Isfahan Medical Faculty, Anatomical Sciences Department 1 Isfahan Medical Faculty, Anatomical Sciences Department 1385 1

IP CHEMOTHERAPY دکتر وحید گوهریان

Malignant peritoneal mesothelioma: treatment with maximal cytoreductive surgery plus intraperitoneal chemotherapy. Hyperthermia combined with intra-thoracic chemotherapy and radiotherapy for malignant pleural mesothelioma.

Compared with intravenous (IV) treatment, intraperitoneal (IP) administration permits a several-fold increase in drug concentration to be achieved within the abdominal cavity. Analysis of intratumoral drug concentrations demonstrates that lesions 2 to 3 mm or smaller will have significantly higher drug exposure from intraperitoneal administration as compared with intravenous administration. extraperitoneal spread in patients with PMP or DPAM(Noninvasive malignancies), penetration into tumor tissue is limited to a maximum of 1 to 2 mm from the surface avascular tumors are exposed to higher drug concentrations with intraperitoneal compared with intravenous delivery.

predict a poor outcome from aggressive cytoreduction and HIPEC segmental obstruction of the small bowel . the presence of tumor nodules >5 cm in diameter on small bowel surfaces or directly adjacent to the small bowel mesentery in the jejunum or upper ileum IN contrast (oral and intravenous [IV])-enhanced CT of the chest, abdomen, and pelvis . extensive disease in the right upper quadrant on preoperative CT appears to be particularly related to a poorer survival outcome.

Indications for IP chemotherapy Based on available clinical data, intraperitoneal (IP) chemotherapy may be most useful in women with optimally debulked (to ≤1.0 cm) stage III epithelial ovarian cancer (EOC) women treated with neoadjuvant chemotherapy who undergo an optimal interval cytoreduction. that IP chemotherapy should not be administered in the setting of stage IV EOC or tumors that have not been optimally debulked (residual tumor greater than 1 cm in diameter)

Contraindications for IP chemotherapy Inability to tolerate cytoreductive surgery Active peritonitis or sepsis Extensive intraabdominal adhesions, which prevent adequate distribution of instilled chemotherapeutic agents Obvious peritoneal contamination Inadequate renal function for cisplatin clearance Inability to undergo the schedule of IP chemotherapy administration Bowel resection is not a contraindication to IP port placement; We therefore prefer to delay insertion of the IP catheter in these patients to lessen the risk of complications. Older age is not necessarily a contraindication to IP chemotherapy

TECHNICAL ISSUES issues related to the IP port itself, The device typically consists of a port and a catheter. the single-lumen implanted port with a silicone peritoneal catheter (14.3 French) or a fully implantable power port attached to a single-lumen, radiopaque, polyurethane venous catheter of large size (8 French or higher). The power port is larger in size and more easily accessible post-placement and therefore may be more suitable for women with more adipose tissue on the abdominal wall. do not use peritoneal catheters designed for dialysis (eg, Tenckhoff catheters) the risk of bowel complications not for the withdrawal of fluid the Dacron cuff on Tenckhoff dialysis catheters may erode into the peritoneal cavity and be associated with bowel obstructions.

surgical placement, A subcutaneous pocket is created and the port is sutured to the anterior abdominal fascia and remains accessible to allow instillation of chemotherapeutic agents. Connected to the port is the catheter, which is within the peritoneal cavity. at the time of staging surgery, a 3 to 4 cm skin incision over the lower left or right costal margin at the midclavicular line The catheter is inserted through a separate stab incision and is tunneled at the level just above the fascia and below the subcutaneous adipose tissue until it reaches the port pocket. A guide wire is used to insert the catheter end into the peritoneal cavity.

The catheter should be placed where the formation of adhesions is least likely to occur, keeping in mind what tissues were removed and where peritoneal stripping was required. the transverse colon to be adherent to the anterior abdominal wall after a complete omentectomy procedure. For this reason, the entry into the abdominal cavity should be at or below the umbilicus, avoiding the midline incision. The chosen site should be ipsilateral to the IP port incision and about 6 cm lateral to the umbilicus. Abdominal wall closure with a watertight closure to prevent leaking of ascites or IP chemotherapy is also very important. For patients in whom entry into the vagina is required, the vaginal cuff should be closed with delayed absorbable suture to create a watertight seal [20].

