Cytoreduction and Intraperitoneal Chemotherapy for the Management of Non-Gynecological Peritoneal Surface

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1 J. Exp. Clin. Cancer Res., 22, 4, Supplement Cytoreduction and Intraperitoneal Chemotherapy for the Management of Non-Gynecological Peritoneal Surface Malignancy Yan T.D., Esquivel J., Carmignani P., and Sugarbaker P.H. Washington Hospital Center, Washington, DC, USA Peritoneal surface malignancy can arise from pseudomyxoma peritonei, gastrointestinal carcinoma, abdominopelvic sarcoma and peritoneal mesothelioma. In the past, only palliative treatments were offered and the results were poor. We have proposed a new concept in managing patients with peritoneal surface malignancy. It involves an aggressive combined treatment modality of cytoreduction and perioperative intraperitoneal chemotherapy. The results are promising for patients with pseudomyxoma peritonei, peritoneal mesothelioma and well-selected patients with invasive peritoneal surface malignancies. The success in such comprehensive treatment depends on tumor biology, patient s co-morbidities, the completeness of cytoreduction, the efficacy of intraperitoneal chemotherapy administration and the surgeon s experience. The importance of patient selection is emphasized. The rationales and the outline of the current management strategies are described. Large phase II studies have demonstrated the marked survival advantage in this aggressive approach to peritoneal surface malignancy. Key Words: Carcinomatosis, sarcomatosis, peritoneal mesothelioma, peritonectomy, intraperitoneal chemotherapy. Peritoneal seeding frequently represents the terminal stage of gastrointestinal and pelvic malignancies and it may or may not be associated with systemic metastases. In the past, regional tumor recurrence with peritoneal involvement has been difficult to manage and treatment has been focused on short-term palliation. Recent clinical data presents the concept of radical surgical resection of peritoneal surface malignancy to achieve long-term survival in selected patients with pseudomyxoma peritonei, peritoneal carcinomatosis, sarcomatosis and peritoneal mesothelioma. In most cases, these tumor cells may be shed onto peritoneal surfaces, trapped within fibrin on disrupted peritoneum and proliferate under the influence of growth factors in the wound healing process (1). The combined treatment modality of peritonectomy, perioperative intraperitoneal chemotherapy and early postoperative intraperitoneal chemotherapy is aimed at the complete eradication of such disease. This treatment approach has yielded long-term disease-free survival in patients with mucinous appendiceal tumor and improved survival in selected patients with colorectal cancer (2). This review presents the rationale, treatment parameters and results for management of peritoneal surface dissemination of mucinous appendiceal tumor, peritoneal mesothelioma, colorectal cancer, gastric cancer, and abdomino-pelvic sarcomas. Rationales for cytoreduction and intraperitoneal chemotherapy in non-gynecological peritoneal surface malignancy Appendiceal Malignancy as a Paradigm Pseudomyxoma peritonei is characterized by copious amount of mucin and tumor that occupies the predictable anatomic sites within the peritoneal cavity, as termed redistribution phenomenon. This can originate 109

2 Yan T.D. et al. from an appendiceal mucinous adenoma, a gastrointestinal mucin-producing adenocarcinoma, a primary ovarian mucinous tumor or mucinous peritoneal carcinomatosis of an unknown primary tumor. Among them, appendiceal tumors give rise to the majority of cases. Mucinous appendiceal tumor is the paradigm for successful treatment of peritoneal surface malignancy. It is a minimally aggressive epithelial tumor which has limited capability of invasion in that it does not infiltrate the peritoneum and rarely metastasizes to lymph nodes or the liver. Since the appendix has a very narrow lumen, the tumor enlarges, obstructs the lumen and eventually perforates into the peritoneal cavity (Fig. 1). The seeding of the peritoneum by mucinous Fig. 2: Omental cake with clear small bowel, the classic clinical features of pseudomyxoma peritonei of appendiceal origin. Fig. 1: Appendiceal tumor at the base of the cecum with a ruptured malignant mucocele. tumor cells happens before lymph nodal or hepatic involvement. These tumor cells do not have adherence molecules expressed on the cell surfaces, therefore they can not attach on the epithelium (3). Adenomatous epithelial cells together with a large volume of mucin accumulate at the sites of peritoneal fluid absorption, such as the undersurface of the right hemidiaphragm, the greater omentum, and within dependent areas, such as pelvis, right retrohepatic space, the left abdominal gutter and the ligament of Treitz. The continuous