IN MANY PATIENTS WITH ABDOMINAL OR PELVIC MALIGNANCIES, surgical treatment

Sugarbaker, Cancerología 3 (2008): 119-124 1 Washington Cancer Institute, Washington, DC, USA Overview of Peritoneal Carcinomatosis Paul H. Sugarbaker 1 Abstract IN MANY PATIENTS WITH ABDOMINAL OR PELVIC MALIGNANCIES, surgical treatment failure is isolated to the resection site or to peritoneal surfaces. Elimination of peritoneal surface spread will probably have an impact on survival. Prior to the use of cytoreductive surgery and hiperthermic intraperitoneal chemotherapy, carcinomatosis was a uniformly fatal condition eventually resulting in intestinal obstruction over the course of months or years. This procedure remains controversial, but in experienced centers the application of this new and more comprehensive cancer management strategy remains broad. Key words: Carcinomatosis, Cytoreductive Surgery, HIPEC Resumen La falla del tratamiento quirúrgico se presenta en el sitio de la resección o en la superficie peritoneal en muchos pacientes con cáncer localizado en el abdomen o en la pelvis. La eliminación de la diseminación peritoneal puede tener un impacto en la super vivencia. Anteriormente al uso de la cirugía citorreductiva y la quimioterapia intraperitoneal hipertérmica, la carcinomatosis peritoneal era una condición uniformemente fatal, que eventualmente desarrollaba obstrucción intestinal en el transcurso de meses o años. Este procedimiento es controversial, pero esta nueva estrategia de manejo oncológico se realiza en activamente en centros con experiencia. Palabras clave: Carcinomatosis, Cirigía Citorreductiva, HIPEC Correspondence: Paul H. Sugarbaker, MD, FACS, FRCS Director, Program in Peritoneal Surface Malignancy, Washington Cancer Institute 106 Irving St., NW, Suite 3900. Washington, DC 20010, USA. Phone: 1-202-877-3911. Fax: 1-202-877-8602 e-mail: Paul.Sugarbaker@medstar.net 119

Overview of Peritoneal Carcinomatosis Introduction Changes in the use of chemotherapy in patients with peritoneal carcinomatosis, peritoneal sarcomatosis, and peritoneal mesothelioma have shown favorable results of treatment. A change in route of drug administration has occurred: Chemotherapy is given intraperitoneally, or by combined intraperitoneal (ip) and intravenous (iv) routes. In this new strategy, iv chemotherapy alone is rarely indicated. Also, a change in timing has occurred: Chemotherapy begins in the operating room and may be continued for the first 5 postoperative days. A change in selection criteria of treatment of cancer has also occurred. The lesion size (LS) of peritoneal implants is of crucial importance. Only patients with small-sized ip tumor nodules with limited distribution within the abdomen and pelvis are likely to show prolonged benefit. In order to achieve maximum benefit meticulous cytoreductive surgery is necessary prior to the ip chemotherapy instillation. Aggressive treatment strategies for large-volume invasive carcinomatosis will not produce long-term benefits and are often the cause of excessive morbidity or mortality. The initiation of treatments for peritoneal surface malignancy (PSM) must occur as early as possible in the natural history of these diseases in order to achieve the greatest benefits. A definitive role for prevention of carcinomatosis for patients at high risk for peritoneal dissemination has been demonstrated. The greatest change that now needs to occur with PSM is a change in oncologists attitudes toward these diseases. They may be cured if treated early with aggressive local-regional treatment strategies. Background Cancers that occur within the abdomen and pelvis will disseminate by three different routes: hematogenous metastases, lymphatic metastases, and through peritoneal spaces to surfaces within the abdomen and pelvis. In a substantial number of patients, surgical treatment failure is isolated to the resection site or to peritoneal surfaces. This leads to a hypothesis that suggests that the elimination of peritoneal surface spread will have an impact on the survival of these cancer patients. There can be no doubt that a leading cause of death and suffering in patients with these malignancies is progression of peritoneal surface disease. Prior to the use of cytoreductive surgery and ip chemotherapy, carcinomatosis was a uniformly fatal condition eventually resulting in intestinal obstruction over the course of months or years. Occasionally, patients with low-grade malignancies, such as pseudomyxoma peritonei, survived for several years, but all endresult reporting have shown fatal outcomes. Peritoneal-Plasma Barrier IP chemotherapy gives high response rates within the abdomen because the peritoneal-plasma barrier provides dose-intensive therapy. (1) Figure 1 shows that large molecular weight substances such as mitomycin C (MMC) are confined to the