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A Coliseum with frail foundations: a critical analysis of the state-of-the-art open-abdomen HIPEC technique

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Some considerations that made me convinced that the Coliseum HIPEC technique cannot be considered an adequate technique for the delivery of Hyperthermia.

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A Coliseum with frail foundations: a critical analysis of the state-of-the-art open-abdomen HIPEC technique

  1. 1. a Coliseum with frail foundations a critical analysis of the state-of-the-art open-abdomen HIPEC technique Marco Lotti MD Advanced Surgical Oncology Unit Papa Giovanni XXIII Hospital - Bergamo (Italy) im.marco.lotti@gmail.com
  2. 2. Morbidity and Mortality Analysis of 200 Treatments With Cytoreductive Surgery and Hyperthermic Intraoperative Intraperitoneal Chemotherapy Using the Coliseum Technique Arvil D. Stephens, MD, Robert Alderman, PA-C, David Chang, MD, Gary D. Edwards, PA-C, Jesus Esquivel, MD, Gilbert Sebbag, MD, Mark A. Steves, MD, and Paul H. Sugarbaker, MD Background: Peritoneal carcinomatosis from gastrointestinal cancers is a fatal diagnosis without special combined surgical and chemotherapy interventions. Guidelines for cytoreductive surgery and hyperthermic intraoperative intraperitoneal chemotherapy (HIIC) by using the Coliseum tech- nique have been developed to treat patients with peritoneal carcinomatosis and other peritoneal surface malignancies. The purpose of this study was to analyze the morbidity and mortality of patients undergoing cytoreductive surgery and HIIC by using mitomycin C. Methods: Data were prospectively recorded on 183 patients who underwent 200 cytoreductive surgeries with HIIC between November 1994 and June 1998. Seventeen of the 183 patients returned for a second-look surgery plus HIIC. All HIIC administrations occurred after cytoreduction and used continuous manual separation of intra-abdominal structures to optimize drug and heat distribution. Origins of the tumors were as follows: appendix (150 patients), colon (20 patients), stomach (7 patients), pancreas (2 patients), small bowel (1 patient), rectum (1 patient), gallbladder (1 patient), and peritoneal papillary serous carcinoma (1 patient). Morbidity was organized into 20 categories that were graded 0 to IV by the National Cancer Institute’s Common Toxicity Criteria. In an attempt to identify patient characteristics that may predispose to complications, each morbidity variable was analyzed for an association with the 25 clinical variables recorded. Results: Combined grade III/IV morbidity was 27.0%. Complications observed included the following: peripancreatitis (6.0%), fistula (4.5%), postoperative bleeding (4.5%), and hematological toxicity (4.0%). Morbidity was statistically linked with the following clinical variables: duration of surgery (P Ͻ .0001), the number of peritonectomy procedures and resections (P Ͻ .0001), and the number of suture lines (P ϭ .0078). No HIIC variables were statistically associated with the presence of grade III or grade IV morbidity. Treatment-related mortality was 1.5%. Conclusions: HIIC may be applied to select patients with peritoneal carcinomatosis from gastroin- testinal malignancies with 27.0% major morbidity and 1.5% treatment-related mortality. The frequency of complications was associated with the extent of the surgical procedure and not with variables associated with the delivery of heated intraoperative intraperitoneal chemotherapy. The technique has shown an acceptable frequency of adverse events to be tested in phase III adjuvant trials. Key Words: Morbidity—Mortality—Cytoreductive surgery—Hyperthermia—Intraperitoneal chemotherapy—Mitomycin C—5-Fluorouracil—Pseudomyxoma peritonei—Colon cancer. Peritoneal carcinomatosis and sarcomatosis are uni- formly fatal diagnoses without special combined surgical and intraperitoneal chemotherapy interventions. Malig- nancies that present within the abdominopelvic cavity often cause their great morbidity and mortality through progressive involvement of the peritoneal surfaces. Ex- amples of this can be seen in patients with appendiceal Received March 5, 1999; accepted August 18, 1999. From the Washington Cancer Institute, Washington, DC. Annals of Surgical Oncology, 6(8):790–796 Published by Lippincott Williams & Wilkins © 1999 The Society of Surgical Oncology, Inc. Hyperthermic intraoperative intraperitoneal chemo- therapy was first added to cytoreductive surgery at the Washington Hospital Center in March 1992. Sixty pa- tients were enrolled in an Institutional Review Board- approved phase I/II clinical trial. Informed consent was obtained from all patients before surgery. This trial com- bined cytoreductive surgery with heated intraoperative mitomycin C administered by a closed abdominal tech- nique. The techniques,2 pharmacokinetics,3,4 safety con- siderations,5 and morbidity and mortality6 of the closed intraoperative intraperitoneal chemotherapy technique have been reported. Deficiencies were noted in the dis- tribution of methylene blue dye with the closed tech- nique, which may cause a high frequency of complica- tions and nonuniform treatment. This prompted the development of the Coliseum technique for HIIC, which allowed for manual distribution of heat and drugs.7,8 After the conclusion of the investigative phase, clinical guidelines combining cytoreductive surgery and HIIC for biopsy-confirmed peritoneal carcinomatosis from gastrointestinal malignancies were used. These data were prospectively recorded for 200 treatments in 183 patients that occurred between November 1994 and June 1998. The techniques of cytoreductive surgery have been 9 dialysis solution containing 12.5 mg/m2 of mitomycin C for males (maximum dose, 25 mg) or 10.0 mg/m2 for females (maximum dose, 20 mg) was heated and infused at approximately 1 liter/minute. Temperatures were mea- sured with a Labcraft digital thermometer (Curtin Mathe- son Scientific, Jessup, MD). The temperature at the in- flow line was approximately 44°C. The Tenckhoff temperature probe was maintained between 42°C and 43°C, and a distant intra-abdominal site averaged 39.6°C. Throughout the perfusion, the surgeon continu- ously manipulated the viscera to distribute both heat and chemotherapy. All bowel anastomoses were constructed with hand- sewn two-layer closures with two exceptions. Low colo- rectal anastomoses were performed with a 33-mm-diameter intraluminal stapler and esophagojejunal anastomoses with a 29-mm-diameter intraluminal stapler (Ethicon Endo- surgical, Cincinnati, OH). If a pyloroplasty was per- formed, it was a full-thickness incision closed with a single layer of interrupted silk sutures. TABLE 1. Patient characteristics No. of patients receiving 1 cytoreduction ϩ HIIC 166 No. of patients receiving 2 cytoreductions ϩ HIIC 17 The Coliseum technique was developed to overcome the uneven distribution of the perfusion fluid that was observed with the closed-abdomen technique. The key concept of the Coliseum technique is the manual distribution of heat and chemotherapy. Marco Lotti MD
  3. 3. It has been 30 years since the first HIPEC was delivered by ratt et al5 in 1979 at the University of Louisville to a male patient h pseudomyxoma peritonei. During these 3 decades, there have en significant changes on how to deliver the heated perfusate, different sites of the circuit and the intraperitoneal cavity: heat generator, heat exchanger, inflow and outflow catheters and some centers add temperature probes to the liver and bladder. During the Milan consensus, it was agreed that the desirable intra-abdominal temperature range that needs to be maintained during HIPEC should be between 41.5°C and 43°C. This temperature is usually accom- 6 FIGURE 2. Open “colisuem” technique for HIPEC. GURE 1. Concentration of mitomycin C in plasma versus ritoneal fluid. The “Coliseum” Open Abdomen HIPEC 22 Smoke evacuator tubing Plastic sheet Self retaining retractor Technical Handbook for the Integration of Cytoreductive Surgery and Perioperative Intraperitoneal Chemotherapy into the Surgical Management of Gastrointestinal and Gynecologic Malignancy 4th Edition Paul H. Sugarbaker, MD, FACS, FRCS Contents I. Background and rationale II. Quantitative prognostic indicators III. Peritonectomy IV. Sugarbaker retractor V. Heater circulator apparatus VI. Heated intraoperative intraperitoneal chemotherapy VII. Early postoperative intraperitoneal chemotherapy VIII. Clinical pathway for postoperative care IX. Results of treatment X. Current indications for cytoreductive surgery plus perioperative intraperitoneal chemotherapy XI. Conclusions XII. Appendix Foundation for Applied Research in Gastrointestinal Oncology December 5, 2005
  4. 4. It has been 30 years since the first HIPEC was delivered by ratt et al5 in 1979 at the University of Louisville to a male patient h pseudomyxoma peritonei. During these 3 decades, there have en significant changes on how to deliver the heated perfusate, different sites of the circuit and the intraperitoneal cavity: heat generator, heat exchanger, inflow and outflow catheters and some centers add temperature probes to the liver and bladder. During the Milan consensus, it was agreed that the desirable intra-abdominal temperature range that needs to be maintained during HIPEC should be between 41.5°C and 43°C. This temperature is usually accom- 6 FIGURE 2. Open “colisuem” technique for HIPEC. GURE 1. Concentration of mitomycin C in plasma versus ritoneal fluid. 22 Smoke evacuator tubing Plastic sheet Self retaining retractor Technical Handbook for the Integration of Cytoreductive Surgery and Perioperative Intraperitoneal Chemotherapy into the Surgical Management of Gastrointestinal and Gynecologic Malignancy 4th Edition Paul H. Sugarbaker, MD, FACS, FRCS Contents I. Background and rationale II. Quantitative prognostic indicators III. Peritonectomy IV. Sugarbaker retractor V. Heater circulator apparatus VI. Heated intraoperative intraperitoneal chemotherapy VII. Early postoperative intraperitoneal chemotherapy VIII. Clinical pathway for postoperative care IX. Results of treatment X. Current indications for cytoreductive surgery plus perioperative intraperitoneal chemotherapy XI. Conclusions XII. Appendix Foundation for Applied Research in Gastrointestinal Oncology December 5, 2005 We have: • a plastic barrier • a forced air flow • a basin filled with fluid and viscera • a hand-shaped impeller
