has been proposed that positive peritoneal lavage cytology could be an indicator of a poor prognosis in colorectal cancer patients, but further studies are needed to clarify the prognostic impact of peritoneal lavage cytology [13, 14].

Recent reports suggest that potentially curative treatment is possible. Several phase II studies have reported the use of a combined therapeutic strategy of cytoreductive surgery and HIPEC for patients with colorectal carcinomatosis, achieving 3-year survival rates ranging from 25 to 47 % [15, 16, 17, 18, 19, 20, 21]. A phase III study demonstrated median survival of 22.3 vs. 12.6 months after the standard therapy arm [22]. A collaborative effort of 28 institutions reported median survival of 32.4 months for patients who underwent complete cytoreductive surgery [23]. Other reports suggest that HIPEC plays a potential role in the prevention of carcinomatosis and local recurrence and that a more aggressive preventive surgical approach combined with HIPEC reduces the incidence of peritoneal recurrence in patients with colonic cancer and significantly increases their disease-free survival [24, 25, 26].

Despite multiple studies suggesting the benefits of this combined treatment strategy, cytoreductive surgery and HIPEC are performed only in specialized cancer institutions. One of the main reasons for its limited distribution in many countries is the high cost of the perfusion machines, and the lack of affordable perfusion equipment and disposable kits. To overcome these obstacles, we developed a simple and affordable hyperthermic perfusion system. The purpose of this study is to demonstrate the effectiveness of our simple system of hyperthermic perfusion for maintaining stable temperatures throughout the abdomen and pelvis during hyperthermic intraperitoneal chemotherapeutic perfusion.

Patients and methods

The eligibility criteria for inclusion in this study were as follows: histologically proven peritoneal metastases of colorectal adenocarcinoma, or pseudomyxoma, diagnosed either at initial presentation or at recurrence; and an age younger than 75 years, with a good performance status (Eastern Cooperative Oncology Group <2), and a low cardiovascular risk.

All procedures were performed in the Hospital de Oncologia, Centro Medico Nacional Siglo XXI, Mexico City, Mexico. Laparotomy under general anesthesia was performed through a xyphoid to pubis incision. After opening the abdomen, the presence of tumor was recorded according to the peritoneal cancer index described by Sugarbaker [27] (Fig. 1). The surgical goal was to achieve complete cytoreduction, leaving no macroscopic tumor behind. To achieve this, peritonectomy was carried out as described by Sugarbaker, et al. [27] and infiltrated viscera were resected en bloc.
Fig. 1

Peritoneal cancer index

After the cytoreduction was completed, the patient’s skin was pulled and sutured to the mechanical retractor to create a “Coliseum” container for instillation of the peritoneal perfusate. Inflow and outflow catheters were then placed. The abdominal wall was manually agitated during the perfusion period in an attempt to achieve uniform distribution of the chemotherapy and heat.

Modified system

The system we used is simple and affordable. It consists of two cardiovascular pumps (Fig. 2), a chemotherapy reservoir, a filter, a serpentine tube, a water container, and a portable electric heater (Fig. 3). Once the cytoreduction has been completed, four plastic sterile tubes are installed in the abdomen. French 15- or 19-guage surgical drain tubes can be used for this. Redivac or Jackson-Pratt® (Cardinal Health Inc. McGaw Park, IL, USA) drain tubes are also excellent options for this purpose. Two tubes are inserted in the right side of the abdomen: one in the upper abdomen and one in the lower abdomen. This are considered the inflow tubes. The drain holes are directed to the sites with more residual tumor volume. The inflow tubes are coupled with a “y” connector to a tube that comes from the heater system using a sterile plastic tube. The chemotherapy is pumped to the heater with a cardiovascular mechanical device. Two tubes are inserted in the left side of the abdomen and are set to the upper and lower abdomen for outflow. They are also connected with a “y” connector to the “outflow” cardiovascular pump. The reservoir containing the chemotherapy with the perfusion liquid is connected to this pump.
Fig. 2

Cardiovascular pumps used for perfusion

Fig. 3

Heater system used for perfusion, consisting of a serpentine tube, a water container, and a portable electric heater. The water is heated to 50 °C, with an expected outflow temperature from the serpentine of 42 °C

The heater system consists of a container filled with 3 L of non-sterile water, a sterile serpentine tube and a portable electric heater. The water temperature is elevated to 50 °C. The perfusate is passed into the serpentine tube submerged in the container. The serpentine tube is a 1-m-long sterilized tube with a diameter of 15–20 cm. The flow rate was 2 L/min. The chemotherapy was prepared with 650 mg/m2 body surface area of 5-fluorouracil diluted in 2 L of isotonic saline solution and was kept in the reservoir.