peristaltic motion of the small intestine prevents tumor implantation on its surfaces, which makes cytoreductive procedure with preservation of adequate small intestine feasible (Fig. 2). In contrast, the stomach and the large bowel are variably involved, but to a lesser extent than quiescent surfaces such as liver and parietal peritoneum. Mucinous appendiceal tumor only exfoliates and redistributes intraperitoneally, so that after a complete cytoreduction, intraperitoneal chemotherapy can reach and eventually eradicate the microscopic residual disease. This increases the likelihood of a long-term disease-free survival and results in a cure for some patients. The treatment strategies currently used in our institution for pseudomyxoma peritonei include complete cytoreductive surgery, heated intraoperative intraperitoneal chemotherapy with mitomycin-c and early postoperative intraperitoneal chemotherapy with 5- flourouracil. Recent data showed an 80% 5-year survival rate and 3% perioperative mortality of 500 patients with primary mucinous appendiceal tumor (Fig. 3) (4). Peritoneal Mesothelioma Mesothelioma is a rare neoplasm originating from the mesothelial surface lining the human body cavities and can exhibit a spectrum of histopathological appearances, ranging from well-differentiated adenomatoid forms to poorly differentiated sarcomatoid variants. It may involve the pleura, peritoneum and, rarely, the pericardium and the tunica vaginalis, and it may be associated with asbestos exposure (5). Peritoneal mesothelioma represents one-third of all mesotheliomas and is generally a rapidly fatal disease with a median survival of less than 1 year (6). Patients may 110

3 Combined treatment for peritoneal surface malignancy Fig. 3: Survival of 500 patients with appendiceal epithelial tumors with peritoneal seeding. Dark line = lymph node negative; light line = lymph nodes not assessed; dotted line = lymph node positive. Fig. 4: Survival of 41 male and 21 female patients with peritoneal mesothelioma treated at the Washington Cancer Institute. P = present with abdominal distension or localized abdominal pain or both. With palliative treatments, such as systemic chemotherapy, radiotherapy or debulking surgery alone, these patients subsequently develop intestinal obstruction, fistula formation, starvation and eventually die. However, the disease is usually confined to the peritoneum and rarely metastasizes. This has led our group to pursue an aggressive regional treatment modality for selected patients with peritoneal mesothelioma. It consists of complete cytoreductive surgery, combined with heated intraoperative chemotherapy with cisplatin and doxorubicin, early postoperative and delayed postoperative intraperitoneal chemotherapy with paclitaxel. A recent report showed that 51 patients with this aggressive treatment for their peritoneal mesothelioma had a median survival of 56 months and that female gender, age younger than 53, no weight loss and smaller volume of disease were associated with a better prognosis for survival (Fig. 4) (7). Colorectal peritoneal carcinomatosis Colorectal cancer (CRC) can disseminate through lymphatic channels or via hematogenous spread to other organs, such as the liver and the lungs. It can also gain access to the peritoneal cavity either through fullthickness invasion of the bowel wall or dissemination during colorectal tumor resections, resulting in peritoneal carcinomatosis. Peritoneal carcinomatosis from colorectal origin is a common and lethal condition. Currently, there is no reported long-term survival in patients with colorectal peritoneal carcinomatosis treated by systemic chemotherapy. A recent retrospective analysis of 3019 patients with colorectal cancer showed that 13% of patients presented with carcinomatosis and had a median survival of 7 months (8). It has been generally accepted that without peritoneal carcinomatosis, complete surgical resection of CRC with lymph nodal metastases was associated with approximately a 50% 5-year survival and liver resection for colorectal hepatic metastases, could achieve a 30% 5-year survival. Despite the lack of randomized controlled trial, liver resection has been regarded as the only curative treatment for colorectal liver metastases. Sugarbaker has suggested that colorectal peritoneal carcinomatosis could present at an early stage of disease progression or result from of surgical manipulation during the primary tumor resection. Cytoreductive surgery may eradicate macroscopic tumor and perioperative intraperitoneal chemotherapy may eliminate the microscopic residual disease. The importance of patient selection cannot be overemphasized. It depends on the absence of distant metastases, a smaller volume of peritoneal surface dissemination, the ability to obtain a tumor-free margin with the primary tumor resection and a good performance status. 111