  5. 5. A single inflow and four outflow tubes are placed through the lateral aspect of the abdominal wall for hyperthermic peritoneal irrigation. The inflow catheter is secured to a temperature probe within the mid-abdomen. During the hyperthermic chemotherapy irrigation the inflow catheter is placed beneath the right hemidiaphragm. After the skin edges are elevated by monofilament suture, a lid, also made of stainless steel, closes off the space above the peritoneal cavity except for an access site. An impermeable disposable drape covers the entire operative field with a cruciate cut in its central portion to open the access site. The surgeon’s double-gloved arm is placed through the access site to continuously mix the heated chemotherapy solution (Figure 33). If desired to further seal off the open abdomen, the access site may be secured to the surgeon’s arm by hand assist laparoscopy equipment. If the access Technical Handbook for the Integration of Cytoreductive Surgery and Perioperative Intraperitoneal Chemotherapy into the Surgical Management of Gastrointestinal and Gynecologic Malignancy 4th Edition Paul H. Sugarbaker, MD, FACS, FRCS Contents I. Background and rationale II. Quantitative prognostic indicators III. Peritonectomy IV. Sugarbaker retractor V. Heater circulator apparatus VI. Heated intraoperative intraperitoneal chemotherapy VII. Early postoperative intraperitoneal chemotherapy VIII. Clinical pathway for postoperative care IX. Results of treatment X. Current indications for cytoreductive surgery plus perioperative intraperitoneal chemotherapy XI. Conclusions XII. Appendix Foundation for Applied Research in Gastrointestinal Oncology Behind the Coliseum technique is the trust that hand mixing leads to the homogeneous distribution of heat and chemo. Marco Lotti MD
  6. 6. “have the homogeneous distribution” González-Moreno S et al. HIPEC: Rationale and Technique of drugs are in micrograms, so that it is not possible to have a major spill; (13) Cleaning the operating room after 10 11 12 13 14 15 Figure 1 Administration of HIPEC by the coliseum (open) technique. Constant manipulation of the perfusate ensures a homogeneous distribution of the heated chemotherapy within the peritoneal cavity. Note that elbow-length double gloving, goggles and an impervious gown are used. A single inflow and four outflow tubes are placed through the lateral aspect of the abdominal wall for hyperthermic peritoneal irrigation. The inflow catheter is secured to a temperature probe within the mid-abdomen. During the hyperthermic chemotherapy irrigation the inflow catheter is placed beneath the right hemidiaphragm. After the skin edges are elevated by monofilament suture, a lid, also made of stainless steel, closes off the space above the peritoneal cavity except for an access site. An impermeable disposable drape covers the entire operative field with a cruciate cut in its central portion to open the access site. The surgeon’s double-gloved arm is placed through the access site to continuously mix the heated chemotherapy solution (Figure 33). If desired to further seal off the open abdomen, the access site may be secured to the surgeon’s arm by hand assist laparoscopy equipment. If the access Technical Handbook for the Integration of Cytoreductive Surgery and Perioperative Intraperitoneal Chemotherapy into the Surgical Management of Gastrointestinal and Gynecologic Malignancy 4th Edition Paul H. Sugarbaker, MD, FACS, FRCS Contents I. Background and rationale II. Quantitative prognostic indicators III. Peritonectomy IV. Sugarbaker retractor V. Heater circulator apparatus VI. Heated intraoperative intraperitoneal chemotherapy VII. Early postoperative intraperitoneal chemotherapy VIII. Clinical pathway for postoperative care IX. Results of treatment X. Current indications for cytoreductive surgery plus perioperative intraperitoneal chemotherapy XI. Conclusions XII. Appendix Foundation for Applied Research in Gastrointestinal Oncology “mix the solution” This trust has been readily shared by many… Marco Lotti MD
  7. 7. gical staff. Thus, the following factors must be taken into account: (1) the per- ceived risk of environmental chemotherapy exposure (the real risk is negligi- ble if proper safety measures are followed); (2) concerns regarding possible differences in uniform distribution of the chemotherapeutic agent or heat throughout the peritoneal cavity, which may result in visceral thermal injury; and (3) possible differences in dosage and perfusate volume inherent to the closed method. Table 10.2 Choosing the hyperthermic intraperitoneal chemotherapy (HIPEC) procedure Feature Open Closed Semiopen Uniform heat and chemotherapy distribution Minor heat dissipation No direct contact of surgeon with chemotherapeutic agent Minimize risk of chemotherapeutic agent exposure to operating-room staff Minimize risk of thermal injury User friendliness 37Journal of Gastrointestinal Oncology Vol 7, No 1 February 2016 Table 4 Credits and debits of two different technologies for hyperthermic intraperitoneal chemotherapy Features Open abdomen manually distributed Closed abdomen Efficiency Allows continued cytoreduction of bowel and mesenteric surfaces No surgery possible during chemotherapy Environmental hazard No aerosols detected Perception of increased safety Distribution Uniform distribution of heat and chemotherapy solutions, tissues close to skin edge not immersed Possible poor distribution to dependent sites and closed spaces Pressure No increased intraabdominal pressure Increased intraabdominal pressure may increase chemotherapy penetration into tissue Pharmacology Allows pharmacokinetic monitoring of tumor and normal tissue Tissue uptake of chemotherapy cannot be determined Abdominal incision and suture lines Treated prior to performing the suturing Risk of recurrence in abdominal incision and suture lines Diaphragm perforation with peritonectomy Pleural space treated by hyperthermic chemotherapy may prevent seeding of pleural space Diaphragm closed prior to hyperthermic intraperitoneal chemotherapy so pleural space is not treated Intestinal perforation Detected by observing immersed bowel loops Not detected Hyperthermia Increased heat necessary to maintain 42 ℃ Less heat required to maintain 42 ℃ Surgical technology and pharmacology of hyperthermic perioperative chemotherapy Paul H. Sugarbaker1 , Kurt Van der Speeten2 1 Center for Gastrointestinal Malignancies, MedStar Washington Hospital Center, Washington, DC, USA; 2 Department of Surgical Oncology, Ziekenhuis Oost-Limburg, Genk, Belgium Contributions: (I) Concept and design: All authors; (II) Administrative support: Foundation for Applied Research in Gastrointestinal Oncology; (III) Provision of study materials or patient: All authors; (IV) Collection and assembly of data: All authors; (V) Data analysis and interpretation: All authors; (VI) Manuscript writing: All authors; (VII) Final approval of manuscript: All authors. Correspondence to: Paul H. Sugarbaker, MD, FACS, FRCS. MedStar Washington Hospital Center, 106 Irving St., NW, Suite 3900, Washington, DC 20010, USA. Email: Paul.Sugarbaker@medstar.net. Abstract: Although cytoreductive surgery (CRS) and hyperthermic perioperative chemotherapy (HIPEC) have not been shown to be effective by themselves, as a combined treatment they are now standard of care for peritoneal metastases from appendiceal cancer and from colorectal cancer as well as peritoneal mesothelioma. The timing of the HIPEC in relation to the CRS is crucial in that the HIPEC is to destroy minimal residual disease that remains following the CRS and prevent microscopic tumor emboli within the abdomen and pelvis from implanting within the resection site, within fibrinous clot, or within blood clot. Proper selection of chemotherapy agents is crucial to the long-term benefit of CRS and HIPEC. One must consider the response expected with the cancer chemotherapy agent, its area under the curve (AUC) ratio indicating the amount of dose intensity within the peritoneal space, and the drug retention within the peritoneal space for a prolonged exposure. Hyperthermia will augment the cytotoxicity of the cancer chemotherapy agents and improve drug penetration. Irrigation techniques should not be overlooked as an important means of reducing the cancer cell burden within the abdomen and pelvis. Multiple technologies for HIPEC exist and these have advantages and disadvantages. The techniques vary from a totally open technique with a vapor barrier over the open abdominal space to a totally closed technique whereby the HIPEC is administered at the completion of the surgical procedure. The open techniques depend on a table-mounted retractor for suspension of the skin edges allowing a reservoir to occur within the abdomen and pelvis. There are nearly a dozen commercially available hyperthermia pumps, all of which seem to perform adequately for HIPEC although there is a variable degree of convenience and documentation of the HIPEC procedure. As the management of peritoneal metastases has progressed over three decades, early cases are now seen in which a laparoscopic CRS and HIPEC may be appropriate. Also, prophylactic use of laparoscopic HIPEC with perforated appendiceal malignancies and T4 colon cancers may be appropriate. Keywords: Peritoneal metastases; carcinomatosis; peritoneal mesothelioma; irrigation; laparoscopy; laparoscopic cytoreductive surgery; hyperthermic perioperative chemotherapy (HIPEC) Submitted Jun 27, 2015. Accepted for publication Aug 20, 2015. doi: 10.3978/j.issn.2078-6891.2015.105 Updates in Surgery Treatment of Peritoneal Surface Malignancies Angelo Di Giorgio Enrico Pinto Editors In collaboration with Paolo Sammartino and Franco Roviello State of the Art and Perspectives …and definitely credited to the Coliseum technique Marco Lotti MD
  8. 8. The image of the Surgeon who acts with her/his hands to distribute heat and chemo is very powerful. It is a suggestion that influenced many operators, who became mirrors of the belief that hand mixing entails the homogeneous distribution of the desired therapy. Marco Lotti MD