Delayed insertion laparoscopically mini-laparotomy

timing of placement: concomitant with surgical staging and cytoreduction or at a later time as a second procedure) via laparoscopy, mini-laparotomy, or interventional radiology at a second procedure, usually performed a few weeks ( If a bowel resection

in the absence of complete diagnosis and staging , IP port to be placed, the patient must be counseled about chemotherapy treatment, toxicities, and delivery options.

CHEMOTHERAPY ADMINISTRATION in the operating room or as early as 24 hours postoperatively. waiting until the patient has resumed normal bowel function (ie, postoperative ileus has resolved) in primary surgery. a second surgical procedure (or was otherwise delayed), treatment may begin 24 hours after an IP catheter has been placed.

Intravenous hydration saline infused intraperitoneally is not adequate hydration to prevent renal toxicity. Intravenous prehydration with a liter of normal saline is given to ensure adequate urine output of 100 mL per hour before administration of the IP cisplatin to prevent renal toxicity. post-intravenous hydration with another liter of normal saline is recommended to prevent renal toxicity, with an aim to maintain urine output of 100 cc per hour. Furosemide or mannitol can be utilized if the appropriate balance of input and output is concerning and the patient is not dehydrated.

Patients administered either IP cisplatin or paclitaxel should receive the same supportive care drugs used with intravenous (IV) administration of these agents. Chemotherapy should be administered into the IP port using a 19 or 20 gauge right-angled needle (eg, Huber needle). mix chemotherapy in 1 liter of warmed (37°C) normal saline, predominantly to ensure patient comfort. Treatment should be infused under gravitational flow alone. A second liter of saline should be instilled as tolerated, which helps drug distribution. this should be stopped if the patient becomes too uncomfortable.

Position:in a supine or semi-Fowler's position with her head no higher than 30 degrees the bed. during the second liter of hydration), we reposition the patient from side to side every 15 minutes for one hour to help disperse the infusate. The end:are flushed with at least 10 mL of heparin 100 units/mL. The dressing can be removed after 12 hours.

COMPLICATIONS abdominal pain, catheter-related problems and signs of infection, neurotoxicity, renal toxicity, and myelosuppression. do not routinely administer growth factor support during the first cycle. related to the drugs themselves and those related to the port: Catheter-related — Catheter-related problems are frequent: in 119 pt catheter-related infection (25 patients), a blocked catheter (10 patients), leakage around the port or into the subcutaneous tissues (five patients), access problems (eight patients)evaluate with fluoroscopy, and vaginal leakage of infusion fluid (in two).  

Management depends on the specific problem that is identified: Rotational problems :suturing it in the correct position. A kinked catheter : replaced with the sturdier 9.6 or 14.3 Fr silicone catheters. the catheter cut by the Huber needle :surgically corrected. A blocked catheter or the demonstration of retrograde flow at the port or where the catheter perforates the peritoneum is often caused by adhesions blocking free flow into the peritoneal cavity: removal of the catheter and placement on the opposite side. Leakage of infusate through the vaginal and abdominal surgical wounds may cease when these wounds heal.

Contraindications to replacement peritonitis, an infected port, intraabdominal abscess, bowel injury, or fistula.

Gastrointestinal complications Diagnostic evaluation : Abdominal pain with the possibility of peritonitis or gastrointestinal injury :rebound, guarding, nausea, vomiting, diarrhea, fever, or an elevated white blood cell count. irrigating the catheter with 50 mL of normal saline, aspirating, and sending the specimen for cell count and culture. free air related to perforated bowel: An upright abdominal radiograph . computed tomography (CT) with oral and IV contrast immediate surgical evaluation injecting the port with a water-soluble radiographic contrast the catheter in the lumen of the bowel; does not necessarily imply the need for laparotomy to repair the bowel, as long as peritonitis is absent. Sealing of the bowel can occur spontaneously, treated with removal of the catheter alone. However, management of this complication must be individualized.

