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 these procedures, 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 in the operating room with moderate hyperthermia and is referred to as heated intraoperative intraperitoneal chemotherapy. If tolerated, additional intraperitoneal chemotherapy can be administered during the first 5 postoperative days. The use of these combined treatments, ie, cytoreductive surgery and intraperitoneal chemotherapy, improves survival, optimizes quality of life, and maximally preserves function. Part 1 of this two-part article describes 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 are also defined and described. Part 2, to be published next month in this journal, 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.
The quality of care directed toward patients with gastrointestinal cancer has a profound effect on survival. Nevertheless, the treatments that have evolved over the past several decades have become increasingly complex. Currently, the use of radiotherapy and systemic chemotherapy combined with surgery continues to improve survival, optimize quality of life, and maximally preserve function. Surgical procedures also continue to evolve toward new standards of care. Undoubtedly, the increasing complexity of the management of gastrointestinal cancer has improved patient care.
A better understanding of the natural progression of surgically treated gastrointestinal cancer has also evolved over the past several decades. The emphasis in clinical research on "anatomic sites of surgical treatment failure" has provided oncologists with a target for radiation and chemotherapeutic clinical investigations. One aspect of surgical treatment failure in gastrointestinal cancer that presents itself as a prominent need for better understanding and concentrated research activities is peritoneal surface dissemination. Until recently, peritoneal carcinomatosis was a universally fatal manifestation of gastrointestinal cancer.
Despite the grim outlook for patients with this disease, laboratory and clinical research efforts have continued (Table 1).[3-17] Recent success with a curative approach stems from two treatment innovations-one surgical and the second chemotherapeutic- specifically developed for the management of peritoneal carcinomatosis. The new surgical interventions are collectively referred to as peritonectomy procedures. Using highvoltage electrosurgery and a thorough knowledge of the distribution patterns of peritoneal carcinomatosis, the surgeon resects the lining of the abdomen and pelvis at all sites with visible evidence of cancerous implants.
The second innovation, perioperative intraperitoneal chemotherapy, is employed to eradicate small-volume residual disease. This intraperitoneal chemotherapy must be an integral part of the surgery for peritoneal carcinomatosis, because the perioperative timing of intraperitoneal drug administration is crucial for success.[ 18] In a majority of peritoneal surface malignancy treatment centers, the intraperitoneal chemotherapy is administered in the operating room with moderate hyperthermia; this treatment is referred to as heated intraoperative intraperitoneal chemotherapy. Additional chemotherapy may be used as an abdominal lavage for the first 5 postoperative days, and such treatment is referred to as early postoperative intraperitoneal chemotherapy.
Because these combined treatment modalities have been employed in large numbers of patients, selection factors associated with improved longterm survival and acceptable morbidity and mortality have been established. The purpose of this article is to present the management plans and updated results of the combined treatment-ie, cytoreductive surgery with peritonectomy procedures plus perioperative intraperitoneal chemotherapy- in patients with peritoneal carcinomatosis from gastrointestinal cancer.
Natural History Studies
Surgeons, especially those involved in reoperative surgery for gastrointestinal cancer, have repeatedly observed the intracoelomic dissemination of cancer. Nevertheless, little was done to clarify the impact of peritoneal seeding on survival until a report by Chu and colleagues was published. These investigators studied 100 patients with nongynecologic malignancy who had biopsyproven peritoneal carcinomatosis. Themean survival of 45 colorectal cancer patients was 8.5 months; of 20 pancreatic cancer patients, 2.4 months; and of 6 gastric cancer patients, 2.2 months. The presence or absence of ascites was an important prognostic variable in all these patients.
In 2000, Sadeghi and coworkers reported on 370 patients with peritoneal carcinomatosis from nongynecologic malignancies who were enrolled in a European prospective multicenter trial (Evolution of Peritoneal Carcinomatosis 1 [EVOCAPE 1]). These patients had the benefit of fluorouracil (5-FU)-based systemic chemotherapy, but the results were remarkably similar to those reported by Chu a decade earlier. The mean survival of 118 patients with carcinomatosis from colorectal cancer was 6.9 months; of 58 patients with pancreatic cancer, 2.9 months; and of 125 patients with gastric cancer, 6.5 months.
In 2002, Jayne and colleagues from Singapore used a database of 3,019 colorectal cancer patients to identify 349 (13%) with peritoneal carcinomatosis. Of special interest were the 125 patients (58%) who had synchronous primary colorectal cancer and peritoneal implants. The median survival of those patients was only 7 months. The authors reported that survival was adversely affected by the extent of peritoneal carcinomatosis and the stage of the primary cancer.