  9. 9. “Constant manipulation of the perfusate ensures a homogeneous distribution of the heated chemotherapy within the peritoneal cavity” “In the methodology described by Sugarbaker, access to the abdomen and pelvis is maintained during the chemotherapy treatment so that the surgeon can distribute the heat and the chemotherapy solution uniformly. This resulted in a decreased morbidity associated with the procedure and is likely to improve its effectiveness” “The main benefit of the Coliseum technique is that heated chemotherapy is adequately distributed throughout the abdominal cavity and there is no pooling of temperature or chemotherapy” Annals of Surgical Oncology, 9(2): 186-191 Published by Lippincon Williams & Wilkins 9 2002 The Society of Surgical Oncology, Inc. Safety Monitoring of the Coliseum Technique for Heated Intraoperative Intraperitoneal Chemotherapy With Mitomycin C O. Anthony Stuart, BS, Arvil D. Stephens, BS, Laura Welch, MD, and Paul H. Sugarbaker, MD Background: Treatment of carcinomatosis may involve the use of heated intraperitoneal che- motherapy; the cytotoxic solution is administered in the operating room with the abdomen open so that manual distribution results in uniform treatment. The potential risk of this procedure to the operating room personnel has not been previously investigated. Methods: Mitomycin C was perfused through the peritoneal cavity, which was partially covered by a plastic sheet. Large volumes of air were suctioned from 5 and 35 cm above the abdominal skin edge. Urine from the surgeon and from the perfusionist were assayed. Sterile gloves worn in the operating room for manipulating the viscera during treatment were assayed for their permeability to mitomycin C. All samples were analyzed by high-performance liquid chromatography. Results: Analysis of samples of operating room air and urine from 10 procedures showed no detectable levels of mitomycin C. Six tests of three different types of gloves showed a 10-fold range of mitomycin C penetration. The least permeable gloves leaked a mean of 3.8 parts per million over 90 minutes. Conclusions: No detectable safety hazard to the surgeon or other operating room personnel was demonstrated. Key Words: Safety monitoring--Operating room--Hyperthermia--Intraperitoneal chemothera- py--Mitomycin C---Latex gloves. Gastrointestinal and gynecologic malignancies fre- quently disseminate to the peritoneal surfaces. Preven- tion or adequate treatment of disease at this anatomical site would improve the survival of patients if dissemina- tion did not occur elsewhere in the body. For patients with distant metastases, eradication of cancer on abdom- inal and pelvic surfaces would result in a quality of life advantage because intestinal obstructions would occur much less frequently. 1One method currently used at this institution in >450 patients to treat the peritoneal surface component of these malignancies is heated intraoperative intraperitoneal chemotherapy. 2 Heat synergizes the cyto- toxic effects of chemotherapy. 3 In addition, heat in- creases the penetration of chemotherapy solution into cancer nodules, 4 To improve penetration of tumor nod- ReceivedAugust 9, 2000; acceptedSeptember20, 2001. From the WashingtonCancer Institute, Occupationaland Environ- mental Medicine,WashingtonHospitalCenter,Washington,DC. Addresscorrespondenceand reprintrequeststo: PaulH. Sugarbaker, MD, WashingtonCancer Institute, WashingtonHospital Center, 110 IrvingSt., N.W.,Washington,DC 20010;Fax: 202-877-8602;E-mail: paul.sugarbaker@medstar.net. ules by chemotherapy, the size of tumor nodules is maximally cytoreduced before the heated chemotherapy treatments. In the methodology described by Sugarbaker et al.,2 access to the abdomen and pelvis is maintained during the chemotherapy treatment so that the surgeon can distribute the heat and the chemotherapy solution uniformly. This resulted in a decreased morbidity asso- ciated with the procedure and is likely to improve its effectiveness. 5 With an increasing number of institutions adopting this strategy to treat and prevent peritoneal surface malignancy, there has been a growing concern regarding the safety of this technique for operating room personnel. The most common chemotherapy agent used in heated intraoperative intraperitoneal chemotherapy procedures is mitomycin C. It was suitable for this study because it is highly soluble in methanol and because it is rapidly absorbed and excreted unchanged in the urine, 6 Mitomy- cin C can also be accurately assayed by established high-performance liquid chromatography (HPLC) tech- niques. 7-9 The purpose of this study was to assay in 10 patients for any detectable level of mitomycin C in the 186 Santiago González-Moreno, Luis A González-Bayón, Gloria Ortega-Pérez, Peritoneal Surface Oncology Program, Department of Surgical Oncology, Centro Oncológico MD Anderson International España, 28033 Madrid, Spain Author contributions: González-Moreno S, Ortega-Pérez G, and González-Bayón LA designed, discussed the paper contents and collected pertinent information; González-Moreno S wrote the paper. Correspondence to: Santiago González-Moreno, MD, PhD, Peritoneal Surface Oncology Program, Department of Surgical Oncology, Centro Oncológico MD Anderson International España, Calle Arturo Soria 270, 28033 Madrid, Spain. sgonzalez@mdanderson.es Telephone: +34-91-7878600 Fax: +34-91-7680681 Received: July 2, 2009 Revised: January 11, 2010 Accepted: January 18, 2010 Published online: February 15, 2010 Abstract The combination of complete cytoreductive surgery and perioperative intraperitoneal chemotherapy provides the only chance for long-term survival for selected patients diagnosed with a variety of peritoneal neoplasms, either primary or secondary to digestive or gynecologic malignancy. Hyperthermic intraperitoneal chemotherapy (HIPEC) delivered in the operating room once the cytoreductive surgical procedure is finalized, constitutes the most common form of administration of perioperative intraperitoneal chemotherapy. This may be complemented in some instances with early postoperative intraperitoneal chemotherapy (EPIC). HIPEC combines the pharmacokinetic advantage inherent to the intracavitary delivery of certain cytotoxic drugs, which results in regional dose intensification, with the direct cytotoxic effect of hyperthermia. Hyperthermia exhibits a selective cell-killing effect in malignant cells by itself, potentiates the cytotoxic effect of certain chemotherapy agents and enhances the tissue penetration of the administered drug. The chemotherapeutic agents employed in HIPEC need to have a cell cycle nonspecific mechanism of action and should ideally show a heat-synergistic cytotoxic effect. Delivery of HIPEC requires an apparatus that heats and circulates the chemotherapeutic solution so that a stable temperature is maintained in the peritoneal cavity during the procedure. An open abdomen (Coliseum) or closed abdomen technique may be used, with no significant differences in efficacy proven to date. Specific technical training and a solid knowledge of regional chemotherapy management are required. Concerns about safety of the procedure for operating room personnel are expected but are manageable if universal precautions and standard chemotherapy handling procedures are used. Different HIPEC drug regimens and dosages are currently in use. A tendency for concurrent intravenous chemotherapy administration (bidirectional chemotherapy, so-called “HIPEC plus”) has been observed in recent years, with the aim to further enhance the cytotoxic potential of HIPEC. Future trials to ascertain the ideal HIPEC regimen in different diseases and to evaluate the efficacy of new drugs or drug combinations in this context are warranted. © 2010 Baishideng. All rights reserved. Key words: Hyperthermia; Intracavitary chemotherapy; Peritoneal neoplasms; Peritoneal carcinomatosis; Cytoreductive surgery Peer reviewer: Akihiko Tsuchida, MD, PhD, Associate Professor, Department of Surgery, Tokyo Medical University, 6-7-1 Nishi- Shinjuku, Shinjuku-ku, Tokyo 160-0023, Japan González-Moreno S, González-Bayón LA, Ortega-Pérez G. Hyperthermic intraperitoneal chemotherapy: Rationale and technique. World J Gastrointest Oncol 2010; 2(2): 68-75 Available from: URL: http://www.wjgnet.com/1948-5204/full/ v2/i2/68.htm DOI: http://dx.doi.org/10.4251/wjgo.v2.i2.68 Online Submissions: http://www.wjgnet.com/1948-5204office wjgo@wjgnet.com doi:10.4251/wjgo.v2.i2.68 World J Gastrointest Oncol 2010 February 15; 2(2): 68-75 ISSN 1948-5204 (online) © 2010 Baishideng. All rights reserved. 68 February 15, 2010|Volume 2|Issue 2|WJGO|www.wjgnet.com Hyperthermic intraperitoneal chemotherapy: Rationale and technique Santiago González-Moreno, Luis A González-Bayón, Gloria Ortega-Pérez TOPIC HIGHLIGHT Antonio Macrì, MD, Professor,Series Editor Updates in Surgery Treatment of Peritoneal Surface Malignancies Angelo Di Giorgio Enrico Pinto Editors In collaboration with Paolo Sammartino and Franco Roviello State of the Art and Perspectives Marco Lotti MD
  10. 10. but what is the desired therapy? Marco Lotti MD
  11. 11. the desired therapy is called HIPEC • Exposure of the WHOLE peritoneal surface to HEAT and CHEMO • An adequate volume of PERFUSION FLUID is needed • The perfusion fluid should be maintained at 41-42°C • And FREELY recirculate through the abdomen for 30-90 min Marco Lotti MD
  12. 12. As far as HEAT is concerned, one can argue that the statement that hand mixing entails the homogeneous distribution of the desired therapy is not supported by sound evidence. Moreover, when it comes to physical laws, that claimed homogeneous distribution is very unlikely to occur. Marco Lotti MD
  13. 13. The Level of Evidence affair Marco Lotti MD
  14. 14. could be extended to the clinical ground; (2) what is the impact of the duration of the procedure when we used high temperature? The duration of hyperthermia. There is clinical data demon- strating the safety of hyperthermia with different schemes established on empirical bases, but not from systematic experimental studies. These schemes are the following: to use a temperature of 418C but during 90 min, or to use 438C but during 30–40 min. Also, some teams use a temperature of 428C during 60 min. Long duration hyperthermia needs to use cooling systems to decrease the body’s temperature. Unfortunately, there is no systematic study about the escalation of the level and also of the duration of hyperthermia in animals or in human. However, it appears that low hyperthermia allows long duration of the procedure and that high hyperthermia do not allow it. At that time nobody knows if it more efficient to privilege high temperature or long duration. If they were equivalent, the first should be cheaper. Also, it is necessary to obtain a thermal homogeneity in the whole abdominal cavity to be sure that every site of the diffuse peritoneal disease will receive the optimal treatment. It is well accepted in the literature that only the coliseum technique with a continuous stirring of the viscera, allows to obtain it. Even with this continuous stirring, and a high flow rate in the pumps (2 L/min), and with a moderate volume of perfusate (2 L/m2 ), in the experience of Elias et al., to obtain a minimum of 428C in the out-drains, it is necessary to have between 44 and 458C in the in-drains. The Different Parameters Impacting on Pharmacokinetics and Efficacy of HIPEC Journal of Surgical Oncology 2008;98:247–252 Drugs, Carrier Solutions and Temperature in Hyperthermic Intraperitoneal Chemotherapy SHIGEKI KUSAMURA, MD, PhD,1 ELIAS DOMINIQUE, MD, PhD,2 *,{ DARIO BARATTI, MD,1 RAMI YOUNAN, MD,3 AND MARCELLO DERACO, MD 1 1 Department of Surgery, National Cancer Institute of Milan, Italy 2 Department of Surgical Oncology, Institut Gustave Roussy, Villejuif, France 3 Department of Surgery-Surgical Oncology Unit, CHUM, University of Montreal Health Centre, Montreal, Canada Fifth International Workshop on Peritoneal Surface Malignancy, in Milan, the consensus on technical aspects of cytoreductive surgery for peritoneal surface malignancy was obtained through the Delphi process. Conflicting points concerning drugs, carrier solution and l temperature for hyperthermic intraperitoneal chemotherapy (HIPEC) were discussed. g. Oncol. 