Hyperthermic intraperitoneal chemotherapy

Intraperitoneal hyperthermic chemoperfusion (HIPEC or IPHC) is a type of hyperthermia therapy used in combination with surgery in the treatment of advanced abdominal cancers.[1] In this procedure, warmed anti-cancer medications are infused and circulated in the peritoneal cavity (abdomen) for a short period of time. The chemotherapeutic agents generally infused during IPHC are mitomycin-C and cisplatin.

Hyperthermic intraperitoneal chemotherapy
Schematic overview of HIPEC
Other namesHyperthermic intraperitoneal chemotherapy (HIPEC), intra-abdominal hyperthermic chemoperfusion, intraoperative chemohyperthermic peritoneal perfusion (CHPP), or the Sugarbaker technique
SpecialtySurgical oncology

Medical uses

IPHC is generally used after surgical removal of as much cancer as possible (debulking), which may include the removal of all involved peritoneal areas. Evidence supports a benefit in certain cases of ovarian cancer.[2]

Evidence is insufficient as of 2020 to support its use in primary advanced epithelial ovarian, fallopian tube or primary peritoneal carcinoma, recurrent ovarian cancer, peritoneal colorectal carcinomatosis, gastric peritoneal carcinomatosis, malignant peritoneal mesothelioma, or disseminated mucinous neoplasm of the appendix.[3]

These procedures can be 8–10 hours long and carry a significant rate of complications.[4]

The chest counterpart of HIPEC is the hyperthermic intrathoracic chemotherapy (HITOC).

Chemotherapy agents

Various chemotherapies are used[5] and there is no clear consensus on which drugs should be used. Mitomycin C and oxaliplatin are the most commonly used agent for colorectal cancer, while cisplatin is used in ovarian cancer.[6]

History

In 1934, Joe Vincent Meigs in New York originally described tumor debulking surgery (cytoreductive surgery) for ovarian cancer under the premise of reducing macroscopic disease.[7] In the 60s and 70s this aggressive cytoreductive approach began to be accepted. During this time, Dr. Kent Griffith at the National Cancer Institute also reported on prognostic indicators of survival in stage II and III ovarian cancer patients, importantly noting that residual tumor mass size (<1.6 cm) after cytoreductive surgery was significantly associated with extended survival.[7] During this time research started to show hyperthermia as well as intraperitoneal chemotherapy was effective in killing cancer cells. Spratt et al. in the 1980s, at the University of Louisville in Kentucky combined these concepts into a thermal transfusion infiltration system (TIFS) for delivery of heated chemotherapy into the peritoneal space of canines.[8] The first human was subjected to TIFS with administration of hyperthermic chemotherapy for locally advanced abdominal malignancy in 1979.[9] Further studies in the 1980s delivered chemotherapeutic agents at concentrations up to 30 times greater than those safely administered via IV route. In the mid to late 1980s, Sugarbaker led the Washington Cancer Institute further investigation into therapy for gastrointestinal malignancies with peritoneal dissemination and was able to report survival benefits.[10] It became apparent early that completness of cytoreduction was associated with survival benefits.[7] In 1995, Sugarbaker created a stepwise approach to cytoreduction, in an attempt to standardize and optimize this process.[11]

The HIPEC technique was also further improved upon by suggesting multiple modalities of delivery. The "Coliseum" technique as well as a similar approach described by Dr. Paul Sugarbaker in 1999 were open abdominal techniques where heated chemotherapy was poured in. Benefits of this open approach included direct access by the surgeon to the cavity during administration of the hyperthermic agents to manipulate the fluid and bowel in order to achieve a quick and homogenous temperature and distribution of drug within the abdomen. Additionally, care can be taken to ensure that all peritoneal surfaces are exposed equally throughout the duration of the therapy as well as avoid dangerous temperatures or over-exposure to normal tissues. In comparison, the closed technique involves the closure of the abdominal wall prior to infusion of the chemotherapy reducing the issue of heat loss from peritoneal surfaces. In attempts to combine potential advantages of these two techniques, Sugarbaker employed a semi-open method by developing a new containment instrument (Thompson retractor) described in 2005 to support watertight elevation of the abdominal skin edges. More recently, a laparoscopic approach for CRS with HIPEC in highly selected patients with minimal disease burden has been described.

