202410052031
Status:
Tags: Oncology,
Hyperthermic intraperitoneal chemotherapy
Cytoreductive surgery (CRS) combined with hyperthermic intraperitoneal chemotherapy (HIPEC) has long been an established treatment for patients with pseudomyxoma peritonei (PMP), a rare malignancy originating from the appendix
The aim of CRS is to eradicate all macroscopic tumours using a laparotomy approach.
The surgical procedure involves removing all or part of any affected organs and the lining of the peritoneal cavity. In PMP, pathognomonic mucin is also removed.
Cytoreductive surgery often includes, but is not limited to, the resection of:
- Right hemicolon, spleen, gall bladder, greater and lesser omenta and parts of the stomach
- Stripping of the peritoneum, including pelvic and diaphragmatic
- Stripping tumour from liver capsule or liver capsulectomy
- Removal of ovaries and uterus in women.
Even with optimal macroscopic cytoreduction, microscopic tumour deposits will remain. This invisible residual disease is treated with on-table topical HIPEC.
During HIPEC, the abdominal cavity is perfused with chemotherapy solution heated to between 40 and 43°C for 30–120 min
Intraperitoneal administration of chemotherapy during surgery allows the drug to be applied uniformly to all surfaces of the abdomen and pelvis. This topical approach removes the need for high systemic concentrations of chemotherapeutic agents and is not reliant on local blood supply to carry the cytotoxin to affected areas.
The actual method of delivery of chemotherapy into the abdominal cavity varies between units from purpose-built pumps to modified bypass or Belmont pumps, and this method may be performed by a nurse, a perfusionist or an anaesthetist.
The penetration into peritoneal metastases of intraperitoneal chemotherapy is limited to a depth of between 2 and 5 mm, highlighting the importance of complete macroscopic cytoreduction before HIPEC administration
Heat is known to potentiate the effects of chemotherapeutic agents and increase their penetration into tumour tissue, and it also appears to reduce mechanisms of tumour resistance to chemotherapy.
The synergy between heat and drug cytotoxicity appears to require a minimum temperature of 39°C and starts to diminish above 43°C. Temperatures above 44°C can result in apoptosis of normal cells
The majority of chemotherapeutic drugs used for HIPEC are ‘cell cycle non-specific’, acting in the cell resting phase, as opposed to more traditional chemotherapeutic agents that aim to act during a certain phase of the cell cycle, and hence delivered at intervals in several doses.
Another major advantage of HIPEC is regional dose intensity
The peritoneal cavity is exposed to higher concentrations of the chemotherapy agent than the rest of the body.
The concentration differential arises because peritoneal clearance of the chemoactive agent is relatively slow compared with clearance from the rest of the body.
The rate of systemic absorption ∝
- lipophilicity,
- molecular weight
- degree of ionisation.
Low-molecular-weight and highly lipophilic drugs are better absorbed, and so the drugs chosen for HIPEC are the reverse.
Open vs closed technique
Open
The open abdomen = coliseum technique
abdominal wall is elevated to create a funnel and the chemoperfusate flows between the inflow and outflow lines, which are attached to the pump and heating unit
optimal distribution of both cytotoxic solution and heat because of the manual stirring performed by the surgeon
↑ risk of spillage of cytotoxic agents
Closed
the closed technique, in which the inflow and outflow of HIPEC are delivered through separate incisions, after the laparotomy incision has been closed, has been proposed to retain temperature more effectively and also reduce exposure risk to operating theatre staff by reducing local atmospheric contamination. However, homogeneous distribution of the fluid may not be achieved.
Chemo agent
Agents used commonly include mitomycin C, cisplatin, oxaliplatin and 5-fluorouracil
Dose calculations of chemotherapeutic agents are usually based on body surface area. However, there is currently no international consensus on dosage or duration of HIPEC administration.
cisplatin is a/w postoperative renal impairment (5%)
- renal excretion → accumulation in proximal tubule
- IV hydration ↓ cisplatin T1/2 & transit time in proximal tubules
- may be combined w/ mannitol or lasix
- ↓ nephrotoxicity w/ Sodium thiosulfate
oxaliplatin a/w higher risk of postoperative bleeding
- diluted in D5 ∵ tendency to be converted to oxalate = risk of peripheral neuropathy
Parenteral sodium thiosulfate before HIPEC with cisplatin could be performed to avoid nephrotoxicity.