4 Yan T.D. et al. Elias et al. (9) reported a 2- and 5- year survival of 60% and 27% respectively for 64 colorectal peritoneal carcinomatosis patients treated with the combination of a complete cytoreductive surgery with intraoperative intraperitoneal chemotherapy or early postoperative intraperitoneal chemotherapy. Sugarbaker et al. (10) reported a median survival of 24 months and a 5- year survival of 30% of 104 such patients underwent cytoreductive surgery combined with heated intraoperative intraperitoneal chemotherapy with mitomycin C and early postoperative intraperitoneal 5-flourouracil. The same report also showed that a better survival advantage of the patients with colorectal peritoneal carcinomatosis treated with concomitant management of primary tumor. A Dutch randomized controlled trial (11) on cytoreduction and hyperthermic intraperitoneal chemotherapy versus systemic chemotherapy alone (5- flourouracil and Leucovorin) in patients with colorectal peritoneal carcinomatosis demonstrated the a median survival of 22.4 months versus 12.6 months, respectively and 2-year survival rates of 43% versus 16%, respectively (P=0.001). A recent international registration (12) of 506 patients with colorectal carcinomatosis treated by cytoreduction and perioperative intraperitoneal chemotherapy with a curative intent, from 28 institutions has been submitted. The overall median survival was 19.2 months. The median survival of patients who received a complete cytoreductive surgery and those who did not, were 32.4 months and 8.4 months, respectively (P < 0.001). Multivariate analysis demonstrated that complete cytoreduction, treatment by a second procedure, limited extent of peritoneal carcinomatosis, age less than 65 and use of adjuvant chemotherapy are independently associated with a better survival. The use of neoadjuvant chemotherapy, lymph nodal involvement, presence of liver metastases and poor histological differentiation were negative independent prognostic indicators (Table 1). These data suggest that complete cytoreductive surgery and perioperative intraperitoneal chemotherapy offer promising results in a substantial proportion of patients with colorectal peritoneal carcinomatosis. Gastric Cancer Gastric cancer can also disseminate by 3 different routes: lymphatic, hematogenous and peritoneal seeding. Peritoneal dissemination occurs when cancer cells invade through the serosal layer, exfoliate and implant on the peritoneal surfaces, or after surgical tumor manipulation. Cancer cells are spilled into the peritoneal cavity, where they firmly adhere and progress. Surgery has been regarded as the only curative treatment for gastric cancer. Table 1. Multivariate analysis of 506 patients treated with cytoreduction and perioperative intraperitoneal chemotherapy. A dash indicates improved survival. (Modified from Glehen O et al.12) Variables Cox coefficient P Complete of cytoreduction 0.71 < Treatment with second procedure <0.001 Carcinomatosis extent 0.51 <0.001 Lymph node involvement Age Tumor differentiation Synchronous resection of liver metastasis Preoperative systemic chemotherapy Adjuvant systemic chemotherapy Treatment with IPCH_ Treatment with EPIC_ Sex Synchronous resection of primary tumor _ - Intraperitoneal chemohyperthermia _ - Early postoperative intraperitoneal chemotherapy 112

5 Combined treatment for peritoneal surface malignancy Approximately 40% of recurrences after curativeintent gastrectomy were confined to the peritoneal cavity. This high rate of local disease progression after curative-intent gastrectomy is related to persistent microscopic residual disease. Strong clinical data suggests that the management of the microscopic residual disease must be integrated into the care for gastric cancer patients by surgeons. Great effort should be made in achieving total surgical clearance of the primary gastric tumor, the involved lymph nodes and adjacent peritoneal surfaces to obtain complete containment of the malignant process, by using a technique called centripetal gastrectomy (13). In the data by Yu et al., this is followed by perioperative intraperitoneal chemotherapy (14). The management of gastric cancer with established peritoneal carcinomatosis can be more perplexing. In the United States, 20-30% of patients being explored for potential curative resection will be found to have peritoneal seeding. Systemic chemotherapy for these patients has been uniformly disappointing. Despite the fact that stage IV gastric cancer with peritoneal carcinomatosis carries a dismal prognosis, the combined treatment modality of extended gastrectomy, cytoreduction and perioperative intraperitoneal chemotherapy might benefit a selected group of patients. A comprehensive review (13) of numerous publications strongly supported the use of palliative gastrectomy in advanced gastric