2008;98:247–252. ß 2008 Wiley-Liss, Inc. KEY WORDS: peritoneal carcinomatosis; hyperthermic intraperitoneal chemotherapy; consensus INTRODUCTION December 4–6, 2006, the National Cancer Institute of Milan zed a consensus statement on the management of peritoneal malignancy (PSM). This conference brought together experts field of local–regional therapy in an effort to discuss current ches to this PSM. Eligible Drugs for Hyperthermic Intraperitoneal Chemotherapy eral drugs are available for intraperitoneal use, as outlined in . Theoretically, only cell cycle phase non-specific agents are ed for this single-shot cancer treatment. In other words cell hase specific agents should be not suitable for HIPEC. the concentration of agents in the perfusate, the volume of the carrier solution should also be taken in consideration [1,2]. In Table III different types of carrier solution and their respective main characteristics are outlined. Intraperitoneal Temperature During HIPEC There is two different but synergic points to consider: the suitable temperature to obtain and the duration of hyperthermia. What is the theoretical optimal temperature? Different levels of target temperatures have been reported in the literature: from 40 to 418C [3], from 41 to 438C [4], from 41.5 to 42.58C [20], 428C [5], from 42 to 438C [6] and from 42 to 458C [7]. The establishment of the optimal temperature level during the per- fusion requires the consideration of several aspects regarding the inter- Journal of Surgical Oncology 2008;98:242–246 Hyperthermic Intraperitoneal Chemotherapy: Nomenclature and Modalities of Perfusion OLIVIER GLEHEN, MD, PhD,1,2 * EDDY COTTE, MD,1,2 SHIGEKI KUSAMURA, MD, PhD,3 MARCELLO DERACO, MD,3 DARIO BARATTI, MD,3 GUILLAUME PASSOT, MD,1,2 ANNIE-CLAUDE BEAUJARD, MD,2,4 AND GILLY FRANCOIS NOEL, MD, PhD,1,2 1 Department of Oncologic surgery, Centre Hospitalo-Universitaire Lyon Sud, Pierre Be´nite Cedex, France 2 EA 3738, UCBL, Faculte´ de me´dicine Lyon Sud, Oullins Cedex, France 3 Fondazione IRCCS Istituto Nazionale dei Tumori Milano, Milan, Italy 4 Department of Anesthesiology, CHLS—HCL, Pierre Be´nite Cedex, France Following international consensus, HIPEC should be the acronym used in the scientific literature to refer to the hyperthermic intraperitoneal chemotherapy. Several modalities of perfusion are used to deliver HIPEC: open abdominal technique (Coliseum), closed abdominal technique, peritoneal cavity expander, semi-opened abdominal technique. There is no sufficient evidence in literature confirming the superiority of one technique over the others in terms of outcome, morbidity and safety to the personnel of the operating theatre. Each option has its own operational advantages and disadvantages and future prospective studies must be conducted to establish which one is the best alternative. Today, the best technique is the one which is routinely used and improved into each specialized institution involved in the management of peritoneal surface malignancy. J. Surg. Oncol. 2008;98:242–246. ß 2008 Wiley-Liss, Inc. KEY WORDS: hyperthermia; peritoneal carcinomatosis; techniques; intraperitoneal chemotherapy INTRODUCTION Patients with peritoneal carcinomatosis have long been considered as a terminal condition with no curative options. Over the past decade, novel therapeutic approaches to peritoneal surface malignancies have emerged. Loco-regional treatments including cytoreductive surgery and peritonectomy procedures for the macroscopic disease in combination with perioperative intraperitoneal chemotherapy for the microscopic residual disease have been developed for this loco- regional disease. There are different modalities for perioperative intraperitoneal chemotherapy administration. Most of peritoneal surface malignancy treatment centers exclusively use hyperthermic intraperitoneal chemotherapy (HIPEC), some others only early post- operative administration and others use both sequentially. Several devices or technologies of HIPEC have been described and are Modalities of Perfusion Early postoperative intraperitoneal chemotherapy. Early post- operative intraperitoneal chemotherapy (EPIC) is delivered by a Tenckhoff catheter or by a subcutaneous port placed through the abdominal wall in the approximate area at the greatest risk of recurrence after cytoreductive surgery. Closed suction drains are placed in dependant areas in the pelvis and below each hemi- diaphragm. Intraperitoneal chemotherapy is administered postoper- atively on postoperative days 1–5, but can be initiated immediately postoperatively and continued in the outpatient setting [3]. EPIC has the advantages to administer multiple cycles of chemotherapy. During each treatment, the chemotherapeutic drug is not drained for at least 24 hr, to increase the duration of exposure of tumor cells to therapy. results to a longer bathing duration with decreased drug concentration. The best duration is not known and depends on the protocol used [8,9]. Among the different devices reported into scientific literature we will discuss advantages and inconvenient of open abdomen (coliseum) technique, closed abdomen technique, peritoneal cavity expander and semi-open technique. Open abdomen technique. The open abdominal technique has also been referred to as the ‘‘Coliseum technique’’. A silastic sheet is sutured over a Thompson retractor and to the patient’s skin over the abdominal incision. This suspends that abdominal wall creating a ‘‘Coliseum’’ or ‘‘soup bowl-like’’ container for instillation of the peritoneal perfusate. An incision is made in the middle of the sheet to allow manual manipulation of the intra-abdominal contents to prevent stasis of the heated perfusate. A smoke evacuator is used to clear aerosolized chemotherapy liberated during the procedure (Fig. 1). Elias et al. [14] did a prospective phase II trial testing seven different techniques in 32 patients. They found that complete closure of the abdominal wall before the perfusion restricted the volume of the perfusion, decreased spatial diffusion of the instillate, and resulted in lack of thermal homogeneity. Use of the a peritoneal cavity expander o G p r g H t t i Journal of Surgical Oncology T C A S V E S K G treated with cytoreductive surgery combined with perioperative intraperitoneal chemotherapy [5]. Its efficacy is limited by adhesions that can result in pooling of the chemotherapeutic drugs in intraperitoneal loculations. Not only does this sequester the treatment from tumor cells, loculations also result in exposure of normal tissue to high concentrations of drug, thereby adding to the morbidity of the therapy [6]. EPIC do not involve hyperthermia. However heat has been shown to be cytotoxic in vitro at 42.58C [7], and hyperthermia has been shown to enhance the antitumor effect of agents such as oxapliplatin, mitomycin, doxorubicin, and cisplatin, by augmenting cytotoxicity and increasing the penetration of drugs into tissue [8–10]. Moreover, Elias et al. recently compared two groups of patients with colorectal carcinoma- tosis with characteristics as similar as possible. One was treated with EPIC using 5-FU and mitomycin C and one with HIPEC using oxaliplatin at 438C. All results were in favor of HIPEC group: mortality, morbidity, rate of peritoneal recurrence which was twice in EPIC group and overall survival [11]. Thus, EPIC may be used in the treatment of microscopic residual peritoneal disease, but following HIPEC which seems to be more efficient, with an increased risk of postoperative complications. HIPEC. To take advantage of the synergistic effect of chemo- therapy and hyperthermia, several different HIPEC devices to enable intraoperative perfusion of the peritoneal cavity with hyperthermic chemotherapy have been developed. Constant hyperthermia is ob- tained by a closed continuous circuit, with pump, heater, heat exchanger, and real-time temperature monitoring. Open circuit without recirculation and reheating of the instillate should be avoided [8,9]. To avoid systemic hyperthermia during the perfusion procedure, core temperature have to be not more than 34–358C at the beginning of the allowed an immediate thermal homogeneity, but the expander isolated the abdominal wall from the instillate, resulting in early parietal peritoneal recurrence. The use of coliseum technique was identified into this single institution as the best technique in terms of thermal homogeneity and spatial diffusion. Because the surgeons can manipulate the intra-abdominal viscera during perfusion, all peritoneal surfaces are equally exposed to therapy. Furthermore, excessive heating of normal tissue that can exacerbate post-operative ileus and increase the incidence of postoperative perforation or fistula formation is avoided [15]. Disadvantage of this technique is that the open abdomen naturally Fig. 1. The coliseum apparatus. [Color figure can be viewed in the online issue, available at www.interscience.wiley.com.] … … The Level of Evidence affair Marco Lotti MD
  15. 15. the claimed evidence is based on two articles: 1. Elias D, Antoun S, Goharin A, Otmany AE, Puizillout JM, Lasser P. Research on the best chemohyperthermia technique of treatment of peritoneal carcinomatosis after complete resection. Int J Surg Investig. 2000;1(5):431-9. 2. Stephens AD, Alderman R, Chang D, Edwards GD, Esquivel J, Sebbag G, Steves MA, Sugarbaker PH. Morbidity and mortality analysis of 200 treatments with cytoreductive surgery and hyperthermic intraoperative intraperitoneal chemotherapy using the coliseum technique. Ann Surg Oncol. 1999 Dec;6(8):790-6. The Level of Evidence affair Marco Lotti MD
  16. 16. Elias D, Antoun S, Goharin A, Otmany AE, Puizillout JM, Lasser P. Research on the best chemohyperthermia technique of treatment of peritoneal carcinomatosis after complete resection. Int J Surg Investig. 2000;1(5):431-9. The Level of Evidence affair • The International Journal of Surgical Investigation started in 1999 and ended in 2001. It is not to be found on the web. I could not find any link to the journal website available by Google search. My librarian was not able to retrieve the article. • I tried to request the article on ResearchGate and Mendeley, without success. • I could just make some considerations about the Abstract. Marco Lotti MD