abdominal cavity for long time periods which means that the exposure of peritoneal surfaces to pharmacologically active molecules can be increased considerably by giving the drugs via the ip route rather than by the iv route. (2) For chemotherapy agents used to treat peritoneal carcinomatosis or peritoneal sarcomatosis, the area under the curve (AUC) ratios of ip to iv exposure are favorable. Table 1 presents the AUC (ip/ iv) for the drugs in routine clinical use in patients with peritoneal seeding. (3-5) In the author s studies, these include 5-fluorouracil (5-FU), MMC, doxorubicin, cisplatin, paclitaxel, and gemcitabine. One should not assume that the ip administration of chemotherapy eliminates their systemic toxicities. Although the drugs sequestered within the peritoneal space, they eventually are cleared into the systemic circulation. For this reason, the safe dose of most drugs instilled into the peritoneal cavity is similar to the iv dose. The exceptions are drugs with hepatic degradation, such as 5-FU and gemcitabine. An increased dose of approximately 120

Sugarbaker, Cancerología 3 (2008): 119-124 Table 1 Area under curve ratios of peritoneal surface exposure to systemic exposure for drugs used to treat intraabdominal cancer. Drug 5-fluorouracil Mitomycin C Doxorubicin Cisplatin Paclitaxel Gemcitabine 100 10 1 0.1 0.01 Molecular Weight 130 334 544 300 808 263 0.001 0 1 2 3 4 5 0.003 6 µg/ml Time (Hours) µmol/l Peritoneal fluid 50% is possible with 5-FU. The dose for a 5-day course of iv 5-FU is approximately 500 mg/m 2 / day; for ip 5-FU, the dose is 750 mg/m 2 /day. This approximate 50% increase in dose of 5-FU is of benefit in eliminating peritoneal carcinomatosis. Tumor Cell Entrapment AUC 250 75 500 20 1000 50 299.4 29.94 2.99 0.299 0.029 Urine Plasma Portal plasma Figure 1 Large molecular weight compounds, when instilled into the peritoneal cavity, are sequestered at the site for long time periods. The physiologic barrier to the release of ip drugs is called the peritoneal plasma barrier. In this experiment, 15 mg MMC was infused into the cavity as rapidly as possible. IP, iv portal venous pressure and urine MMC concentrations were determined by high pressure liquid chromatography assay. The tumor cell entrapment hypothesis explains the rapid progression of PSM in patients who undergo treatment of carcinomatosis using surgery alone. This theory relates the high incidence and rapid progression of peritoneal surface implantation to free ip tumor emboli as a result of serosal penetration by cancer; leakage of malignant cells from transected lymphatics; dissemination of malignant cells directly from the cancer specimen as a result of surgical trauma and backflow of venous blood; fibrin entrapment of intraabdominal tumor emboli on traumatized peritoneal surfaces; and promotion of these entrapped tumor cells through growth factors involved in the wound healing process. This phenomenon may cause a high incidence of surgical treatment failure in patients treated for primary GI cancer. Also, the reimplantation of malignant cells into peritonectomized surfaces in a reoperative setting must be expected. Chemotherapy used in the perioperative period not only directly destroys tumor cells but it also eliminates viable platelets while blood cells and monocytes form the peritoneal cavity which diminishes the promotion of tumor growth associated with the wound healing process. Consequently, the results of ip chemotherapy show a reduction in local cancer recurrence and peritoneal surface recurrence in patients with intraabdominal cancer. Removal of the leukocytes and monocytes also decreases the ability of the abdomen to resist an infectious process; therefore, strict aseptic technique is imperative when administering chemotherapy or when handling tubes and drains. In order to interrupt implantation of tumor cells at the resection site and on other abdominal and pelvic surfaces, the abdominal cavity is flooded with chemotherapy in a large volume of fluid during the operation (HIPEC = heated intraperitoneal chemotherapy) and in he early postoperative period (EPIC = early postoperative intraperitoneal chemotherapy). Most patients with a guarded prognosis may also receive adjuvant ip and systemic chemotherapy. (6) Therefore, the strategy for treatment and prevention of peritoneal carcinomatosis and sarcomatosis involves not only a change in the route (from iv to ip) but also a change in the timing (postoperative to perioperative) of chemotherapy administration. This new approach to surgical treatment of abdominal and pelvic malignancy begins in the operating room after a complete resection of a primary cancer or after the complete cytoreduction of peritoneal carcinomatosis, peritoneal 121