These survival statistics as they relate to the natural history of peritoneal surface dissemination demonstrate the aggressive behavior of gastrointestinal cancer with carcinomatosis. These studies also show that peritoneal carcinomatosis can occur along with lymph node and liver metastases or as isolated peritoneal surface dissemination. In the Sadeghi et al study, 91 of the 118 colorectal cancer patients (77%) had no liver or lung metastases at the time that carcinomatosis was diagnosed. In the Jayne et al study, 80% of the carcinomatosis patients in the synchronous group had no liver or systemic metastases.
These natural history studies have proven to be helpful in understandingthe lethal nature of peritoneal carcinomatosis. However, the full impact of the profound deterioration of quality of life that accompanies disease progression has not been adequately communicated. Intestinal obstruction, bowel perforation with fistula formation, and nutritional deprivation cause immeasurable prolonged suffering in this group of patients. One of the most agonizing cancer deaths occurs from the progression of peritoneal carcinomatosis.
Pathobiology of Peritoneal Dissemination of Cancer
Although metastases through lymphatic channels to local lymph nodes and through the portal blood to the liver have been intensively studied, the dissemination of cancer cells on peritoneal surfaces has received less attention. In 1931, Sampson may have been the first to describe this type of cancer dissemination in humans. He observed that cancer cells escaped from primary ovarian cancer into the free peritoneal cavity, that they adhered to the mesothelial surface, that invasion occurred, and that a visible cancer nodule became apparent. He also distinguished cancer dissemination by implantation (spread) within the coelomic space from dissemination by way of lymphatic channels (metastases).
Sampson described the "life history of peritoneal carcinomatosis implants" as follows: (1) escape of the cancer cells from the primary ovarian tumor into the free peritoneal cavity; (2) migration of these cells to their site of implantation; (3) reaction of the peritoneal surface injured by the cancer cells so that fixation of the cancer in fibrin and organization of this fibrin occurred; and (4) progression of the cancerous implant at that site.
An important concept in tumor biology that has great relevance to the understanding of carcinomatosis derives from the studies of Weiss. He described the phenomenon of "metastatic inefficiency," recognizing that the bloodstream may "teem with cancer cells" and yet no metastases may develop. In other words, eventhough the portal vasculature of the liver may receive innumerable cells from a primary malignancy on a daily basis, less than half of gastrointestinal cancer patients will develop liver metastases. Thus, hematogenous dissemination of gastrointestinal cancer is rightfully characterized as metastatically inefficient.
In contrast, cancer cells disseminate with great efficiency within the peritoneal cavity. A profound example of the metastatic efficiency of intraperitoneal cancer cells was reported by Kodera and colleagues. They observed no long-term survival among 10 gastric cancer patients with a positive peritoneal cytology. Also, 8 of these 10 patients developed clinical evidence of carcinomatosis. In 81 patients with a negative cytology, the 5-year survival rate was 70%, and only 2 patients developed clinical evidence of carcinomatosis. In this study of peritoneal cytology in gastric cancer patients, the presence of positive vs negative free intraperitoneal cancer cells was an even more definitive predictor of prognosis than positive vs negative lymph nodes.
Peritoneal cancer implantation is spontaneous in 20% to 30% of patients with primary gastrointestinal cancer as a result of full-thickness invasion of the bowel wall. There can be an iatrogenic component of carcinomatosis. The profound impact of a fresh wound induced by surgery on the likelihood of cancer cell implantation was clearly demonstrated by Zoetmulder (Amsterdam) in a thesis presentation. He showed in an experimental colon cancer model that a fresh surgical wound would increase the likelihood of tumor growth by a factor of 100; the peritoneal wound was observed to be a cancer promoter.[ 27] The smallest amount of tumor contamination at a surgically traumatized site will readily progress to clinical symptoms as a result of metastatic efficiency and tumor growth enhancement from healing tissues.
Patterns of Intracoelomic Dissemination
The general surgical literature, especially manuscripts dealing with the spread of intraperitoneal infection, has described a characteristic pattern for the intracoelomic distribution of particles, bacterial organisms, or cancer cells. Autio identified six major compartments within the peritoneal cavity that could act as a reservoir for intracoelomic contaminants. He also showed that there was a stream of peritoneal fluid from the lower abdomen along the right paracolic sulcus to the upper abdomen. Meyers studied the flow of intraperitoneal contrast radiologically and documented that intra-abdominal cancer cells in fluid disseminated via well-defined routes. He emphasized that cancer dissemination in the presence of ascitic fluid was neither random nor limited to the immediate area of the primary neoplasm.