  17. 17. BACKGROUND: AIMS: METHODS: RESULTS: Abstract The complete or almost complete resection of peritoneal carcinomatosis (PC) followed by intraperitoneal chemohyperthermia (IPCH) is potentially capable of curing some patients presenting with disease confined to the peritoneum. The aim of this prospective phase I-II study was to develop an efficient IPCH procedure with good thermal homogeneity and good spatial diffusion, that would be reproducible (and thus could be standardized and exported), and to evaluate patient tolerance and its efficiency in eradicating tumor tissue. Seven IPCH procedures were tested successively in 32 patients (up to a total of 35 IPCH). Each procedure was tested in at least 4 patients before modifications for technical reasons or due to inacceptable tolerance. Five of them were followed by early postoperative intraperitoneal chemotherapy (EPIC) lasting 4 days. Thermal homogeneity was measured with 6 thermal probes placed in different positions inside the abdominal cavity. Spatial diffusion was studied in the last patients by adding methylene blue to the IPCH liquid. The mean follow-up was 23.85 months for the series. From the technological point of view, we have progressively shown that procedures with closure of the abdomen are not satisfactory: it was impossible to obtain thermal homogeneity when the entire parietal wound was closed, but markedly improved when only the skin was closed. However, these "closed" procedures did not allow us to treat all surfaces at risk. The peritoneal cavity "expander" did not permit treatment of the parietal wound and an indeterminate amount of the perfusion oozed out at its periphery. The open technique with traction of the skin upwards was superior. Using different procedures successively undermined the quality of the postoperative results. Three patients (8.6%) died and morbidity (albeit minimal) Author information BACKGROUND: AIMS: METHODS: RESULTS: Int J Surg Investig. 2000;1(5):431-9. Research on the best chemohyperthermia technique of treatment of peritoneal carcinomatosis after complete resection. Elias D , Antoun S, Goharin A, Otmany AE, Puizillout JM, Lasser P. Abstract The complete or almost complete resection of peritoneal carcinomatosis (PC) followed by intraperitoneal chemohyperthermia (IPCH) is potentially capable of curing some patients presenting with disease confined to the peritoneum. The aim of this prospective phase I-II study was to develop an efficient IPCH procedure with good thermal homogeneity and good spatial diffusion, that would be reproducible (and thus could be standardized and exported), and to evaluate patient tolerance and its efficiency in eradicating tumor tissue. Seven IPCH procedures were tested successively in 32 patients (up to a total of 35 IPCH). Each procedure was tested in at least 4 patients before modifications for technical reasons or due to inacceptable tolerance. Five of them were followed by early postoperative intraperitoneal chemotherapy (EPIC) lasting 4 days. Thermal homogeneity was measured with 6 thermal probes placed in different positions inside the abdominal cavity. Spatial diffusion was studied in the last patients by adding methylene blue to the IPCH liquid. The mean follow-up was 23.85 months for the series. From the technological point of view, we have progressively shown that procedures Format: Abstract 1 Author information PubMedThe Level of Evidence affair 7 procedures tested in 32 patients Each procedure tested in 4 (maybe 5) patients 6 thermal probes used to measure thermal homogeneity Marco Lotti MD
  18. 18. BACKGROUND: AIMS: METHODS: RESULTS: Int J Surg Investig. 2000;1(5):431-9. Research on the best chemohyperthermia technique of treatment of peritoneal carcinomatosis after complete resection. Elias D , Antoun S, Goharin A, Otmany AE, Puizillout JM, Lasser P. Abstract The complete or almost complete resection of peritoneal carcinomatosis (PC) followed by intraperitoneal chemohyperthermia (IPCH) is potentially capable of curing some patients presenting with disease confined to the peritoneum. The aim of this prospective phase I-II study was to develop an efficient IPCH procedure with good thermal homogeneity and good spatial diffusion, that would be reproducible (and thus could be standardized and exported), and to evaluate patient tolerance and its efficiency in eradicating tumor tissue. Seven IPCH procedures were tested successively in 32 patients (up to a total of 35 IPCH). Each procedure was tested in at least 4 patients before modifications for technical reasons or due to inacceptable tolerance. Five of them were followed by early postoperative intraperitoneal chemotherapy (EPIC) lasting 4 days. Thermal homogeneity was measured with 6 thermal probes placed in different positions inside the abdominal cavity. Spatial diffusion was studied in the last patients by adding methylene blue to the IPCH liquid. The mean follow-up was 23.85 months for the series. From the technological point of view, we have progressively shown that procedures with closure of the abdomen are not satisfactory: it was impossible to obtain thermal Format: Abstract 1 Author information PubMed The Level of Evidence affair 7 procedures tested in 32 patients Each procedure tested in 4 (maybe 5) patients 6 thermal probes used to measure thermal homogeneity As far as Statistics is concerned and sample size calculation is considered, only huge differences between techniques can be found to be significant by means of so small samples. Otherwise, the differences found between samples cannot be credited to any of the techniques and are likely to be subject to the opinion of the Researchers. Marco Lotti MD
  19. 19. BACKGROUND: AIMS: METHODS: RESULTS: Abstract The complete or almost complete resection of peritoneal carcinomatosis (PC) followed by intraperitoneal chemohyperthermia (IPCH) is potentially capable of curing some patients presenting with disease confined to the peritoneum. The aim of this prospective phase I-II study was to develop an efficient IPCH procedure with good thermal homogeneity and good spatial diffusion, that would be reproducible (and thus could be standardized and exported), and to evaluate patient tolerance and its efficiency in eradicating tumor tissue. Seven IPCH procedures were tested successively in 32 patients (up to a total of 35 IPCH). Each procedure was tested in at least 4 patients before modifications for technical reasons or due to inacceptable tolerance. Five of them were followed by early postoperative intraperitoneal chemotherapy (EPIC) lasting 4 days. Thermal homogeneity was measured with 6 thermal probes placed in different positions inside the abdominal cavity. Spatial diffusion was studied in the last patients by adding methylene blue to the IPCH liquid. The mean follow-up was 23.85 months for the series. From the technological point of view, we have progressively shown that procedures with closure of the abdomen are not satisfactory: it was impossible to obtain thermal homogeneity when the entire parietal wound was closed, but markedly improved when only the skin was closed. However, these "closed" procedures did not allow us to treat all surfaces at risk. The peritoneal cavity "expander" did not permit treatment of the parietal wound and an indeterminate amount of the perfusion oozed out at its periphery. The open technique with traction of the skin upwards was superior. Using different procedures successively undermined the quality of the postoperative results. Three patients (8.6%) died and morbidity (albeit minimal) Author information BACKGROUND: AIMS: METHODS: RESULTS: Int J Surg Investig. 2000;1(5):431-9. Research on the best chemohyperthermia technique of treatment of peritoneal carcinomatosis after complete resection. Elias D , Antoun S, Goharin A, Otmany AE, Puizillout JM, Lasser P. Abstract The complete or almost complete resection of peritoneal carcinomatosis (PC) followed by intraperitoneal chemohyperthermia (IPCH) is potentially capable of curing some patients presenting with disease confined to the peritoneum. The aim of this prospective phase I-II study was to develop an efficient IPCH procedure with good thermal homogeneity and good spatial diffusion, that would be reproducible (and thus could be standardized and exported), and to evaluate patient tolerance and its efficiency in eradicating tumor tissue. Seven IPCH procedures were tested successively in 32 patients (up to a total of 35 IPCH). Each procedure was tested in at least 4 patients before modifications for technical reasons or due to inacceptable tolerance. Five of them were followed by early postoperative intraperitoneal chemotherapy (EPIC) lasting 4 days. Thermal homogeneity was measured with 6 thermal probes placed in different positions inside the abdominal cavity. Spatial diffusion was studied in the last patients by adding methylene blue to the IPCH liquid. The mean follow-up was 23.85 months for the series. From the technological point of view, we have progressively shown that procedures Format: Abstract 1 Author information PubMedThe Level of Evidence affair I am concerned that this is opinion more than evidence Marco Lotti MD
  20. 20. The Level of Evidence affair Hyperthermic intraoperative intraperitoneal chemo- therapy was first added to cytoreductive surgery at the Washington Hospital Center in March 1992. Sixty pa- tients were enrolled in an Institutional Review Board- approved phase I/II clinical trial. Informed consent was obtained from all patients before surgery. This trial com- bined cytoreductive surgery with heated intraoperative mitomycin C administered by a closed abdominal tech- nique. The techniques,2 pharmacokinetics,3,4 safety con- siderations,5 and morbidity and mortality6 of the closed intraoperative intraperitoneal chemotherapy technique have been reported. Deficiencies were noted in the dis- tribution of methylene blue dye with the closed tech- nique, which may cause a high frequency of complica- tions and nonuniform treatment. This prompted the development of the Coliseum technique for HIIC, which allowed for manual distribution of heat and drugs.7,8 After the conclusion of the investigative phase, clinical guidelines combining cytoreductive surgery and HIIC for biopsy-confirmed peritoneal carcinomatosis from gastrointestinal malignancies were used. These data were prospectively recorded for 200 treatments in 183 patients that occurred between November 1994 and June 1998. The techniques of cytoreductive surgery have been dialysis solution containing 12.5 mg/m2 of mitomycin C for males (maximum dose, 25 mg) or 10.0 mg/m2 for females (maximum dose, 20 mg) was heated and infused at approximately 1 liter/minute. Temperatures were mea- sured with a Labcraft digital thermometer (Curtin Mathe- son Scientific, Jessup, MD). The temperature at the in- flow line was approximately 44°C. The Tenckhoff temperature probe was maintained between 42°C and 43°C, and a distant intra-abdominal site averaged 39.6°C. Throughout the perfusion, the surgeon continu- ously manipulated the viscera to distribute both heat and chemotherapy. All bowel anastomoses were constructed with hand- sewn two-layer closures with two exceptions. Low colo- rectal anastomoses were performed with a 33-mm-diameter intraluminal stapler and esophagojejunal anastomoses with a 29-mm-diameter intraluminal stapler (Ethicon Endo- surgical, Cincinnati, OH). If a pyloroplasty was per- formed, it was a full-thickness incision closed with a single layer of interrupted silk sutures. TABLE 1. Patient characteristics No. of patients receiving 1 cytoreduction ϩ HIIC 166 Morbidity and Mortality Analysis of 200 Treatments With Cytoreductive Surgery and Hyperthermic Intraoperative Intraperitoneal Chemotherapy Using the Coliseum Technique Arvil D. Stephens, MD, Robert Alderman, PA-C, David Chang, MD, Gary D. Edwards, PA-C, Jesus Esquivel, MD, Gilbert Sebbag, MD, Mark A. Steves, MD, and Paul H. Sugarbaker, MD Background: Peritoneal carcinomatosis from gastrointestinal cancers is a fatal diagnosis without special combined surgical