We used 2 L of isotonic salt solution to test the perfusion circuit and two cardiovascular pumps for better control of inflow and outflow, although it can be peformed with only one pump. The temperature was measured with a thermometer probe connected to the anesthesia machine introduced intra-abdominally via the inflow and outflow site. The chemotherapy was added to the perfusate when the inflow target temperature had been reached. The patient’s core temperature was monitored with an esophageal temperature probe. Every 15 min, we measured the urine output, and recorded pulse and blood pressure to monitor for hemodynamic instability. We switched off the device for a few minutes when temperature rose above 42 °C in the inflow thermometer, and switched it on when dropped below 41 °C.

After cytoreductive surgery, the abdomen was re-opened and the perfusate was evacuated. A Tenckhoff catheter was placed through the abdominal wall in the area with the highest risk of recurrence. Closed suctions drains for the perfusion were placed in dependent areas in the pelvis and below each side of the diaphragm. The abdomen was closed and then thoroughly drained through the Tenckhoff catheter to wash out blood clots or tissue debris.

All patients were given early postoperative intraperitoneal chemotherapy (EPIC) with fluorouracil (650 mg/m2) in 1 L of solution. It was drained through the closed suction drains after 23 h for 5 postoperative days. Temperatures where recorded every 10 min during the 90 min of hyperthermic perfusion. Morbidity associated with hyperthermia was recorded

Statistical analysis

The main end point was temperature recording. Survival was recorded as the time from the procedure to death from any cause. Patients alive at the time of analysis were censored at their last follow-up examination. Survival was estimated by the Kaplan–Meier method and tested with the log-rank test following the intention-to treat principle. Statistically analysis was carried out with the SPSS v.15 software package.

Results

Between January, 2005 and December, 2005, ten patients were prospectively included in this study (six women and four men; mean age, 50 years; range, 29–68 years). Table 1 summarizes the patients’ characteristics. The primary tumor was located in the right colon in 70 % of patients, the sigmoid colon in 20 %, and the rectum in 10 %. Half of the patients presented with synchronous carcinomatosis and the other half with carcinomatosis as the result of disease progression.
Table 1

Patients’ characteristics

Characteristics

n

%

Symptoms

 Obstruction

1

10

 Rectal bleeding

1

10

 Pain

6

60

 Other

2

20

Primary tumor

 Right colon

7

70

 Sigmoid

2

20

 Rectum

1

10

Carcinomatosis

 Initial

5

50

 Progression

5

50

 Blood transfusion

7

70

Histology

 Adenocarcinoma

7

70

 Pseudomixoma

3

30

Tumor

  

 T3

2

20

 T4

8

80

N

 N0

6

60

 N1

1

10

 N2

3

30

M

 M0

5

50

M1

5

50

Staging

 IIA

2

20

 IIB

1

10

 IIIB

1

10

 IIIC

1

10

 IV

5

50

The mean operative time was 417 min ± SD 163 (105–690) and mean blood loss was 1055 ml ± SD 1097 (150–4000). Seven patients required blood transfusion. Complete cytoreduction (CC0/1) was achieved in 60 % of the patients as three patients (30 %) had gross disease left behind. The temperature was measured every 10 min for the 90 min of perfusion therapy. The mean temperature of all patients was 41.44° ± SD 0.79, maintaining intraoperative intraperitoneal temperatures at 40.1°–41.69° (Table 2).
Table 2

Temperatures of ten patients treated with peritonectomy and intraperitoneal hyperthermic chemotherapy delivered by our modified perfusion system

 

0′

10′

20′

30′

40′

50′

60′

70′

80′

90′

Mean

Patient 1

41.3

41.5

41

41.3

42

42.3

42

41.9

41.5

41.5

41.63

Patient 2

42

41.5

41.4

41.2

40

39.7

42

41.9

41.5

41.5

41.27

Patient 3

38

42

42.5

41.9

41.9

41.5

41

41.3

40

40.2

41.03

Patient 4

40

40.1

40.3

40.2

40.1

39.9

40

40

40.2

40.2

40.1

Patient 5

39.8

40

41.2

41.3

41.1

40.9

41

41.5

42

42.1

41.09

Patient 6

41.1

41.1

40.9

40

40.1

40.3

40.5

40.5

40.4

40.9

40.58

Patient 7

40.5

41.2

42

42

41.9

41.5

41.4

42

42.1

42

41.66

Patient 8

39.9

40

41

41.5

41.5

41.7

42.1

42

41.5

41

41.22

Patient 9

40.5

41

41.5

42

41.9

41.8

41.5

40

39.5

41

41.69

Patient 10

41.5

41

41.5

42

41.9

41.8

41.5

40

39.5

41

41.17

The final histopathological diagnosis was adenocarcinoma in seven patients and pseudomyxoma in three patients. Two patients had postoperative ileus that resolved with conservative therapy. There were no complications associated with hyperthermia. The mean hospital stay was 15 days. The mean follow up was 19 months ± SD 20.34 (2–68). The-year disease free survival rate was 30 %, with a median survival of 30 months. Four patients had local recurrence, and three had distant metastases.