The role of lymphoid aggregates within the peritoneal surface and an associated peritoneal fluid resorption at these sites was described by Takahashi and colleagues. They found a close correlation between infiltrating cancer cells and the density oflymphoid aggregates; these aggregates were shown to be foci of lymphoid tissue on the peritoneal surface through which fluid and small particles were absorbed from the peritoneal cavity into the subperitoneum. The lymphoid aggregates were abundant within the greater omentum, perigonadal tissue, and mesentery and could be identified by their uptake of activated carbon particles. The authors suggested that not only the flow of peritoneal fluid but also its absorption at specific anatomic sites, such as beneath the hemidiaphragms and within the greater omentum, were important mechanisms of intraperitoneal cancer dissemination.
Impact of Intraperitoneal Fluid on Dissemination Patterns
Sugarbaker described the profound impact of intraperitoneal fluid on the patterns of cancerous dissemination within the peritoneal cavity. From observations collected from reoperative surgical procedures, he contrasted three important mechanisms of intracoelomic cancer dissemination. In the absence of intraperitoneal fluid and surgical intervention, gastrointestinal cancer cells metastasize in a randomfashion immediately adjacent to the primary neoplasm that has penetrated the serosal surface. A pattern of random and proximal spread is expected from invasive nonmucinous cancers. The cells adhere, implant, and then progress at the initial site of cell contact with the peritoneal surface. However, such a distribution pattern contrasts with that of cancers that invade the gastrointestinal cancer wall but also produce ascitic fluid or mucus. The fluid causes a characteristic "redistributed" pattern of implants. In this model, both the peritoneal compartments and the flow of intraperitoneal fluid determine the pattern of implant distribution. Mucinous adenocarcinoma progresses as cancer cells move with the flow of peritoneal fluid and become trapped within the large crevices between stationary surfaces or the fluid pools created by gravity.
The dominant regions for redistributed cancer progression would be the space between the right diaphragm and liver, the lower part of the left paracolic sulcus, and the cul-de-sac of Douglas. Of course, fluid drawn to milky spots within the greater or lesser omentum, gonadal or perigonadal tissue, and mesenteric border of the small bowel would also accumulate a larger proportion of the intraperitoneal malignant cells. A prospective study documenting the profound impact that intraperitoneal mucin has on the patterns of intraperitoneal cancer dissemination was presented by Carmignani and colleagues.
Tumor Cell Entrapment
The third pattern of intraperitoneal cancer dissemination is caused by surgical dissection; this mechanism of cancer dissemination is referred to as "tumor cell entrapment." The anatomic sites associated with an increased incidence of cancerous implants would be all the traumatized peritoneal surfaces. Cancer implants would be observed at anastomotic sites, at sites where bowel was repeatedly handled, within the abdominal closure, and within the raw tissues created by a retroperitoneal dissection. In summary, fibrin plus cancer cells results in cancer implants at specifictraumatized sites; ascites plus cancer cells results in a redistributed pattern of dissemination.
The paper by Carmignani et al documented a fourth mechanism influencing the distribution of intraperitoneal cancer cells in mucinous or serous ascitic fluid. These investigators described the "motion hypothesis" in which the movement of an intra-abdominal structure largely determines the volume of malignancy associated with its peritoneal surface. Many structures within the abdomen are largely stationary, whereas others, such as the surfaces of the small bowel and its mesentery, are in continuous motion by peristalsis. This motion greatly influences the distribution of tumor and, therefore, the surgical management of mucinous carcinomatosis. If the small bowel is largely clear of tumor nodules, then peritonectomy procedures can remove the remainder of the disease from other peritoneal surfaces.
The thin wall of the smooth muscle tube that constitutes the small bowel creates a difficult anatomic site for peritonectomy. Nodules of invasive cancer on the small bowel surface must be left in place by the surgeon, or a portion of the small bowel must be resected. Nodules of cancer on the liver, stomach, undersurface of the diaphragm, or pelvic sidewalls can be peritonectomized with negative margins. The observation that mucinous adenocarcinomas spare the small bowel surfaces but are located in large volume at other sites, especially within the omental cake and in dependent areas, is the original observation that led to a rationale for a curative approach to mucinous peritoneal carcinomatosis (Figure 1).
Distribution of Mucinous/ Nonmucinous Adenocarcinoma
The studies by Carmignani et al quantitatively documented differences in the distribution of mucinous adenocarcinoma and nonmucinous adenocarcinoma throughout the abdomen and pelvis. The lesser omentum was involved with mucinous tumors in a majority of patients and wascinous tumors. The undersurface of the right hemidiaphragm was nearly always involved with mucinous tumors, but was rarely involved with nonmucinous tumors. The same could be said for the surface of the liver.
For high-grade nonmucinous malignancies from colorectal cancer, the proximity of the tissue to the primary cancer for which the incidence of implants was determined was very important. The bladder surface was frequently involved by ovarian malignancy but seldom by mucinous or nonmucinous adenocarcinoma. Also, the vaginal cuff opened at the time of hysterectomy showed a high incidence of metastases with ovarian cancer but was rarely, if ever, involved in other types of cancer.
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