and chemotherapy interventions. Guidelines for cytoreductive surgery and hyperthermic intraoperative intraperitoneal chemotherapy (HIIC) by using the Coliseum tech- nique have been developed to treat patients with peritoneal carcinomatosis and other peritoneal surface malignancies. The purpose of this study was to analyze the morbidity and mortality of patients undergoing cytoreductive surgery and HIIC by using mitomycin C. Methods: Data were prospectively recorded on 183 patients who underwent 200 cytoreductive surgeries with HIIC between November 1994 and June 1998. Seventeen of the 183 patients returned for a second-look surgery plus HIIC. All HIIC administrations occurred after cytoreduction and used continuous manual separation of intra-abdominal structures to optimize drug and heat distribution. Origins of the tumors were as follows: appendix (150 patients), colon (20 patients), stomach (7 patients), pancreas (2 patients), small bowel (1 patient), rectum (1 patient), gallbladder (1 patient), and peritoneal papillary serous carcinoma (1 patient). Morbidity was organized into 20 categories that were graded 0 to IV by the National Cancer Institute’s Common Toxicity Criteria. In an attempt to identify patient characteristics that may predispose to complications, each morbidity variable was analyzed for an association with the 25 clinical variables recorded. Results: Combined grade III/IV morbidity was 27.0%. Complications observed included the following: peripancreatitis (6.0%), fistula (4.5%), postoperative bleeding (4.5%), and hematological toxicity (4.0%). Morbidity was statistically linked with the following clinical variables: duration of surgery (P Ͻ .0001), the number of peritonectomy procedures and resections (P Ͻ .0001), and the number of suture lines (P ϭ .0078). No HIIC variables were statistically associated with the presence of grade III or grade IV morbidity. Treatment-related mortality was 1.5%. Conclusions: HIIC may be applied to select patients with peritoneal carcinomatosis from gastroin- testinal malignancies with 27.0% major morbidity and 1.5% treatment-related mortality. The frequency of complications was associated with the extent of the surgical procedure and not with variables associated with the delivery of heated intraoperative intraperitoneal chemotherapy. The technique has shown an acceptable frequency of adverse events to be tested in phase III adjuvant trials. Key Words: Morbidity—Mortality—Cytoreductive surgery—Hyperthermia—Intraperitoneal chemotherapy—Mitomycin C—5-Fluorouracil—Pseudomyxoma peritonei—Colon cancer. Annals of Surgical Oncology, 6(8):790–796 Published by Lippincott Williams & Wilkins © 1999 The Society of Surgical Oncology, Inc. • the Authors were disappointed by the closed-abdomen technique • their disappointment brought them to develop the Coliseum technique • They describe their experience and the results of 200 treatments Marco Lotti MD
  21. 21. Fistula Fistulas were observed in nine patients (4.5%). Exten- sive lysis of fibrous and cancerous adhesions between small bowel surfaces may have caused seromuscular tears that later developed into fistula. Jacquet et al.6 reported a spontaneous fistula of the small bowel after a patient underwent cytoreductive surgery and HIIC with a closed abdominal technique. This fistula was thought to result from the patient experiencing continuous high intra-abdominal inflow temperatures at a single site. We did not observe a statistical association with the occur- rence of combined grade III/IV morbidity and any intra- peritoneal chemotherapy parameter despite higher Tenckhoff temperatures during HIIC with manual distri- bution of the heated chemotherapy. We attribute the lack of association to the change from a closed abdominal procedure to the Coliseum technique described above. The Coliseum technique allows the surgeon to move the Tenckhoff catheter around the abdominopelvic cavity, thus improving the distribution of both heat and drug. Postoperative Bleeding not All stra cel thr pan adm bee mi tien (72 dos W tali the clo HI rep stra Fo ies Th nia Morbidity and Mortality Analysis of 200 Treatments With Cytoreductive Surgery and Hyperthermic Intraoperative Intraperitoneal Chemotherapy Using the Coliseum Technique Arvil D. Stephens, MD, Robert Alderman, PA-C, David Chang, MD, Gary D. Edwards, PA-C, Jesus Esquivel, MD, Gilbert Sebbag, MD, Mark A. Steves, MD, and Paul H. Sugarbaker, MD Background: Peritoneal carcinomatosis from gastrointestinal cancers is a fatal diagnosis without special combined surgical and chemotherapy interventions. Guidelines for cytoreductive surgery and hyperthermic intraoperative intraperitoneal chemotherapy (HIIC) by using the Coliseum tech- nique have been developed to treat patients with peritoneal carcinomatosis and other peritoneal surface malignancies. The purpose of this study was to analyze the morbidity and mortality of patients undergoing cytoreductive surgery and HIIC by using mitomycin C. Methods: Data were prospectively recorded on 183 patients who underwent 200 cytoreductive surgeries with HIIC between November 1994 and June 1998. Seventeen of the 183 patients returned for a second-look surgery plus HIIC. All HIIC administrations occurred after cytoreduction and used continuous manual separation of intra-abdominal structures to optimize drug and heat distribution. Origins of the tumors were as follows: appendix (150 patients), colon (20 patients), stomach (7 patients), pancreas (2 patients), small bowel (1 patient), rectum (1 patient), gallbladder (1 patient), and peritoneal papillary serous carcinoma (1 patient). Morbidity was organized into 20 categories that were graded 0 to IV by the National Cancer Institute’s Common Toxicity Criteria. In an attempt to identify patient characteristics that may predispose to complications, each morbidity variable was analyzed for an association with the 25 clinical variables recorded. Results: Combined grade III/IV morbidity was 27.0%. Complications observed included the following: peripancreatitis (6.0%), fistula (4.5%), postoperative bleeding (4.5%), and hematological toxicity (4.0%). Morbidity was statistically linked with the following clinical variables: duration of surgery (P Ͻ .0001), the number of peritonectomy procedures and resections (P Ͻ .0001), and the number of suture lines (P ϭ .0078). No HIIC variables were statistically associated with the presence of grade III or grade IV morbidity. Treatment-related mortality was 1.5%. Conclusions: HIIC may be applied to select patients with peritoneal carcinomatosis from gastroin- testinal malignancies with 27.0% major morbidity and 1.5% treatment-related mortality. The frequency of complications was associated with the extent of the surgical procedure and not with variables associated with the delivery of heated intraoperative intraperitoneal chemotherapy. The technique has shown an acceptable frequency of adverse events to be tested in phase III adjuvant trials. Key Words: Morbidity—Mortality—Cytoreductive surgery—Hyperthermia—Intraperitoneal chemotherapy—Mitomycin C—5-Fluorouracil—Pseudomyxoma peritonei—Colon cancer. Peritoneal carcinomatosis and sarcomatosis are uni- formly fatal diagnoses without special combined surgical and intraperitoneal chemotherapy interventions. Malig- nancies that present within the abdominopelvic cavity often cause their great morbidity and mortality through progressive involvement of the peritoneal surfaces. Ex- amples of this can be seen in patients with appendiceal Received March 5, 1999; accepted August 18, 1999. From the Washington Cancer Institute, Washington, DC. Annals of Surgical Oncology, 6(8):790–796 Published by Lippincott Williams & Wilkins © 1999 The Society of Surgical Oncology, Inc. I tried to follow their reasoning Marco Lotti MD
  22. 22. Fistula Fistulas were observed in nine patients (4.5%). Exten- sive lysis of fibrous and cancerous adhesions between small bowel surfaces may have caused seromuscular tears that later developed into fistula. Jacquet et al.6 reported a spontaneous fistula of the small bowel after a patient underwent cytoreductive surgery and HIIC with a closed abdominal technique. This fistula was thought to result from the patient experiencing continuous high intra-abdominal inflow temperatures at a single site. We did not observe a statistical association with the occur- rence of combined grade III/IV morbidity and any intra- peritoneal chemotherapy parameter despite higher Tenckhoff temperatures during HIIC with manual distri- bution of the heated chemotherapy. We attribute the lack of association to the change from a closed abdominal procedure to the Coliseum technique described above. The Coliseum technique allows the surgeon to move the Tenckhoff catheter around the abdominopelvic cavity, thus improving the distribution of both heat and drug. Postoperative Bleeding not All stra cel thr pan adm bee mi tien (72 dos W tali the clo HI rep stra Fo ies Th nia Morbidity and Mortality Analysis of 200 Treatments With Cytoreductive Surgery and Hyperthermic Intraoperative Intraperitoneal Chemotherapy Using the Coliseum Technique Arvil D. Stephens, MD, Robert Alderman, PA-C, David Chang, MD, Gary D. Edwards, PA-C, Jesus Esquivel, MD, Gilbert Sebbag, MD, Mark A. Steves, MD, and Paul H. Sugarbaker, MD Background: Peritoneal carcinomatosis from gastrointestinal cancers is a fatal diagnosis without special combined surgical and chemotherapy interventions. Guidelines for cytoreductive surgery and hyperthermic intraoperative intraperitoneal chemotherapy (HIIC) by using the Coliseum tech- nique have been developed to treat patients with peritoneal carcinomatosis and other peritoneal surface malignancies. The purpose of this study was to analyze the morbidity and mortality of patients undergoing cytoreductive surgery and HIIC by using mitomycin C. Methods: Data were prospectively recorded on 183 patients who underwent 200 cytoreductive surgeries with HIIC between November 1994 and June 1998. Seventeen of the 183 patients returned for a second-look surgery plus HIIC. All HIIC administrations occurred after cytoreduction and used continuous manual separation of intra-abdominal structures to optimize drug and heat distribution. Origins of the tumors were as follows: appendix (150 patients), colon (20 patients), stomach (7 patients), pancreas (2 patients), small bowel (1 patient), rectum (1 patient), gallbladder (1 patient), and peritoneal papillary serous carcinoma (1 patient). Morbidity was organized into 20 categories that were graded 0 to IV by the National Cancer Institute’s Common Toxicity Criteria. In an attempt to identify patient characteristics that may predispose to complications, each morbidity variable was analyzed for an association with the 25 clinical variables recorded. Results: Combined grade III/IV morbidity was 27.0%. Complications observed included the following: peripancreatitis (6.0%), fistula (4.5%), postoperative bleeding (4.5%), and hematological toxicity (4.0%). Morbidity was statistically linked with the following clinical variables: duration of surgery (P Ͻ .0001), the number of peritonectomy procedures and resections (P Ͻ .0001), and the number of suture lines (P ϭ .0078). No HIIC variables were statistically associated with the presence of grade III or grade IV morbidity. Treatment-related mortality was 1.5%. Conclusions: HIIC may be applied to select patients with peritoneal carcinomatosis from gastroin- testinal malignancies with 27.0% major morbidity and 1.5% treatment-related mortality. The frequency of complications was associated with the extent of the surgical procedure and not with variables associated with the delivery of heated intraoperative intraperitoneal chemotherapy. The technique has shown an acceptable frequency of adverse events to be tested in phase III adjuvant trials. Key Words: Morbidity—Mortality—Cytoreductive surgery—Hyperthermia—Intraperitoneal chemotherapy—Mitomycin C—5-Fluorouracil—Pseudomyxoma peritonei—Colon cancer. Peritoneal carcinomatosis and sarcomatosis are uni- formly fatal diagnoses without special combined surgical and intraperitoneal chemotherapy interventions. Malig- nancies that present within the abdominopelvic cavity often cause their great morbidity and mortality through progressive involvement of the peritoneal surfaces. Ex- amples of this can be seen in patients with appendiceal Received March 5, 1999; accepted August 18, 1999. From the Washington Cancer Institute, Washington, DC. Annals of Surgical Oncology, 6(8):790–796 Published by Lippincott Williams & Wilkins © 1999 The Society of Surgical Oncology, Inc. 3 2 1 1. Jacquet reported a fistula of the small bowel due to scald injury. 