A further advance was made in 2016, when Lotti M. et al. described a new technique, the Laparoscopy-Enhanced HIPEC (LE-HIPEC) technique, in which the hyperthermic chemotherapy is delivered after the closure of the abdominal wound, and a laparoscopic approach is used to stir the abdominal content during the perfusion.[12][13] Lotti M called into question the statement that the Coliseum technique could achieve the homogeneous distribution of heat.[14][15] The aim of the LE-HIPEC is to achieve a better heat delivery and preservation (as is in the closed technique) and a better circulation of the perfusion fluid (as is in the open technique).[16] Compared to the standard closed-abdomen technique, the LE-HIPEC technique allows the surgeon to open the abdominal compartments to let the inflow of the heated perfusion fluid. Moreover, it allows the identification and division of the early intra-abdominal adhesions that can hamper the circulation of the perfusion fluid during a standard closed-abdomen perfusion. In a further study, Lotti M et al. showed that after CRS early intra-abdominal adhesions occur in 70% of the patients, soon after the closure of the wound.[17][18]

Procedure

The procedure is divided into three stages:

  1. Exploration: Here the surgeon will open the abdomen evaluate the peritoneal cancer.
  2. Debulking: In the debulking, or cytoreduction, phase of the procedure the surgeon will remove the visible tumor implants. However, even when all of the visible tumor is removed it is possible for microscopic cancer cells to still remain. The final stage of the procedure is meant to eliminate those cells.
  3. Chemoperfusion: Here the abdominal cavity is rinsed with a heated chemotherapy solution. Unlike systemic chemotherapy that is delivered in the blood stream, throughout the whole body, the chemotherapy in the HIPEC procedure is largely isolated in the peritoneal cavity. Therefore, a much higher concentration of chemotherapy can be utilized, while the toxicity and side-effects associated with systemic chemotherapy are minimized.

Anesthetics

It has been reported that goal-directed therapy may contribute to individually adjusting fluid therapy and drugs, this might allow to avoid overhydration and to ensure hemodynamic stability.[19]

Controversy

While potentially curative, CRS plus HIPEC is associated with substantial perioperative morbidity and mortality and a short-term decline in the quality of life.[20] Skeptics of this procedure argue there is no multi-centered randomized Phase 3 trial comparing CRS+HIPEC with complete cytoreduction followed by systemic therapy. Hence this therapy has not met the scientific bar to be considered standard of care. However, proponents of CRS+HIPEC argue that until now, there has been no systemic therapy that has provided prolonged survival for peritoneal metastases. Peritoneal metastases, based on the primary tumor and extent of the disease, has a median overall survival of less than 36 months based on systemic therapy alone.[21] The treatment of peritoneal carcinomatosis of colorectal origin with cytoreductive surgery (CRS) plus hyperthermic intraperitoneal chemotherapy (HIPEC) has a 5-year recurrence-free or cure rate of at least 16%.[22]

