125© T O U C H B R I E F I N G S 2 0 0 7

a report by

Marcel lo Deraco

Surgical Oncologist, Peritoneal Malignancies Unit, Department of Surgery, National Cancer Institute of Milan

Hyperthermic Oncology

Peritoneal surface malignancy (PSM) is a clinical entity with an

unfavourable prognosis that characterises the evolution of neoplastic

diseases from the abdominal and/or pelvic organs, and could also be the

terminal stage of extra-abdominal tumours.1–3 Examples of diseases that

can spread mainly within the peritoneal cavity include appendiceal

tumours, ovarian cancer, colorectal cancer, abdominal sarcomatosis,

gastric cancer and peritoneal mesothelioma.

Loco-regional therapy is defined as the combination of cytoreductive

surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC).

The rationale of this combined therapy for PSM is based on the fact that

this clinical entity remains confined to the peritoneal cavity for most of its

natural history. This pattern of spread would seem to indicate the

potential usefulness of selectively increasing drug concentration in the

tumour-bearing area by direct IPEC instillation.4

The Rationale for Hyperthermic

Intraperitoneal Chemotherapy

The drug concentration attainable through an IPEC instillation approach

allows the intrinsic or acquired drug resistance to be overcome,

simultaneously minimising the systemic toxicity. Loco-regional drug

delivery under hyperthermia offers several advantages over the same

procedure performed at normal temperature. At 40–42ºC, neoplastic

cells become more chemosensitive due to an increase in the intracellular

concentration of drugs and in their activation process – especially for

alkylating agents – as well as to alterations in the DNA repair process.5,6

Formation of platinum DNA adducts after cisplatin exposure is enhanced

and/or adduct removal is increased in heated cells, resulting in relatively

higher DNA damage.7 Table 1 summarises the most common drug

association used in HIPEC.

Cytoreductive Surgery

Each procedure that composes the peritonectomy technique to achieve

radical re-section of the tumour (see Figure 1) through CRS has a clearly

defined orderly sequence of surgical manoeuvres. One or more of the

following steps can be performed depending on the extension of primary

surgical staging or disease extension at the time of laparotomy in order

to achieve optimal residual status:

• greater omentectomy, right parietal peritonectomy and right colon

re-section;

• left upper quadrant peritonectomy, splenectomy and left parietal

peritonectomy;

• right upper quadrant peritonectomy and Glissonian’s capsule

re-section;

• lesser omentectomy, cholecystectomy, stripping of omental bursa

and antrectomy;

• pelvic peritonectomy with sigmoid colon re-section with or without

hysterectomy and bilateral salpingo-oophorectomy;

• other intestinal re-section and/or abdominal mass re-section; and

• bowel anastomoses.

Hyperthermic Intraperitoneal Chemotherapy

After CRS, four Tenckhoff catheters are placed in the abdominal cavity.

Two inflow catheters are placed in the right subphrenic cavity and at

deep pelvic level, respectively, and two further catheters are placed in the

left subphrenic cavity and in the superficial pelvic site. These catheters are

connected to a device.

The Device

HIPEC requires the employment of lung–heart machine, which comprises

a roller pump, a thermostat, a heat exchanger and an extra-corporeal

circuit. The perfusate flow is controlled and the heat exchanger adjusts

the temperature of perfusate by circulating water at the desired

temperature in the arterial phase of the circuit. The extra-corporeal circuit

consists of interconnected tubes that have: a) an input section (inflow); b)

an output section (outflow); c) an axis of rapid filling up; d) a central body

connected to a filter; e) a de-flow section; and f) a series of

multiperforated catheters in their extremities. The device should be

approved by CE accreditation. Several centres are currently using the

Performer LRT®.

The Perfusate

The perfusate, which is the liquid filling the circuit, could be of various

types: peritoneal dialysis solution;8 physiological solution;9 or a

composition of Normosol solution R pH 7.4 associated with Haemagel (in

the proportion 2:1).10 The recommended type of perfusate is isotonic salt

solutions and dextrose solutions.11

Modalities of Execution

The available modalities of execution are open, closed abdominal or semi-

closed techniques.12–15 In the closed technique, the skin of the abdominal

wall is temporarily closed with a running suture and the Tenckhoff

catheters are connected to the circuit in order to initiate the HIPEC.16 In

the open modality, also known as the Coliseum technique,17 the

abdomen is covered with a plastic sheet and drug vapour is evacuated to

protect the operating room personnel. The catheters are connected to

the extra-corporeal circuit and the pre-heated polysaline perfusate

containing the drug combination is instilled in the peritoneal cavity using

the heart–lung pump at a mean flow of 600–800ml/min for 60–90

minutes in order to achieve an intra-abdominal temperature of 42.5ºC.