2. We used higher temperatures and didn’t observe an increase in fistula rate. 3. Therefore we conclude that the Coliseum technique with manual distribution of the heated chemo is better. Marco Lotti MD
  23. 23. Fistula Fistulas were observed in nine patients (4.5%). Exten- sive lysis of fibrous and cancerous adhesions between small bowel surfaces may have caused seromuscular tears that later developed into fistula. Jacquet et al.6 reported a spontaneous fistula of the small bowel after a patient underwent cytoreductive surgery and HIIC with a closed abdominal technique. This fistula was thought to result from the patient experiencing continuous high intra-abdominal inflow temperatures at a single site. We did not observe a statistical association with the occur- rence of combined grade III/IV morbidity and any intra- peritoneal chemotherapy parameter despite higher Tenckhoff temperatures during HIIC with manual distri- bution of the heated chemotherapy. We attribute the lack of association to the change from a closed abdominal procedure to the Coliseum technique described above. The Coliseum technique allows the surgeon to move the Tenckhoff catheter around the abdominopelvic cavity, thus improving the distribution of both heat and drug. Postoperative Bleeding not All stra cel thr pan adm bee mi tien (72 dos W tali the clo HI rep stra Fo ies Th nia Morbidity and Mortality Analysis of 200 Treatments With Cytoreductive Surgery and Hyperthermic Intraoperative Intraperitoneal Chemotherapy Using the Coliseum Technique Arvil D. Stephens, MD, Robert Alderman, PA-C, David Chang, MD, Gary D. Edwards, PA-C, Jesus Esquivel, MD, Gilbert Sebbag, MD, Mark A. Steves, MD, and Paul H. Sugarbaker, MD Background: Peritoneal carcinomatosis from gastrointestinal cancers is a fatal diagnosis without special combined surgical and chemotherapy interventions. Guidelines for cytoreductive surgery and hyperthermic intraoperative intraperitoneal chemotherapy (HIIC) by using the Coliseum tech- nique have been developed to treat patients with peritoneal carcinomatosis and other peritoneal surface malignancies. The purpose of this study was to analyze the morbidity and mortality of patients undergoing cytoreductive surgery and HIIC by using mitomycin C. Methods: Data were prospectively recorded on 183 patients who underwent 200 cytoreductive surgeries with HIIC between November 1994 and June 1998. Seventeen of the 183 patients returned for a second-look surgery plus HIIC. All HIIC administrations occurred after cytoreduction and used continuous manual separation of intra-abdominal structures to optimize drug and heat distribution. Origins of the tumors were as follows: appendix (150 patients), colon (20 patients), stomach (7 patients), pancreas (2 patients), small bowel (1 patient), rectum (1 patient), gallbladder (1 patient), and peritoneal papillary serous carcinoma (1 patient). Morbidity was organized into 20 categories that were graded 0 to IV by the National Cancer Institute’s Common Toxicity Criteria. In an attempt to identify patient characteristics that may predispose to complications, each morbidity variable was analyzed for an association with the 25 clinical variables recorded. Results: Combined grade III/IV morbidity was 27.0%. Complications observed included the following: peripancreatitis (6.0%), fistula (4.5%), postoperative bleeding (4.5%), and hematological toxicity (4.0%). Morbidity was statistically linked with the following clinical variables: duration of surgery (P Ͻ .0001), the number of peritonectomy procedures and resections (P Ͻ .0001), and the number of suture lines (P ϭ .0078). No HIIC variables were statistically associated with the presence of grade III or grade IV morbidity. Treatment-related mortality was 1.5%. Conclusions: HIIC may be applied to select patients with peritoneal carcinomatosis from gastroin- testinal malignancies with 27.0% major morbidity and 1.5% treatment-related mortality. The frequency of complications was associated with the extent of the surgical procedure and not with variables associated with the delivery of heated intraoperative intraperitoneal chemotherapy. The technique has shown an acceptable frequency of adverse events to be tested in phase III adjuvant trials. Key Words: Morbidity—Mortality—Cytoreductive surgery—Hyperthermia—Intraperitoneal chemotherapy—Mitomycin C—5-Fluorouracil—Pseudomyxoma peritonei—Colon cancer. Peritoneal carcinomatosis and sarcomatosis are uni- formly fatal diagnoses without special combined surgical and intraperitoneal chemotherapy interventions. Malig- nancies that present within the abdominopelvic cavity often cause their great morbidity and mortality through progressive involvement of the peritoneal surfaces. Ex- amples of this can be seen in patients with appendiceal Received March 5, 1999; accepted August 18, 1999. From the Washington Cancer Institute, Washington, DC. Annals of Surgical Oncology, 6(8):790–796 Published by Lippincott Williams & Wilkins © 1999 The Society of Surgical Oncology, Inc. One can reasonably argue that this is just an arbitrary assertion and not a demonstration. But their latter assertion is even more interesting. Let’s go deeper in… Marco Lotti MD
  24. 24. The Thermal Probe affair Marco Lotti MD
  25. 25. The Thermal Probe affair 44°C 39.6°C Stephens AD et al. assumed that a 44°C inflow temperature and an average 39.6°C outflow temperature was indicative of a mean abdominal temperature of 42°C. But there are several ways to arrange the thermal probes inside the abdominal cavity. But what happens if we move the inflow catheter? Marco Lotti MD
  26. 26. Probe 1 Probe 2 Probe 3 By moving the inflow catheter we unconsciously give demonstration of the Heisenberg’s uncertainty principle. Our action is altering the measurements. Unconsciously, of course. Marco Lotti MD
  27. 27. So we can give a different reading: Probe 1 Probe 2 Probe 3 The Coliseum technique allows the surgeon to move the inflow catheter around the abdominopelvic cavity, thus unconsciously affecting the temperature measurements and bringing them to the desired values. result from the patient experiencing continuous high intra-abdominal inflow temperatures at a single site. We did not observe a statistical association with the occur- rence of combined grade III/IV morbidity and any intra- peritoneal chemotherapy parameter despite higher Tenckhoff temperatures during HIIC with manual distri- bution of the heated chemotherapy. We attribute the lack of association to the change from a closed abdominal procedure to the Coliseum technique described above. The Coliseum technique allows the surgeon to move the Tenckhoff catheter around the abdominopelvic cavity, thus improving the distribution of both heat and drug. Postoperative Bleeding Postoperative bleeding requiring transfusion of more than 4 U or reoperation occurred in nine patients (4.5%) and was associated with increased intraoperative blood loss (P ϭ .0083). Two of these nine patients underwent cytoreduction and HIIC during a period in which hetastarch was given intraoperatively to expand plasma volume. Hetastarch is a chemically modified complex polysaccharide with a molecular mass of approximately 4.5 ϫ 105 daltons. Hetastarch has been reported to cause coagulopathy in a dose-related manner by three mecha- tients absorbed an average of 14.34 mg of mitomycin C (72.6% of the dose), and excreted 0.887 mg (4.2% of the dose), during the 90-minute HIIC administration. We have compared the published morbidity and mor- tality of cytoreduction and early postoperative chemo- therapy18 versus cytoreduction and HIIC by using a closed abdominal technique6 versus cytoreduction and HIIC by using the Coliseum technique. This comparison represents a critical review of the evolution of treatment strategies for patients with peritoneal carcinomatosis. Forty-three patients underwent 45 cytoreductive surger- ies with EPIC. Severe morbidity was reported in 37.7%. The most prominent causes of morbidity were pneumo- nia (13.3%), fistula (9%), and postoperative bleeding (9%). No deaths were reported among this group of patients. Jacquet et al. reported on 60 patients who un- derwent 60 cytoreductive surgeries with HIIC performed with a closed abdominal technique.6 Morbidity was 35.0% and was caused by anastomotic leak (10%), fis- tula (8.3%), hematological toxicity (6.7%), and bile leak (5.0%). Mortality in this group of patients was 5%. In patients who had cytoreduction plus HIIC with the Col- iseum technique, the morbidity was 27.0% and the treat- ment-related mortality was 1.5%. Morbidity and Mortality Analysis of 200 Treatments With Cytoreductive Surgery and Hyperthermic Intraoperative Intraperitoneal Chemotherapy Using the Coliseum Technique Arvil D. Stephens, MD, Robert Alderman, PA-C, David Chang, MD, Gary D. Edwards, PA-C, Jesus Esquivel, MD, Gilbert Sebbag, MD, Mark A. Steves, MD, and Paul H. Sugarbaker, MD Background: Peritoneal carcinomatosis from gastrointestinal cancers is a fatal diagnosis without special combined surgical and chemotherapy interventions. Guidelines for cytoreductive surgery and hyperthermic intraoperative intraperitoneal chemotherapy (HIIC) by using the Coliseum tech- nique have been developed to treat patients with peritoneal carcinomatosis and other peritoneal surface malignancies. The purpose of this study was to analyze the morbidity and mortality of patients undergoing