ABSTRACT: Until recently, peritoneal carcinomatosis was a universally fatal manifestation of gastrointestinal cancer. However, two innovations in treatment have improved outcome for these patients. The new surgical interventions are collectively referred to as peritonectomy procedures. During the peritonectomy, all visible cancer is removed in an attempt to leave the patient with only microscopic residual disease. Perioperative intraperitoneal chemotherapy, the second innovation, is employed to eradicate small-volume residual disease. The intraperitoneal chemotherapy is administered intraoperatively with moderate hyperthermia. Part 1 of this two-part article, which appeared in the January issue, described the natural history of gastrointestinal cancer with carcinomatosis, the patterns of dissemination within the peritoneal cavity, and the benefits and limitations of peritoneal chemotherapy. Peritonectomy procedures were also defined and described. Part 2 discusses the mechanics of delivering perioperative intraperitoneal chemotherapy and the clinical assessments used to select patients who will benefit from combined treatment. The results of combined treatment as they vary in mucinous and nonmucinous tumors are also discussed.
Part 1 of this two-part article, which appeared in the January issue of ONCOLOGY, described the natural history of peritoneal carcinomatosis including the dissemination associated with its evolution. Treatment issues related to the use of intraoperative intraperitoneal chemotherapy and peritonectomy procedures were also described. In part 2, the mechanics of delivering perioperative intraperitoneal chemotherapy are reviewed, and factors affecting the success of the combined treatment approaches are presented. Four clinical assessments that assist patient selection for combined treatment protocols are also discussed.
Techniques for Perioperative Intraperitoneal Chemotherapy
Hyperthermic Intraoperative Intraperitoneal Chemotherapy
In order to initiate hyperthermic intraoperative intraperitoneal chemotherapy, a series of tubes and drains (four drainage tubes and a single inflow catheter) must be placed within the peritoneal cavity through the abdominal wall (Figure 1). To prevent leakage of these tubes as they exit the abdominal skin, a purse string suture is used. Generally, the inflow catheter is placed at a site thought to be at highest risk for recurrent disease, because the greatest heat will be generated at this site.
Following tube placement, the selfretaining retractor is partially dismantled. It is reassembled to construct a frame approximately 4 in. above the anterior abdominal wall. A heavygauge monofilament suture is used to elevate the skin edges on the selfretaining retractor, and thereby, create a reservoir for chemotherapy solution within the abdomen (Figure 2).
A perfusion circuit is necessary to maintain a temperature of approximately 41.5oC within the peritoneal cavity (Figure 3). Inflow and outflow tubes are connected to roller pumps and a heat exchanger. A heater/cooler, which maintains a water temperature of 48oC flowing through the heat exchanger, is part of the apparatus. For most drugs, a 90-minute perfusion is indicated to achieve a maximal cytotoxic effect.
The drugs used intraoperatively for hyperthermic chemotherapy are mitomycin(Drug information on mitomycin) (Mutamycin), cisplatin(Drug information on cisplatin), and doxorubicin(Drug information on doxorubicin) or oxaliplatin(Drug information on oxaliplatin) (Eloxatin). The standardized orders utilized at the Washington Cancer Institute for this therapy are shown in Table 1. Following the completion of the intraoperative chemotherapy, the self-retaining retractor is again positioned. At this time, all intestinal anastomoses are completed, seromuscular repairs of the bowel are performed, and the abdomen is closed. Usually, a fifth closedsuction drain is placed within the subcutaneous space. The skin is closed with a watertight, running monofilament suture so that no leakage of fluid occurs from the abdomen postoperatively.
Most patients who receive heated intraoperative intraperitoneal chemotherapy are also given early postoperative intraperitoneal fluorouracil(Drug information on fluorouracil) (5-FU) or paclitaxel(Drug information on paclitaxel). The catheters for drug instillation and abdominal drainage must be kept clear of blood clot, fibrin clot, and tissue debris. To accomplish this, an abdominal lavage utilizing the same tubes and drains as used for the heated intraoperative chemotherapy is initiated in the operating room. Large volumes of fluid are rapidly infused and then drained from the abdomen after a short dwell time. The standardized orders for immediate postoperative lavage are shown in Table 2.
Early Postoperative Intraperitoneal Chemotherapy
If the patient recovers well from the cytoreductive surgery and intraperitoneal heated chemotherapy, then early postoperative intraperitoneal chemotherapy is initiated. At the Washington Hospital Center, early postoperative chemotherapy is initiated in all patients except those with very early disease and a low likelihood of tumor recurrence. The drugs employed in this chemotherapy are cell-cycle-dependent drugs. The standardized orders for early postoperative intraperitoneal 5-FU and early postoperative intraperitoneal paclitaxel are presented in Table 3. All the intra-abdominal catheters are withdrawn after fluid drainage is substantially reduced prior to the patient's discharge from the hospital.