Overview of Peritoneal Carcinomatosis sarcomatosis, or peritoneal mesothelioma. The proper placement of tubes and drains and temperature probes is needed prior to initiation of HIPEC. Suture lines or repair of seromuscular tears occurs after the ip chemotherapy is completed. Before abdominal closure, the temperature probes are removed but the tubes and drains are left in place for EPIC. Proper Patient Selection for IP Chemotherapy Perhaps the greatest impediment to lasting benefits from ip chemotherapy should be attributed to improper patient selection. In the past, most ip chemotherapy protocols, from a theoretical perspective, wound not benefit much, if at all. A great number of patients with gross intraabdominal disease were treated. Even with extensive prior cytoreductive surgery, the patient is not likely to have lasting benefit. Rapid recurrence of ip cancer combined with progression of lymph nodal or systemic disease were likely to interfere with any long-term benefits in these patients. Clinical research has shown that patients who benefit will have minimal disease isolated to peritoneal surfaces that have access to chemotherapy so that complete eradication of disease can occur. Partial responses are not of great benefit in PSMs. Complete and durable responses are the reasonable goal. Of course, the extent of disease when the patient starts treatment will have great bearing on the response achieved. Early and asymptomatic patients must be selected for ip chemotherapy protocols. Clinical Assessments of PSM In the past, peritoneal carcinomatosis was considered to be a fatal disease process. The only assessment used was either carcinomatosis present with a presumed fatal outcome or carcinomatosis absent with curative options available. Currently, there are four important clinical assessments of PSM that need to be used to select patients who will benefit from treatment protocols: the invasive character of the malignancy, the preoperative computed tomography (CT) scan of abdomen and pelvis, the Peritoneal Cancer Index (PCI), and the completeness of cytoreduction score (CC). (7-11) Clinical Evidence that Cytoreductive Surgery and IP Chemotherapy Benefits Patients with PSM Treatments for peritoneal carcinomatosis and sarcomatosis have been shown to provide survival with a portion of patients alive a 5 years and considered cured. The strategy for treating these patients has always involved three essential components: first is a complete cytoreduction utilizing peritonectomy procedures with an attempt to removal all visible tumor; assuming that microscopic residual disease will eventuate in recurrence in all these patients, the second essential component is perioperative ip chemotherapy; and, it is becoming increasingly clear that proper patient selection is the third essential component of these treatment strategies. Although no one questions the essential nature of complete cytoreduction and accurate patient selection, many oncologists are not convinced that ip chemotherapy is of benefit to prevent recurrence of peritoneal surface disease. Data from prospective trials and from clinical observations suggest that ip chemotherapy can reduce or eliminate the recurrence of peritoneal carcinomatosis after surgery to remove large-volume disease. Appendiceal mucinous neoplasms present the paradigm for successful management of peritoneal dissemination. Less cancer invasion, minimal (2%) incidence of lymph nodal or liver metastases, and minimal or absent disease on small bowel surfaces work together to allow successful management. In a recent systematic review by Yan and colleagues, approximately 65% of patients were documented to be disease-free at 5 years. (12) In patients with colon cancer carcinomatosis Verwaal and colleagues performed a single institution 122

Sugarbaker, Cancerología 3 (2008): 119-124 randomized trial of cytoreduction plus HIPEC versus standard of care with systemic chemotherapy. (13) In the group given combined treatment the median survival was 43 months vs. 23 months in the control group. Glehen and colleagues performed a retrospective study of 523 patients with colon cancer carcinomatosis treated by cytoreductive surgery plus HIPEC, EPIC or both HIPEC and EPIC. (14) The median survival was 32 months in patients who had a complete cytoreduction. These results were greatly improved when compared to the 6-12 month median survival in carcinomatosis patients treated by systemic chemotherapy. Several prospective randomized studies in peritoneal carcinomatosis from gastric cancer have been reported. The meta-analysis of eight trials was reported by Yan and coworkers. (15) There was an improved survival in all seven trials using perioperative ip chemotherapy. Indications for the combined use of surgery to remove all visible abdominal or pelvic cancer and perioperative intraperitoneal chemotherapy to eradicate microscopic disease remains controversial. In