Intraoperative loop diuretics and dopamine for renal protection should NOT be performed routinely in patients undergoing CRS and HIPEC.
High risk of M&M
Postoperative complications include
- bowel perforation,
- anastomotic leak,
- fistula formation,
- sepsis,
- acute kidney injury (AKI)
- cardiorespiratory and thromboembolic events
Pre-op
patient selection
based on
- patients' surgical suitability,
- their current general health status
- comorbidities.
Clinical features suggesting a favourable outcome from CRS and HIPEC:
- General medical condition compatible with survival and recovery from the procedure
- Clinical information regarding the peritoneal metastases compatible with a complete or near-complete cytoreduction
- Relative sparing of the small bowel and colon
- Absence of disease outside the abdomen/pelvis
- If hepatic metastases are present, they are limited and are compatible with wedge resection
- Absence of disease within the porta hepatis
- With a high-grade malignancy, a low or moderate peritoneal cancer index
- Patients with symptoms
Clinical features suggesting CRS and HIPEC should NOT be recommended include:
- Poor physical performance status
- Rapid progression of a high-grade disease process
- Low likelihood of a response to perioperative chemotherapy
- Prior abdominal or pelvic radiation therapy
- Asymptomatic from peritoneal metastases
Poor prognosticators:
- recent positive smoking history,
- a poor subjective or objective physical performance status,
- previous extensive surgery
- those who require extensive cytoreduction
pre-op optimisation
Many of these patients are both cachectic and anaemic on presentation, and may require iron transfusions, physiotherapy or nutritional support before surgery
prehab
anaemia
nutrition
smoking / alcohol cessation
assess frailty / cardiac risk / OSA risk
Peritoneal cancer index score
developed in 1996
assess extent of peritoneal cancer throughout peritoneal cavity
divides peritoneal cavity into 13 regions
each region given a score from 0 to 3. ∝ extent of tumour
calculated during surgery
surgery is only attempted if a ‘complete cytoreduction’ (removal of all visible/macroscopic tumour) is considered possible
Anaesthetic consideration
at least one wide-bore cannula for giving fluids, including blood products; an arterial cannula for intraoperative arterial pressure measurement and frequent blood sampling; and central venous access
Although rapid blood loss is rare during these procedures, significant intraoperative fluid shifts are commonplace and cardiac output monitoring is essential to guide perioperative fluid management.
Thoracic epidurals are commonly sited before surgery for both intra- and postoperative pain relief as part of a multimodal approach to analgesia
Concerns RE: epidural
- haemodynamics
- coagulopathy from bleeding
a temperature probe, a urinary catheter and a nasogastric tube are all placed as standard.
Procedures can take anything from 5 to 15 h, and so careful positioning with protection of pressure areas is essential
Risk of aspiration (IO, ascites): ensure adequate pre-op fasting, may need RSI
may be hypothermic before HIPEC phase
Fluids
Ascitic drainage, prolonged surgery and exposed raw visceral surfaces, combined with the cardiovascular effects of HIPEC, often lead to fluid requirements exceeding 12 ml/kg/h
Patients often develop a hyperdynamic circulatory state before HIPEC starts because of profound systemic inflammatory response syndrome secondary to extensive surgical injury
most centres suggest maintaining the MAP within 20% of the patient's preoperative baseline and maintaining the stroke volume variation below 10% with a combination of fluids and vasopressors
Blood loss during CRS can be substantial, but is also often insidious. It is important to remain vigilant to help prevent intraoperative anaemia, acidosis and cardiovascular instability
UO as guide
CO monitoring
Fluid administration of 9–12 mL/kg/h has been advocated, in particular if platinum derivatives are used to ensure a satisfactory urinary output (at least 1 mL/kg/h)
The use of furosemide, dopamine and mannitol for urinary output cannot be generally recommended
During CRS±HIPEC, use of goal-directed fluid therapy and catecholamines guided by advanced/invasive monitoring should be indicated routinely in order to maintain adequate urine output of >1 mL/kg/h.