Discussion

Cytoreductive surgery and peritonectomy procedures with HIPEC have demonstrated that curative treatment is possible for selected patients with peritoneal surface malignancies [22, 23]. While complete surgical eradication is necessary for a good long-term result, there is still considerable variation in the technology of heated intraperitoneal chemotherapy delivery. Which drugs should be given and for how long, what should the optimal temperature be, and what is the best method of delivery (open vs closed vs semi-open) are some of the questions that still need to be answered. In the most recent meeting in September, 2010 in Uppsala, Sweden, it was agreed that further research is needed to answer these questions and that it is still impossible to establish if one method is superior to the others. The current recommendation is to perform the best known and routinely used technique according to what is available at a particular institution.

To deliver intraperitoneal chemotherapy during a surgical procedure with moderate hyperthermia (41–43 °C), perfusion apparatus is required [28, 29]. One of the reasons that HIPEC is not practiced worldwide is because the equipment required to deliver it is too expensive. We modified the system to make it simple and inexpensive to install and use. The materials used in the system are affordable and easily available, making this technology accessible for more surgical teams. Even though we used two cardiovascular perfusion pumps in this study, the delivery can be performed with just one pump.

The optimal target temperature has been reviewed extensively, focusing on key considerations, such as the interaction of heat and chemotherapy agents, the risk of side effects, and the method of achieving and controlling the ideal temperature. According to the 2006 consensus statement on HIPEC for the management of peritoneal carcinomatosis of colorectal disease, the intraperitoneal temperature target ranges between 39 and 42 °C for 60–120 min. However, in 2008, a panel of experts in intraperitoneal chemotherapy agreed to set the target temperature in the range of 41°–43°.

We used the system in ten patients, to deliver temperatures above 41 grades for 90 min, without any variations of temperature. Patients were not exposed to high hyperthermia (above 43 °C), avoiding the risks related to this exposure. In this series, there were two patients with postoperative ileus, which resolved with conservative therapy, consisting of a nasogastric tube and suspension of oral feeding on postoperative days 7 and 10. While this morbidity could be attributed to the hyperthermia, it is a common complication of surgery.

A drawback of the system is the need for continuous monitoring of the perfusate temperature to keep it at 50°. Furthermore, manual control of temperature needs to be done by switching the heating device on and off according to the intraperitoneal temperature probe readings, implying that one person must monitor the temperatures and control the heating device.

Other modalities to deliver intraperitoneal hyperthermia have been assessed. Ortega-Deballon et al. [30] developed an internal heating device to heat the solution within the abdomen in a pig model, avoiding the need for an external circuit. An open-abdomen technique was performed, with the placement of two loop-wires in the supramesocolic and inframesocolic areas, achieving the target temperature in 14 min and keeping homogenous temperature levels by continuously stirring the intraperitoneal fluid. They reported that the procedure was safe, feasible, and affordable for most institutions. Nevertheless, continuous stirring of the intraabdominal fluid needs to be done by one person to reduce the risk of thermal injury and it has not been performed in humans.

In conclusion, this modified version of the perfusion system is affordable to hospitals and countries that are not able to perform cytoreductive surgery and HIPEC because they cannot afford an expensive hyperthermic perfusion machine. It provides a feasible, safe, and reliable treatment alternative for patients with peritoneal carcinomatosis.

Notes

Acknowledgments

We thank the Hospital de Cardiologia, Centro Medico Nacional “Siglo XXI” headed by Dr. Ruben Argüero, Dr. Careaga, Chairman of Cardiovascular Surgery and Dr. Reyes, Chairman of Perfusion Medicine, for invaluable support provided by lending us the cardiovascular pumps for this study.

Compliance with ethical standards

Conflict of interest

We have no potential conflicts of interest to declare.

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Copyright information

© Springer Japan 2016

Authors and Affiliations

  • Adrian Cravioto-Villanueva
    • 1
  • Magdalena Cavazos
    • 1
  • Pedro Luna-Perez
    • 1
  • Hector Martinez-Gomez
    • 1
  • María Lourdes Ramirez
    • 1
  • Juan Solorzano
    • 1
    • 2
    • 3
  • Hermelindo Montiel
    • 2
  • Jesus Esquivel
    • 3
  1. 1.Hospital de Oncologia, Department of Surgical Oncology, Colorectal serviceHospital de Oncologia Centro Medico Nacional “Siglo XXI” IMSSMexico CityMexico
  2. 2.Department of Cardiovascular Surgery, Perfusion Medicine, Centro Medico Nacional “Siglo XXI” IMSSHospital de CardiologiaMexico CityMexico
  3. 3.Peritoneal Surface Malignancy Program, GI Surgical OncologySt. Agnes Health CareBaltimoreUSA

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