State of the Art – Indications and Results of the Treatment

Table 2 provides information regarding the indications of CRS and HIPEC.

Cytoreductive Surgery and Intraperitoneal Hyperthermic Perfusion

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126 E U R O P E A N O N C O L O G I C A L D I S E A S E 2 0 0 7

Hyperthermic Oncology

Colorectal Carcinoma

In 2004, colorectal cancer was the second most common form of cancer

(381,000 cases) and the second most common cause of death due to

cancer (203,700 deaths) in Europe. At initial diagnosis of colon cancer,

the peritoneal surface is tumorous in 10–15% of patients. The

peritoneal surface is the second most common site for cancer recurrence

after so-called curative colorectal cancer re-sections, occurring in as

many as 50% of patients.

Recent advances in the systemic treatment of advanced and/or metastic

colorectal cancer – with the introduction of oxaliplatin/irinotecan

associated or not with biological therapies – have allowed the

achievement of median survival of up to 20 months.18 However, these

favourable results should not be expected for patients with peritoneal

carcinomatosis, as this subset of patients represents a minority of

the population deemed as advanced and/or metastatic cases in the

main studies.

A systematic review of relevant studies on CRS with early peri-operative

IPEC before March 2006 has recently been published.19 Two randomised

controlled trials, one comparative study, one multi-institutional registry

study and the 10 most recent case-series studies were evaluated. The

median survival of patients treated by CRS associated with early peri-

operative IPEC varied from 13 to 29 months, and five-year survival rates

ranged from 11 to 19%. Patients who received complete cytoreduction

benefited most, with median survival varying from 28 to 60 months and

five-year survival ranging from 22 to 49%. The overall morbidity rate

varied from 23 to 44% and the mortality rate ranged from 0 to 12%. The

authors concluded that the current evidence suggests that CRS combined

with peri-operative IPEC is associated with improved survival compared

with systemic chemotherapy for peritoneal carcinomatosis from

colorectal carcinoma.

Gastric Cancer

In 2004, gastric cancer was the fifth most common form of cancer

(171,000 cases) and the third most common cause of death due to

cancer (137,000 deaths) in Europe. A meta-analysis has recently been

conducted involving 10 randomised controlled trials in which patients

with gastric cancer were randomly assigned to receive surgery combined

with IPEC versus surgery without IPEC.20 A significant improvement in

survival was associated with HIPEC alone (hazard ratio (HR) 0.60; 95%

confidence interval (CI) 0.43–0.83; p=0.002) or HIPEC combined with

early post-operative IPEC (HR 0.45; 95% CI 0.29–0.68; p=0.0002). The

authors concluded that HIPEC with or without early post-operative IPEC

after re-section of advanced gastric primary cancer is associated with an

improved overall survival.

Ovarian Cancer

Ovarian cancer – with an incidence of 44,000 cases a year in Europe in

2004 – remains the most lethal of all gynaecological malignancies, being

responsible for about 50% of all deaths from female genital tract

cancer.21 A recent systematic review of 14 studies published in the English

literature evaluating the effects of CRS+HIPEC in patients with ovarian

cancer has been carried out.22 Seven studies showed that patients with

complete cytoreduction had the greatest benefit. Median overall survival

for primary and recurrent disease ranged from 22 to 54 months, and

median disease-free survival from 10 to 26 months. The rates of

significant morbidity associated with this combined treatment were low,

ranging from 5 to 36%. The median mortality was 3% (range 0–10%).

Cytoreductive surgery combined with heated IPEC is a treatment option

for patients with ovarian cancer that is worthy of further investigation.

The Italian Society of Integrated Loco-regional Therapy (SITILO) is

conducting a prospective multicentre randomised study to test the

effectiveness of secondary CRS associated with HIPEC in patients with

epithelial ovarian cancer as second-line therapy.

Appendiceal Mucinous Tumours and

Pseudomyxoma Peritonei

A recent published systematic review reported on five observational

studies with relatively large series (n≥100) in patients affected by

pseudomyxoma peritonei (PMP). The median survival after the treatment

CRS+HIPEC ranged from 51 to 156 months. One-, two-, three- and five-

year survival rates varied from 80 to 100%, 76 to 96%, 59 to 96% and

52 to 96%, respectively. Overall morbidity rate varied from 33 to 56%,

and overall mortality rates ranged from 0 to 18%. In summary, some

promising long-term results were observed compared with historical

controls. Due to the rarity of this disease, a well designed, prospective,

multi-institutional study would be meaningful.23

Peritoneal Mesothelioma

According to an epidemiological study conducted in six western

European countries, projections for the period 1995–2029 suggest that

the number of men dying from mesothelioma each year will almost

Table 1: Drugs Schedule for Hyperthermic Intraperitoneal Chemotherapy

Author/Year Drug Dosage Drug Dose Duration of the IndicationPerfusion

Rossi et al. 200226 Cisplatin 43mg/l of perfusate Adriamycin 15.25mg/l of perfusate 90 min Ovarian cancer and

peritoneal mesothelioma

Fujimoto et al. 199327 Cisplatin 25.0mg/m2/l of Mitomycin C 3.3gm/m2/l of perfusate 60 min Pseudomyxoma peritonei

perfusate Colorectal cancer

Elias et al. 200228 Oxaliplatin 460mg/m2 in 2l/m2 30 min Colorectal cancer

of perfusate

De Bree et. al 200329 Docetaxel 75mg/m2 Ovarian cancer

HIPEC = hyperthermic intraperitoneal chemotherapy.