Mx of coagulation
Patients undergoing extensive CRS and HIPEC will often develop a coagulopathy.
Risk factors include
- tumour type,
- common with PMP and mesothelioma cases;
- specific procedures,
- such as liver capsulectomy or deep pelvic surgery;
- overall duration of surgery,
- possibly reflecting the extent of disease or the difficulty of the surgery
The exact cause of the coagulopathy in CRS and HIPEC is still poorly understood. However, it is probably a combination of consumption and dilution of coagulation factors
Centres using bedside viscoelastography have noted that an acquired fibrinogen deficiency is common, supporting the accumulating evidence for the critical role of fibrinogen in haemostasis during haemorrhage. Regular doses of tranexamic acid are commonly given to prevent fibrinolysis
Cryoprecipitate and fresh frozen plasma are the mainstays of treatment for the coagulopathy associated with this type of surgery.
Giving platelets in isolation is rare and usually associated with a preoperative deficiency
Pain
A combination of thoracic epidural anaesthesia and PCA is commonly used to control postoperative pain. Some centres use intrathecal opiates in preference to epidural analgesia. PCAs are typically opioid based and supplemented with regular simple analgesics, such as paracetamol, and other adjuncts, such as ketamine or lignocaine infusions.
Patients undergoing CRS and HIPEC commonly require analgesia to cover pain distributed from high thoracic dermatomes down to the sacral roots. Most have a large midline excision and have undergone surgical dissection in all quadrants of the abdomen. Extensive pelvic dissection or diaphragm stripping can be particularly painful
Epidural analgesia (T5-T11, low dose of local anaesthetic and opioids) for ≥72 h after CRS/HIPEC should be indicated routinely to obtain pain relief, spare opioids and hasten the resumption of bowel function.
HIPEC phase
During the HIPEC phase, patients become hyperthermic, as heat is absorbed from the abdomen from the warmed chemotherapy fluid (range: 36–41°C).
Moderate hyperthermia is tolerated, but most centres aim to keep the patients' core temperatures below 39°C.
Active cooling techniques include cooled i.v. fluids, ice packs and cooling mattresses. Very rarely, the HIPEC temperature needs to be reduced to control the core temperature
A hyperdynamic circulation often develops, which may require treatment with both fluids and vasopressors.
hyperglycaeima ∵ dextrose instillate
Electrolyte disturbances from carrier fluids / PD fluid
- hypoNa ∵
- diffusion from peritoneal solution
- hyperglycaemia → fluid shift
lactic acidosis ∵ hypermetabolic state
- ↑ glucose metabolism
↓ AKI by normovolaemia & sodium thiosulfate
Environmental consideration
The chemotherapy solution poses a risk to operating theatre teams, and careful use of PPE should be undertaken (filtering face piece 3 mask, goggles, face shield, gloves and shoe covers).
Adequate neuromuscular block is vital to avoid any accidental coughing or movement of the patient, leading to spillage of the chemotherapy solution. The cytotoxic agent may be present in body fluids for anything between 1 and 7 days, depending on what agent is used, and is important information to all staff caring for the patient
Post-op
post-op ICU
If the diaphragm has been ‘stripped’ of disease, bilateral chest drains are often used to avoid the development of large pleural effusions
Multiple tubes and drains increase the postoperative analgesic requirements for patients undergoing CRS and HIPEC.
PONV common
During the first 24 h after surgery, patients will lose up to 10 L of fluid per day, most of it via intraabdominal drains. Therefore, there is a need to substitute this loss, mostly with crystalloids and albumin.
Monitoring of blood glucose in critically ill patients after CRS ± HIPEC and correction of glycaemia using short-acting insulin to keep blood glucose levels at 140–180 mg/dL (7.8–10 mmol/L) are recommended routinely in order to reduce postoperative mortality.
References
Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy - BJA Ed