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References
  1. Esquivel, Jesus (2010). "Technology of Hyperthermic Intraperitoneal Chemotherapy in the United States, Europe, China, Japan and Korea". In Vincent T. DeVita Jr.; Theodore S. Lawrence; Steven A. Rosenberg (eds.). Cancer: Principles & Practice of Oncology—Annual Advances in Oncology, Volume 1. Lippincott Williams & Wilkins. pp. 188–193. ISBN 978-1-4511-0314-4.
  2. Huo, YR; Richards, A; Liauw, W; Morris, DL (December 2015). "Hyperthermic intraperitoneal chemotherapy (HIPEC) and cytoreductive surgery (CRS) in ovarian cancer: A systematic review and meta-analysis". European journal of surgical oncology : the journal of the European Society of Surgical Oncology and the British Association of Surgical Oncology. 41 (12): 1578–89. doi:10.1016/j.ejso.2015.08.172. PMID 26453145.
  3. Auer, RC; Sivajohanathan, D; Biagi, J; Conner, J; Kennedy, E; May, T (March 2020). "Indications for hyperthermic intraperitoneal chemotherapy with cytoreductive surgery: a systematic review". European journal of cancer (Oxford, England : 1990). 127: 76–95. doi:10.1016/j.ejca.2019.10.034. PMID 31986452.
  4. "UC HealthNews : HEALTH LINE: Heated".
  5. Newton, Andrew D.; Bartlett, Edmund K.; Karakousis, Giorgos C. (2016-02-01). "Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy: a review of factors contributing to morbidity and mortality". Journal of Gastrointestinal Oncology. 7 (1): 99–111. doi:10.3978/j.issn.2078-6891.2015.100. ISSN 2078-6891. PMC 4754303. PMID 26941988.
  6. Morales-Soriano, Rafael; Esteve-Pérez, Neus; Segura-Sampedro, Juan José; Cascales-Campos, Pedro; Barrios, Pedro; Spanish Group of Peritoneal Malignancy Surface (GECOP) (February 2018). "Current practice in cytoreductive surgery and HIPEC for metastatic peritoneal disease: Spanish multicentric survey". European Journal of Surgical Oncology: The Journal of the European Society of Surgical Oncology and the British Association of Surgical Oncology. 44 (2): 228–236. doi:10.1016/j.ejso.2017.11.012. ISSN 1532-2157. PMID 29242018.
  7. Neuwirth, Madalyn G.; Alexander, H. Richard; Karakousis, Giorgos C. (2016-02-01). "Then and now: cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (HIPEC), a historical perspective". Journal of Gastrointestinal Oncology. 7 (1): 18–28. doi:10.3978/j.issn.2078-6891.2015.106. ISSN 2078-6891. PMC 4754315. PMID 26941981.
  8. Spratt, John S.; Adcock, Robert A.; Sherrill, William; Travathen, S. (1980-02-01). "Hyperthermic Peritoneal Perfusion System in Canines". Cancer Research. 40 (2). ISSN 0008-5472.
  9. Spratt, J. S.; Adcock, R. A.; Muskovin, M.; Sherrill, W.; McKeown, J. (1980-02-01). "Clinical delivery system for intraperitoneal hyperthermic chemotherapy". Cancer Research. 40 (2): 256–260. ISSN 0008-5472. PMID 6766084.
  10. Sugarbaker, P. H. (1988-01-01). "Surgical management of peritoneal carcinosis: diagnosis, prevention and treatment". Langenbecks Archiv für Chirurgie. 373 (3): 189–196. doi:10.1007/bf01274232. ISSN 0023-8236. PMID 3288830.
  11. Sugarbaker, P. H. (1995-01-01). "Peritonectomy procedures". Annals of Surgery. 221 (1): 29–42. doi:10.1097/00000658-199501000-00004. ISSN 0003-4932. PMC 1234492. PMID 7826158.
  12. Lotti, Marco; Capponi, Michela Giulii; Piazzalunga, Dario; Poiasina, Elia; Pisano, Michele; Manfredi, Roberto; Ansaloni, Luca (2016). "Laparoscopic HIPEC: A bridge between open and closed-techniques". Journal of Minimal Access Surgery. 12 (1): 86–89. doi:10.4103/0972-9941.158965. ISSN 0972-9941. PMC 4746985. PMID 26917929.
  13. Lotti, Marco (7 January 2016). "Laparoscopy-Enhanced Closed Abdomen Hyperthermic Intraperitoneal Chemotherapy". Journal of Laparoendoscopic & Advanced Surgical Techniques Part B, Videoscopy. doi:10.1089/vor.2015.0315.
  14. Lotti, Marco (15 June 2017). "A Coliseum with frail foundations: a critical analysis of the state-o…". slideshare.net.
  15. Lotti, Marco. "HIPEC and the necessary hyperthermia: do we still need the open abdomen?" (PDF). europeanreview.org.
  16. Lotti, Marco (18 September 2016). "the Laparoscopy-Enhanced HIPEC Concept". www.slideshare.net.
  17. Lotti, Marco; Giulii Capponi, Michela; Campanati, Luca; Poiasina, Elia; Ansaloni, Luca; Poletti, Eugenio; Frigerio, Luigi (December 2016). "The Onset of Intra-Abdominal Adhesions During Closed-Abdomen Hyperthermic Intraperitoneal Chemotherapy". Journal of Laparoendoscopic & Advanced Surgical Techniques. 26 (12): 997–1002. doi:10.1089/lap.2016.0396. PMID 27705085.
  18. Lotti, Marco (21 October 2016). "Intra-abdominal adhesions are formed during closed-abdomen HIPEC". www.youtube.com.
  19. Esteve-Pérez, N.; Ferrer-Robles, A.; Gómez-Romero, G.; Fabián-Gonzalez, D.; Verd-Rodriguez, M.; Mora-Fernandez, L. C.; Segura-Sampedro, J. J.; Tejada-Gavela, S.; Morales-Soriano, R. (2018-09-14). "Goal-directed therapy in cytoreductive surgery with hyperthermic intraperitoneal chemotherapy: a prospective observational study". Clinical and Translational Oncology. 21 (4): 451–458. doi:10.1007/s12094-018-1944-y. ISSN 1699-048X. PMID 30218305.
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