cancer and not only demonstrated survival advantage, but also better quality of life. Many encouraging phase II studies and one randomized controlled trial showed a prolonged survival in patients treated with gastrectomy and perioperative intraperitoneal chemotherapy (13). Yonemura et al. (15) reported a 17% 5-year survival in 28 patients having a complete cytoreduction with only 2% 5-year survival in 55 patients having an incomplete cytoreduction (p=0.03). It suggests that complete cytoreduction with resection of gastric cancer improves prognosis. Since systemic chemotherapy has little role in treating patients with stage IV gastric cancer and peritoneal carcinomatosis, the more aggressive treatment modality should be carefully considered for those who have limited co-morbidities, resectable primary cancer, absent distant metastases and adequate small intestine preservation. Sarcomatosis Local recurrence of abdominal or pelvic sarcoma with peritoneal seeding is a common cause of surgical treatment failure, which results in considerable morbidity and a lethal outcome. It was thought that resection of the primary sarcoma was partially responsible for intraperitoneal dissemination of the disease, because the tumor emboli might be trapped by fibrin deposition. Some evidence (16) showed that the distribution of the disease within the peritoneal cavity dramatically increased at the operation for recurrence than that at the primary tumor resection. This suggested that the extent of surgical trauma might be the cause of the intraperitoneal dissemination of the primary sarcoma. In the past, these patients receive no surgical treatment and uniformly die of their disease. A more definitive treatment has been proposed, which combines electroevaporative surgery and heated intraoperative intraperitoneal chemotherapy with cisplatin and doxorubicin and early postoperative intraperitoneal chemotherapy with doxorubicin or doxorubicin and cisplatin for patients with recurrent abdomino-pelvic sarcoma. The results are encouraging. Twenty seven of 43 patients with abdomino-pelvic sarcoma underwent complete cytoreductive surgery with perioperative chemotherapy and demonstrated a 5-year survival of 39 months, in contrast to 13.6 months for those with incomplete cytoreduction (p=0.005).16 The same study showed that the extent of cytoreduction was greatly dependent on the quantitative measurements of volume and distribution of disease. Management of non-gynecological peritoneal surface malignancies Patient selection Patient selection plays an especially important role in the results of this treatment modality. Failure to do so may lead to high morbidity and mortality. Patients with advanced intraperitoneal disease of invasive cancer have been treated with minimal benefit. Nodal involvement or systemic metastases signify poorer prognosis. Patients who benefit most are those with minimal residual disease confined to peritoneal surfaces that have access to chemotherapy so that complete eradication of disease can occur. In the natural history of carcinomatosis and sarcomatosis, prompt initiation of treatment is very important once the diagnosis of peritoneal-surface malignancy is first made. Patients with a small-volume of disease must be selected for intraperitoneal chemotherapy protocols. Clinical assessment of peritoneal surface malignancy Currently, four important clinical indicators are 113

6 Yan T.D. et al. associated with a better prognosis in peritoneal-surface malignancy treatment: 1) histopathology to assess the invasive character of the malignancy; 2) preoperative CT scan; 3) the peritoneal cancer index; and 4) the completeness of cytoreduction score. 1) Histopathology Patients with non-invasive tumors, such as pseudomyxoma peritonei and cystic peritoneal mesothelioma, may present with a large volume of intraperitoneal disease and yet without nodal or systemic metastases and be candidates for complete tumor eradication and perioperative intraperitoneal chemotherapy with a curative intent. However, pseudomyxoma peritonei should be distinguished from mucinous adenocarcinoma with the signet ring morphology. Mucinous adenocarcinoma is capable of invasion, infiltration and metastasis. Lymph nodal and liver metastases may be present and result in an extremely poor prognosis. Histopathology assessment of other invasive malignancies is imperative to treatment planning. 2) Preoperative CT scan A preoperative CT scan is used to exclude systemic metastases and quantify the amount of tumor within the peritoneal cavity. Segmental obstructed small bowel implies an invasive character of the disease, which would be impossible to remove completely. Also the presence of nodules >5 cm in diameter on small bowel surface or its mesentery indicates that the cancer is no longer redistributed. Classically, abdominal computed tomography of a patient with pseudomyxoma peritonei from mucinous appendiceal tumor demonstrates the redistribution phenomenon and that the small intestine is compartmentalized by tumors, without mesentery involvement. 