Selection of Patients for Treatment Using Quantitative Prognostic Indicators
The greatest impediment to achieving long-term benefits from combined treatment with cytoreductive surgery and perioperative intraperitoneal chemotherapy is improper selection of patients. Patients with advanced disease experience minimal benefit and significant morbidity and mortality. Given the risks and benefits for patients with a large volume of invasive cancer, elective cytoreductive surgery should be withheld in this subgroup unless performed by the most experienced surgical teams.
Excluding pseudomyxoma peritonei and cystic mesothelioma, extensive cytoreductive surgery and aggressive intraperitoneal chemotherapy are not likely to produce a lasting benefit in patients with advanced peritoneal surface cancer from a gastrointestinal primary. Rapid recurrence of the peritoneal surface disease combined with progression of lymph nodal, liver, or systemic disease are likely to interrupt any long-term benefit. Asymptomatic patients with small-volume peritoneal carcinomatosis should be referred for treatment.
In the past, peritoneal carcinomatosis was a fatal disease process. The only assessment required was the presence or absence of carcinomatosis. Currently, four important clinical assessments of peritoneal surface malignancy are used to select patients who will benefit from the combined treatment: (1) histopathologic typing to assess the invasive character of the malignancy, (2) preoperative computed tomography (CT) of the chest, abdomen, and pelvis with maximal oral and intravenous contrast, (3) peritoneal cancer index determination, and (4) completeness of cytoreduction (CC) score.
Histopathologic Type and Biologic Aggressiveness of a Peritoneal Surface Malignancy
Noninvasive tumors arising in the appendix (pseudomyxoma peritonei) or from the peritoneal surface itself (cystic mesothelioma) may have largevolume accumulations within the abdomen and pelvis, and yet, may be made visibly disease-free with the use of peritonectomy procedures. Also, these noninvasive malignancies are extremely unlikely to metastasize via lymphatic channels to lymph nodes or via the bloodstream to liver or other systemic sites. Therefore, combined treatment with curative intent in patients with a large mass of widely disseminated pseudomyxoma peritonei or minimally aggressive peritoneal mesothelioma is appropriate. Pathology review and an assessment of the invasive vs nonaggressive nature of a malignant process are essential to treatment planning.
Preoperative CT Scan
A preoperative CT scan of the chest, abdomen, and pelvis is required in planning treatment of a peritoneal surface malignancy. This radiologic examination is essential to exclude liver or systemic metastases and pleural surface spread. Unfortunately, the CT scan is an inaccurate test by which to quantitate nonmucinous carcinomatosis distribution and volume. The malignant tissue progresses as a layer on the peritoneal surfaces and conforms to the normal contours of the abdominopelvic structures-quite different from the metastatic process in the liver or lung, which show up as three-dimensional spherical tumor nodules and can be accurately assessed by CT.
Fortunately, the CT scan is helpful in imaging mucinous adenocarcinoma on peritoneal surfaces. These tumors produce large volumes of mucoid material, readily distinguishable from normal structures by anatomic location, shape, and density. A knowledgeable radiologic interpretation can also distinguish patients with a high likelihood of complete cytoreduction from those who would be designated for incomplete resections. The CT scan excludes patients who are unlikely to receive the benefit of a potentially curative approach from an elective operative intervention. Interventions in patients with advanced disease would be performed for symptom management, and the surgery would be of a palliative, minimally aggressive nature.
The two radiologic criteria found to be most useful in excluding carcinomatosis patients from elective intervention are segmental obstruction of the small bowel and the presence of tumor nodules greater than 5 cm in diameter on small bowel surfaces or directly adjacent to small bowel mesentery in the jejunum or upper ileum. Tumor involvement of the small bowel at the terminal ileum is not thought to be a contraindication to elective surgery, because disease at this site can be resected as part of the cytoreductive surgery.
These criteria reflect radiologically the pathobiology of carcinomatosis. Obstructed segments of bowel indicate an invasive malignancy where portions of small bowel lack peristalsis or become narrowed. Large, greater than 5 cm, mucinous tumor nodules on the small bowel or its mesentery indicate that the cancer is not redistributed away from the intestinal surface by peristaltic motion. Difficulties with dissection of the mucinous tumor from the small bowel signify the need for a palliative effort (Figures 4 and 5).