experienced centers the application of this new and more comprehensive cancer management strategy remains broad. The conditions that benefit are listed in Table 2. The continued expansion of the use of HIPEC and EPIC to improve the results of treatment of abdominal and pelvic cancer remains a work in progress. References 1. Jacquet P, Vidal-Jove J, Zhu B, Sugarbaker PH. Peritoneal carcinomatosis from gastrointestinal malignancy: natural history and new prospects for management. Acta Belg Chir 1994; 94: 191-197 2. Sugarbaker PH, Graves T, DeBruijn EA, et al. Rationale for early perioperative intraperitoneal chemotherapy (EPIC) in patients with advanced gastrointestinal cancer. Cancer Res 1990; 50: 5790-5794 3. Sugarbaker PH, Cunliffe W, Israel M, Sweatman TW. Early perioperative intraperitoneal adriamycin: pharmacologic studies and a preliminary clinical report. Reg Cancer Treat 1991; 4: 127-131 4. Markman M. Intraperitoneal taxol. (In) Sugarbaker PH (ed). Peritoneal Carcinomatosis: Drugs and Diseases. Kluwer: Boston, 1996. 1-5 5. Pestieau SR, Stuart OA, Chang D et al. Pharmacokinetics of intraperitoneal gemcitabine in a rat model. Tumori 1998; 84: 706-711 6. Sugarbaker PH. Cytoreductive Surgery and Intraperitoneal Chemotherapy: A Manual for Physicians and Nurses. Ludann: Grand Rapids, 1995 7. Jacquet P, Jelinek JS, Chang D, et al. Abdominal computed tomographic scan in the selection of patients with mucinous peritoneal carcinomatosis for cytoreductive surgery.[erratum appears in J Am Coll Surg 1996 Jan;182(1):80]. Journal of the American College of Surgeons 1995; 181: 530-538 8. Steller EPH. Comparison of four scoring models for an intraperitoneal immunotherapy model. In: Enhancement and Abrogation: Modifications of Host Immune Status Influence IL-2 and LAK Cell Immunotherapy. Erasmus Universitait: Rotterdam, 1998, pp 56-63 Table 2 Current indications for combined treatment using cytoreductive surgery and perioperative ip chemotherapy. Symptomatic malignant ascites Pseudomyxoma peritonei after complete cytoreduction Peritoneal mesothelioma after complete cytoreduction Primary colon or rectal cancer Small volume and limited distribution peritoneal seeding Perforated colon cancer Colon cancer with adjacent organ involvement Colon cancer with spread to the ovaries Colon cancer with positive ip cytology Tumor spill with resection of primary colon or rectal cancer Recurrent colon or rectal cancer with carcinomatosis Small volume and limited-distribution of peritoneal seeding Colon cancer causing Krukenberg ovarian tumor Tumor spill with resection of recurrent cancer Complete cytoreduction of recurrent disease at more than a single site Recurrent ovarian cancer with spread limited to peritoneal surfaces Limited or absent iv chemotherapy options Long free interval between initial treatment and recurrence Primary gastric cancer after complete resection with limited peritoneal seeding Primary of recurrent abdominopelvic sarcoma Sarcomatosis following complete cytoreduction Primary abdominopelvic sarcoma with equivocal margins of resection Primary abdominopelvic sarcoma with tumor spill during resection 123

Overview of Peritoneal Carcinomatosis 9. Portilla AG, Sugarbaker PH, Chang D. Second-look surgery after cytoreduction and intraperitoneal chemotherapy for peritoneal carcinomatosis from colorectal cancer: analysis of prognostic features. World J Surg 1999; 23: 23-29 10. Berthet B, Sugarbaker TA, Chang D, Sugarbaker PH. Quantitative methodologies for selection of patients with recurrent abdominopelvic sarcoma for treatment. European Journal of Cancer 1999; 35: 413-419 11. Jacquet P, Sugarbaker PH. Clinical research methodologies in diagnoses and staging of patients with recurrent abdominopelvic sarcoma for treatment. (In) Sugarbaker PH (ed). Peritoneal Carcinomatosis: Principles of Management. Kluwer: Boston, 1996, 359-374 12. Yan TD, Black D, Savady R, Sugarbaker PH. A systematic review on the efficacy of cytoreductive surgery and perioperative intraperitoneal chemotherapy for pseudomyxoma peritonei. Ann Surg Oncol 2007; 14: 484-492 13. Verwaal VJ, van Ruth S, de Bree E, et al. Randomized trial of cytoreduction and hyperthermic intraperitoneal chemotherapy versus systemic chemotherapy and palliative surgery in patients with peritoneal carcinomatosis of colorectal cancer. J Clin Oncol 2003; 21: 3737-3743 14. Glehen O, Kwiatkowski F, Sugarbaker PH, et al. Cytoreductive surgery combined with perioperative intraperitoneal chemotherapy for the management of peritoneal carcinomatosis from colorectal cancer: a multiinstitutional study. J Clin Oncol 2004; 22: 3284-3292 15. Yan TD, Black D, Sugarbaker PH, et al. A systematic review and meta-analysis of the randomized controlled trials on adjuvant intraperitoneal chemotherapy for advanced gastric cancer. Ann Surg Oncol 2007; 14: 2702-2713 124