Table 2: Indications of Cytoreductive Surgery and HyperthermicIntraperitoneal Chemotherapy

Resectable PC from ovarian cancer after first-line chemotherapy*

Peritoneal mesothelioma30,31

Resectable PC from colorectal cancer32–36

Mucinous tumour from the appendix with Pseudomyxoma peritonei37,38

Carcinoma of the appendix with resectable PC39

Gastric cancer with resectable PC40–43

PC = peritoneal carcinomatosis. * Under phase III investigation.

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128 E U R O P E A N O N C O L O G I C A L D I S E A S E 2 0 0 7

Hyperthermic Oncology

double over the next 20 years, with a total of about a quarter of a million

deaths over the next 35 years. This projection has been attributed to the

wide use of asbestos in western Europe until 1980; substantial quantities

are still used in several European countries.24 Although these projections

were calculated for the pleural form of mesothelioma, a similar increase

in mortality due to the peritoneal form of the disease could be expected

in the next few years.

A recent systematic review evaluated the current evidence for CRS and

peri-operative IPEC for diffuse malignant peritoneal mesothelioma

(PSM).25 Seven observational studies were available for assessment; these

demonstrated an improved overall survival compared with historical

controls using systemic chemotherapy and palliative surgery. The median

survival ranged from 34 to 92 months. One-, three- and five-year survival

varied from 60 to 88%, 43% to 65% and 29% to 59%, respectively.

Peri-operative morbidity varied from 25 to 40% and mortality ranged

from 0 to 8%.

Conclusion

Loco-regional treatment for PSM is attracting increasing interest from the

scientific community. The procedure is time- and labour-consuming: the

mean duration of the procedure, according to the National Cancer

Institute of Milan experience, is nine hours; average duration of

hospitalisation is 23 days; and mean cost is €30,000. The institution of a

programme in PSM requires not only highly specialised human resources

but also complex technological facilities. At least 130 active centres in

western Europe have already set up such a programme for PSM.

However, each centre is able to perform no more than 50–60 procedures

per year due to its complexity.

Considering the projected constant increase of the prevalence of diseases

treatable by the procedure, more centres should be activated. In this

sense the establishment of clear policy and scientific guidelines is

mandatory in order to allow clinicians to perform CRS+HIPEC safely,

minimising treatment-related morbidity and mortality and maximising

results in terms of survival and quality of life. ■

Consensus Statement on Peritoneal Surface Malignancies

An International Workshop on Peritoneal Surface Malignancies took

place in Milan in December 2006. On this occasion, a panel of experts in

loco-regional therapy achieved an agreement pertaining to conceptual

and technical aspects regarding the methodology and indications of local

regional treatment of PSM. They also managed to establish general

treatment guidelines and investigational future prospects of main

peritoneal surface malignancies. More randomised data for each disease

are necessary to confirm the efficacy of this complex approach. On the

other hand, studies on biological markers with prognostic value should

also be conducted to improve the indications of the procedure. For more

information visit: www.peritonealworkshop2006.it and www.sitilo.org

Figure 1: The Various Phases of Cytoreductive Surgery – thePeritonectomy Procedure

Spleen and omentum

Stomach andlesser omentum

Rectum signoidcolon and pelvicperitoneum

Right colon andparictal peritoneum

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July 25-28, 2007 - Foz do Iguazu, Brazil

Organisers : J. Goldman, G. Daley, C. Jamieson, J. Melo, N. Nardi, P. Quesenberry, L. Silla, D. Tabak, I. Weissman, M. Zago

ESH-SOCIEDADE BRASILEIRA DE HEMATOLOGIA E HEMOTERAPIA-COLEGIA BRASILEIRO DE HEMATOLOGIA CONFERENCE :

MOLECULAR CHARACTERISTICS OF NORMAL AND LEUKEMIA STEM CELLS

September 10-11, 2007 - Mumbai, India

Chairs : F. Cavalli, J. Goldman

Host chair : S. Advani, Scientific organiser : T. Mughal

ESO-ESH-INCTR FIRST GLOBAL CANCER INITIATIVE :LEUKAEMIAS

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