Peritoneal Cancer Index
The third prognostic assessment of peritoneal surface malignancy is the peritoneal cancer index, which is a quantitative indicator of prognosis derived from the integration of the size of the peritoneal implant and the distribution of nodules on the peritoneal surface (Figure 6). This index should be used in the treatment decision-making process while the abdomen is being completely explored. The choice between a definitive cytoreduction and a palliative debulking is greatly influenced by the peritoneal cancer index.
To arrive at a score, the size of the intraperitoneal nodules must be assessed in all abdominopelvic regions; the number of nodules is not scored, only the size of the largest nodule. A lesion score of zero (LS-0) means that no malignant deposits are visualized; an LS-1 signifies the presence of tumor nodules less than 0.5 cm in size; an LS-2 indicates that tumor nodules between 0.5 and 5.0 cm are present; and an LS-3 indicates the presence of tumor nodules greater than 5.0 cm in any dimension. If there is a confluence (layering) of tumor, the lesion size is scored as 3.
To assess the distribution of peritoneal surface disease, an LS is determined for each of the 13 abdominopelvic regions. The summation of the LS score is the peritoneal cancer index for that patient. The maximal score is 39 (13 * 3).
To date, the peritoneal cancer index has been validated in four separate situations: Ottow and colleagues used it successfully to quantitate intraperitoneal tumor in a murine peritoneal carcinomatosis model. Portilla and coworkers showed that it could be used to predict long-term survival in patients with peritoneal carcinomatosis from colon cancer who are undergoing a second cytoreduction.[ 5] Berthet and coworkers showed that it predicted benefits for the treatment of peritoneal sarcomatosis from recurrent visceral and retroperitoneal sarcoma. Sugarbaker showed that it could be used to predict the likelihood of long-term survival in colon cancer patients undergoing combined treatment. In these studies, patients with a favorable prognosis had a peritoneal cancer index of less than 13.
• Exceptions to the Rule—Exceptions to the rules for using the peritoneal cancer index have been established. First, noninvasive malignancy on peritoneal surfaces may be completely cytoreduced even though the peritoneal cancer index is as high as 39. Diseases such as pseudomyxoma peritonei, cystic peritoneal mesothelioma, and grade 1 sarcoma fall into this category. With these minimally invasive tumors, the status of the abdomen and pelvis at completion of cytoreduction may have no relationship to the volume recorded at the time of abdominal exploration; ie, even though the surgeon explores an abdomen with a maximal peritoneal cancer index, it can be brought to an index of 0 by cytoreduction. In these diseases, the prognosis is only related to the condition of the abdomen after the cytoreduction (CC score).
A second caveat for using the peritoneal cancer index is related to cancer at crucial anatomic sites. For example, a small volume of invasive cancer incompletely resected from the common bile duct will result in a poor prognosis despite a low peritoneal cancer index. Invasion of the base of the bladder or unresectable disease on a pelvic sidewall may, by itself, result in residual invasive disease after maximal cytoreduction and eventuate in a poor prognosis. In other words, invasive cancer at crucial anatomic sites may function as systemic disease in the assessment of the prognosis with invasive cancer. Because only patients who undergo a complete cytoreduction can achieve long-term survival, residual disease at anatomically crucial sites will supersede a favorable peritoneal cancer index score.
Completeness of Cytoreduction Score
The most definitive assessment of prognosis to be used with peritoneal surface malignancy is the CC score. This information, however, is of less value to the surgeon in planning treatment than the peritoneal cancer index, because it is not available until after the cytoreduction is complete (the peritoneal cancer index is available at the time of abdominal exploration). If, during exploration, it becomes obvious that the cytoreduction will not be complete, the surgeon may decide that a palliative debulking, which will provide temporary symptomatic relief, is appropriate and may discontinue plans for an aggressive cytoreduction with intraperitoneal chemotherapy.
In both noninvasive and invasive peritoneal surface malignancy, the CC score is the major prognostic indicator. It has been shown to function with accuracy in mucinous appendiceal malignancy, peritoneal carcinomatosis from colon cancer, sarcomatosis, and peritoneal mesothelioma.[5-8]
For gastrointestinal cancer, the CC score has been defined as follows: A CC score of zero (CC-0) indicates that no peritoneal seeding occurred during the complete exploration. A CC-1 score indicates that tumor nodules persisting after cytoreduction are smaller than 2.5 mm. (This is a nodule size thought to be penetrable by intracavitary chemotherapy.) Both CC-0 and CC-1 scores would, therefore, be designated for complete cytoreduction. A CC-2 score indicates residual tumor nodules between 2.5 mm and 2.5 cm. A CC-3 score indicates residual tumor nodules greater than 2.5 cm or a confluence of unresectable tumor nodules at any site within the abdomen or pelvis. CC-2 and CC-3 cytoreductions are considered incomplete (Figure 7).