Peritonitis : If an intraabdominal infection develops, the port and catheter should be removed. Initially, broad spectrum antibiotic therapy with coverage for both skin and gastrointestinal flora . Bowel obstruction : the majority of cases were related to progression of malignant intraabdominal disease . Gastrointestinal necrosis or perforation : postoperative administration of paclitaxel, both intravenously and intraperitoneally . subclinical surgical complications or impaired host defense and repair mechanisms. Bowel injury (fistulas, accidental perforation by the catheter) can also occur, but is uncommon.

CATHETER REMOVAL as soon as all of the courses of chemotherapy have been completed . do not typically form adhesions to bowel or intraperitoneal structures unless a Dacron cuff was utilized

SUMMARY AND RECOMMENDATIONS   ●In women with optimally cytoreduced (to <1.0 cm) stage III epithelial ovarian cancer, intraperitoneal (IP) administration.) ●Contraindications to IP chemotherapy include being a poor candidate for cytoreductive surgery, active peritonitis or sepsis, extensive abdominal adhesions, and inadequate renal function to allow for cisplatin clearance. ●In most cases, the IP port and catheter can be placed at the time of initial surgery, although delayed placement is preferred if there is diagnostic uncertainty, intraoperative issues that preclude safe placement at initial surgery, or if the primary cytoreductive procedure includes a left colon resection with gross fecal contamination of the peritoneal cavity.

● utilize a single-lumen implanted port with a 14 ● utilize a single-lumen implanted port with a 14.3 French (Fr) silicone peritoneal catheter or a fully implantable port attached to a single-lumen venous silicone catheter of large size (9.6 Fr or higher) so that it does not kink and obstruct flow. ●Treatment-related complications, including abdominal discomfort, infection, obstruction, leakage, access problems, and bowel injury, occur in 10 to 35 percent of patients, but IP therapy can be completed in many. ●Replacement of a malfunctioning port = 50 percent of patients to complete their planned IP therapy. Indications for removal of the port and catheter : intraabdominal infection, bowel injury, and non-remediable catheter blockage (such as retrograde flow of dye into the port pocket or at the point where the catheter perforates the peritoneum). ●Potential complications of IP chemotherapy include neurotoxicity or nephrotoxicity secondary to the chemotherapeutic agents themselves, abdominal pain related to intraperitoneal infusion of fluid, or catheter-related problems including blockage, leakage of infusate, or bowel injury.'

The likelihood of nephrotoxicity can be diminished with IV hydration both before and after IP chemotherapy as well as an antiemetic regimen that addresses both acute and delayed nausea. ●After treatment is completed, the IP catheter is removed as soon as possible.

Standard treatment for PMP 'Pseudomyxoma peritonei' surgical debulking for symptomatic disease external beam radiotherapy, intraperitoneal radioisotopes, intraperitoneal chemotherapy, and systemic chemotherapy have been attempted to improve outcomes .

four clinical assessments to select patients who are most likely to benefit from combined treatment Histopathologic assessment : Noninvasive malignancies, such as PMP or peritoneal mesothelioma. Five and ten-year survival rates for distinguish diffuse peritoneal adenomucinosis (DPAM) histology 81 and 70 percent; peritoneal mucinous carcinomatosis59 and 49 percent, and hybrid histology, 78 and 63 percent, respectively. Preoperative contrast (oral and intravenous [IV])-enhanced CT of the chest, abdomen, and pelvis: In addition to excluding liver or other systemic metastases, segmental obstruction of the small bowel and the presence of tumor nodules >5 cm in diameter and extensive disease in the right upper quadrant on . the peritoneal cancer index the completeness of cytoreduction score