cytoreductive surgery and HIIC by using mitomycin C. Methods: Data were prospectively recorded on 183 patients who underwent 200 cytoreductive surgeries with HIIC between November 1994 and June 1998. Seventeen of the 183 patients returned for a second-look surgery plus HIIC. All HIIC administrations occurred after cytoreduction and used continuous manual separation of intra-abdominal structures to optimize drug and heat distribution. Origins of the tumors were as follows: appendix (150 patients), colon (20 patients), stomach (7 patients), pancreas (2 patients), small bowel (1 patient), rectum (1 patient), gallbladder (1 patient), and peritoneal papillary serous carcinoma (1 patient). Morbidity was organized into 20 categories that were graded 0 to IV by the National Cancer Institute’s Common Toxicity Criteria. In an attempt to identify patient characteristics that may predispose to complications, each morbidity variable was analyzed for an association with the 25 clinical variables recorded. Results: Combined grade III/IV morbidity was 27.0%. Complications observed included the following: peripancreatitis (6.0%), fistula (4.5%), postoperative bleeding (4.5%), and hematological toxicity (4.0%). Morbidity was statistically linked with the following clinical variables: duration of surgery (P Ͻ .0001), the number of peritonectomy procedures and resections (P Ͻ .0001), and the number of suture lines (P ϭ .0078). No HIIC variables were statistically associated with the presence of grade III or grade IV morbidity. Treatment-related mortality was 1.5%. Conclusions: HIIC may be applied to select patients with peritoneal carcinomatosis from gastroin- testinal malignancies with 27.0% major morbidity and 1.5% treatment-related mortality. The frequency of complications was associated with the extent of the surgical procedure and not with variables associated with the delivery of heated intraoperative intraperitoneal chemotherapy. The technique has shown an acceptable frequency of adverse events to be tested in phase III adjuvant trials. Key Words: Morbidity—Mortality—Cytoreductive surgery—Hyperthermia—Intraperitoneal chemotherapy—Mitomycin C—5-Fluorouracil—Pseudomyxoma peritonei—Colon cancer. Peritoneal carcinomatosis and sarcomatosis are uni- formly fatal diagnoses without special combined surgical and intraperitoneal chemotherapy interventions. Malig- nancies that present within the abdominopelvic cavity often cause their great morbidity and mortality through progressive involvement of the peritoneal surfaces. Ex- Received March 5, 1999; accepted August 18, 1999. Annals of Surgical Oncology, 6(8):790–796 Published by Lippincott Williams & Wilkins © 1999 The Society of Surgical Oncology, Inc. Marco Lotti MD
  28. 28. Probe 1 Probe 2 Probe 3 When you can influence the measurements of the thermal probes, you can’t assume that the temperature at the tip of the probe is the temperature of the entire region. It is when you are far from there that the measurements become more reliable. Marco Lotti MD
  29. 29. The “Mix the Fluid” affair Marco Lotti MD
  30. 30. Fluid mixers consist of a Tank and an Impeller As the Engineers who design fluid mixers know well, effective mixing requires: • a proper shape of the Tank • a proper shape of the Impeller • a proper positioning of the Impeller • a proper rotational speed of the Impeller The “Mix the Fluid” affair Marco Lotti MD
  31. 31. The “Mix the Fluid” affair RPM (Rounds Per Minute) Turbulence is created at high rotational speed Marco Lotti MD
  32. 32. Propellers generate a different flow pattern than Radial Flow Turbines hands are much more like this Marco Lotti MD
  33. 33. The “Mix the Fluid” affair Effective mixing requires: • Adequate rotational speed • Proper positioning of the impeller • Proper shape of the tank I want to show you a link to a video that I found on Youtube (please go to the next slide) Marco Lotti MD
  34. 34. The abdomen is not a properly shaped tank. It is like a maze with multiple compartments. The hand is not a properly shaped impeller, it is not a propeller and does not rotate. With the wrong tank and the wrong impeller, effective fluid mixing is an illusion. Marco Lotti MD
  35. 35. manipulation of the perfusate plays a negligible role in the distribution of heat therefore, when concerned about the movements of the perfusion fluid, we can get inspired by weather forecasts and movements of the ocean currents, and consider… Marco Lotti MD
  36. 36. The Temperature Gradient affair Marco Lotti MD
  37. 37. The Temperature Gradient affair (it’s Physics) The next one is one of my videos (please go to the next slide) HOT WATER is lightweight and GOES UP COLD WATER is heavy and GOES DOWN There is no doubt: Marco Lotti MD
  38. 38. The temperature gradient is the most powerful engine that shapes the distribution of the perfusion fluid Marco Lotti MD
  39. 39. In the Coliseum technique, a powerful thermal gradient is created between a broad cooling surface and a very small heating area Marco Lotti MD
  40. 40. this temperature gradient is maintained during the entire perfusion period Marco Lotti MD
  41. 41. all the physical modalities of heat dissipation are promoted by the intrinsic architecture of the Coliseum Marco Lotti MD
  42. 42. The heating source is forced to work with full power, to deliver a huge amount of heat in a relatively small area Marco Lotti MD
  43. 43. this need was well acknowledged by the proposers of the Coliseum technique Marco Lotti MD
  44. 44. The temperature gradient is unavoidable in the Coliseum technique, and the temperature of the fluid can never reach equilibrium Marco Lotti MD
  45. 45. Marco Lotti MD
  46. 46. 35 - 40°C Normothermia 41 - 44°C Hyperthermia 45 - 48°C Irreversible cellular damage after 45 min 50 - 52°C Coagulation necrosis in 4-6 min In the hottest areas there is risk of scald injuries to the loops of the bowel Marco Lotti MD
  47. 47. random measurements confirm that the distribution of heat is not homogeneous Marco Lotti MD
  48. 48. distribution of the HIPEC solut temperature remained constant a output temperature varied by <1 temperature of 41.48C. Heat loss w during the open technique than d CO2 technique. To address this pr studies have used the closed tec fluid administered at very high inp (#488C).18 Similarly, Kusamura e a phase II clinical trial that includ with peritoneal carcinomatosis o using an input temperature of studies,18-20 mortality ranged fro and morbidity ranged from 12 t owing to digestive complications, s fistulas, perforations, and sutu which represented 70% of all rec tions in the study by Kusamura et The lack of uniform distributio Fig 4. Thermographic images. A, Closed CO2 technique. The upper images represent ventral views, and the lower images represent lateral views. B, Open technique. The Experimental development of an intra-abdominal chemohyperthermia model using a closed abdomen technique and a PRS-1.0 Combat CO2 recirculation system Susana Sanchez-Garcıa, MD,a David Padilla-Valverde, MD, PhD,a Pedro Villarejo-Campos, MD, PhD,a Jesus Martın-Fernandez, MD, PhD,a Marcial Garcıa-Rojo, MD, PhD,b and Marta Rodrıguez-Martınez, MD,c Ciudad Real, Spain Background. Cytoreductive surgery with hyperthermic intraperitoneal chemotherapy is the best operative treatment currently available for patients with peritoneal carcinomatosis of ovarian origin. The open abdomen technique is the classic technique for hyperthermic intraperitoneal chemotherapy. We developed a closed abdomen model that improves temperature control and increases exposure of peritoneal surfaces to the drug by recirculating the perfusate. Methods. We used a porcine model with 12 female, Large White pigs---4 in the open technique group and 8 in the closed technique CO2 group. We performed cytoreductive surgery and hyperthermic intraperi- toneal chemotherapy for 60 minutes using paclitaxel (175 mg/m2 ) at an input temperature of 428C. Perfusate recirculation was performed under controlled pressure (range, 12–15 mmHg). The infusion of 0.7 L of CO2 via a separate intraperitoneal infusion catheter mixed the perfusate within the peritoneal cavity. Intra-abdominal temperature was assessed using 6 intra-abdominal temperature probes and 2 temperature probes in the inflow and outflow circuits. Drug distribution was assessed using methylene blue staining. Results. Intra-abdominal temperatures remained constant and homogeneous in all intra-abdominal quadrants with a constant input temperature of 428C and a minimum output temperature of 41.48C. The infused CO2 caused the fluid to bubble and created agitation inside the abdominal cavity to facilitate a homogeneous distribution of the drug-containing perfusate. Conclusion. The closed recirculation hyperthermia with intraperitoneal chemotherapy technique developed in this study is safe and feasible, and may provide a more homogeneous delivery of heated chemotherapy to the peritoneal cavity in patients with peritoneal malignancies. (Surgery 2014;155:719-25.) From the General Surgery Department,a Pathology Department,b and Pharmacy Department,c University General Hospital, Ciudad Real, Spain OPTIMAL OPERATIVE DEBULKING in association with intraperitoneal chemotherapy increases overall survival and progression-free survival in women with advanced ovarian cancer.1 The use of hyper- thermia with intraperitoneal chemotherapy (HI- PEC) further increases the therapeutic benefit of the chemotherapeutic drug.2 In addition, heat has a direct cytotoxic effect on the tumor cells. Experimental animal studies demonstrated that tu- mor cells are killed by a temperature of 438C, whereas normal cells can withstand temperatures up to 458C.3-5 Hyperthermia enhances the penetra- tion of drugs administered intra-abdominally into the peritoneum from 3 to 5 mm, thereby increasing their effect of drug-induced apoptosis,6 leading to greater effectiveness of HIPEC at tem- Fig 1. A, Schematic diagram of the te abdominal cavity with the perfusate so for irrigation of the abdominal cavity w inal cavity via a gas exchanger. 5, Cath exchanger. Roller-pump A, Used to preh Surgery Volume 155, Number 4 “thermographic image analysis in the open procedure group revealed heterogeneity in the distribution of the hyperthermic solution“ …and the floating bowel is actually being treated with DRY HYPOTHERMIA Marco Lotti MD
  49. 49. all these considerations made me convinced that the Coliseum technique cannot be considered an adequate technique for the delivery of Hyperthermia no sound evidence exists that the distribution of heat is improved the claimed superior temperature homogeneity is not tenable when it comes to the laws of Physics Marco Lotti MD
  50. 50. all these considerations pushed me to search for a different modality for the delivery of HIPEC and brought me to the concept of the Laparoscopy-Enhanced HIPEC technique You can find further information at: https://www.slideshare.net/MarcoLotti3/lotti-marco-md-the-laparoscopyenhanced-hipec-concept Marco Lotti MD

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