in contrast to PMP, aggressive cytoreductive surgery and HIPEC are less likely to produce lasting benefit for mucinous peritoneal carcinomatosis, and patient selection is critical. . In general, noninvasive malignancies such as PMP or cystic mesothelioma are much more likely to undergo successful debulking and less likely than invasive adenocarcinomas to have spread to regional nodes, liver or other systemic sites.   Although CT scans can sometimes not distinguish diffuse peritoneal adenomucinosis (DPAM) from mucinous peritoneal carcinomatosis, the presence of tumor implants >5 cm on the jejunum, proximal ileum, or adjacent mesentery is more consistent with mucinous adenocarcinoma with secondary peritoneal carcinomatosis than DPAM

peritoneal carcinomatosis from appendiceal or colorectal cancer without evidence of other metastases to surgical debulking (aiming to achieve deposits ≤2.5 mm) with HIPEC versus systemic chemotherapy without debulking. median survival (the major endpoint) was significantly longer in the HIPEC group (22.4 versus 12.6 months, p = 0.032).

SUMMARY AND RECOMMENDATIONS Appendix cancer  ●is rare and most commonly found incidentally in an appendectomy specimen . The main histologic types are carcinoids, adenocarcinomas, adenocarcinoids, cystadenomas, and cystadenocarcinomas. ●For appendiceal well-differentiated neuroendocrine tumors (NETs), there is limited evidence on which to base clear indications for right hemicolectomy. Reoperation and right colectomy for tumors larger than 2 cm and for tumors 1 to 1.9 cm with mesoappendiceal or vascular invasion, positive or uncertain margins, or mixed histology (eg, adenocarcinoid) (Grade 2C). Most patients have localized disease, and the prognosis is excellent.

epithelial tumors of the appendix . Simple appendectomy, taking care not to rupture the tumor intraoperatively A right colectomy is indicated for cystadenocarcinomas with mesenteric or adjacent organ involvement, complicated mucoceles with involvement of the terminal ileum or cecum, cystadenocarcinomas, and for goblet cell carcinoids.

mucinous or nonmucinous appendiceal adenocarcinoma underwent surgical debulking and HIPEC with mitomycin C and/or early postoperative chemotherapy with intraperitoneal fluorouracil . The median survival for the entire group was 56.4 months, and the three-year overall and disease-free survival rates were 59 and 30 percent, respectively.

Pseudomyxoma peritonei (PMP) is a unique condition characterized by diffuse collections of gelatinous material in the abdomen and pelvis, and associated with mucinous implants on the peritoneal surfaces. In our view, this term should be reserved for the clinical situation in which a ruptured cystadenoma seeds the peritoneal cavity with mucus-producing epithelial cells, termed diffuse peritoneal adenomucinosis (DPAM). A standard treatment for PMP is repeated surgical debulking for symptomatic disease. A more aggressive approach using radical surgical cytoreduction of all intraabdominal and pelvic disease, and heated intraperitoneal chemotherapy (HIPEC aiming for cure.

In contrast to other appendiceal tumors, adenocarcinomas more often present with a clinical picture of acute appendicitis. standard treatment is a right colectomy unless the tumor is confined to the mucosa or a well-differentiated lesion that invades no deeper than the submucosa.

HIPEC Indication 1) ECOG performance status two or less 2) no evidence of extra-abdominal disease 3) up to three small, resectable parenchymal hepatic metastases 4) no evidence of biliary obstruction 5) no evidence of ureteral obstruction 6) no evidence of intestinal obstruction at more than one site 7) small bowel involvement: no evidence of gross disease in the mesentery with several segmental sites of partial obstruction 8) small volume disease in the gastro-hepatic ligament

Concerning radiologic features as a prognostic assessment

Principles of management of peritoneal metastases The surgical technology to achieve a complete cytoreduction needs to be incorporated into practice. 2. Patients must be treated at a maximal low peritoneal cancer index (PCI). 3. Patients must be managed to maximally avoid tumor cell entrapment. 4. Mechanical removal of cancer cells and small nodules by irrigation is mandatory. 5. Small volume residual disease requires chemotherapy treatment that will result in a maximal cancer response. 6. The benefits of bidirectional adjuvant normothermic chemotherapy (BANC) used long-term must be considered.