3) Peritoneal cancer index Peritoneal cancer index is recorded during the abdominal exploration. PCI is a clinical integration of both peritoneal-implant size and distribution of peritoneal surface malignancy (Fig. 5). To obtain PCI, the abdomen and pelvis are divided into 13 anatomic regions. Zero indicates no carcinomatosis visible, one indicates nodules less than 0.5 cm, two indicates nodules cm, and three indicates nodules greater than 5.0 cm or a confluence of disease. The summation of the lesion size score in all of the 13 regions is the PCI for the individual patient. It is not useful in predicting survival for non-invasive tumors, such as pseudomyxoma peritonei or cystic mesothelioma. However, PCI is prognostically significant in patients with peritoneal surface malignancies from more invasive tumors, such as colon cancer (17) and peritoneal mesothelioma (7). 4) Completeness of cytoreduction score At the end of the surgical intervention, a completeness of cytoreduction score (CC) is recorded (Fig. 6). CC-0 indicates no macroscopic visible residual tumor after cytoreduction, CC-1 indicates residual tumor nodules less than 0.25 cm, CC-2 indicates residual tumor nodules 0.25 cm 2.5 cm, and a CC-3 indicates residual tumor nodules greater than 2.5 cm. Complete cytoreduction is important in achieving a long-term survival. For example, patients with a complete cytoreduction for colorectal peritoneal carcinomatosis had a 40% 5-year survival. In contrast, patients with an incomplete cytoreduction had a 0% 5-year survival (17). Current management plan for combined treatment This combined treatment modality for peritoneal- Fig. 5: Peritoneal cancer index. Fig. 6: Completeness of cytoreduction score. 114

7 Combined treatment for peritoneal surface malignancy clearance from the peritoneal cavity, (19) hence higher chemotherapy exposure can be achieved. Pharmacokinetic studies of intraoperative intraperitoneal chemotherapy report an absorption of 75-90% of mitomycin C and cisplatin in the first hour (20). 5- fluorouracil has a rapid hepatic first-bypass effect, hence higher dose by 50% may be possible. All patients with cytoreductive procedure for gastrointestinal cancers, excluding gastric cancer will receive early postoperative intraperitoneal chemotherapy with 5-fluorouracil, except those with considerable co-morbidities. Fig. 7: Electroevaporative surgery. Morbidity and Mortality A recent study (21) of 200 patients with cytoreductive surgery and perioperative intraperitoneal chemotherapy for peritoneal carcinomatosis, showed treatment related deaths (1.8%), peri-pancreatitis (7.1%) and bowel fistula (4.7%). Discussion surface malignancy consists of four major steps: electroevaporative surgery for cytoreduction, hyperthermic intraoperative intraperitoneal chemotherapy, reconstruction and early post-operative intraperitoneal chemotherapy. 1) Cytoreductive procedure and centripetal surgery Tumor resection and peritonectomy is performed by using electroevaporative surgery (Fig. 7). It involves dissecting tissue by using a 0.3 cm ball-tipped diathermy with a very high current between MW. Larger vessels are electrocoagulated to minimize blood loss. To avoid heat damage, frequent and intermittent saline irrigation is used at the dissection site. Peritonectomy procedure requires the removal and stripping of all tumor-involved parietal and visceral peritoneum by using electroevaporative surgery. It consists of one to six peritonectomies into one coordinated effort and begins at the furthest extent of the tumor and gradually proceeds towards the deepest extent of the tumor and the major vessels in order to achieve total clearance and containment of the tumor with minimal bleeding (18). 3) Intraperitoneal Chemotherapy Complete cytoreductive surgery is necessary prior to intraperitoneal chemotherapy instillation and this is unlikely for advanced carcinomatosis or sarcomatosis, despite the greatly enhanced drug cytotoxicity because of high concentrations and heat synergy. Agents like mitomycin C, doxorubicin and cisplatin have a slow Peritoneal carcinomatosis in the past has been regarded as a terminal condition, where oncologists would only offer palliative treatment. There is growing evidence that the novel combined treatment modality of cytoreductive surgery and perioperative intraperitoneal chemotherapy improves prognosis in wellselected patients with non-gynecological peritoneal carcinomatosis. The success depends on tumor biology, patient s co-morbidities, the completeness of cytoreduction, the efficacy of intraperitoneal chemotherapy distribution and the surgeon s experience. As the paradigm of peritoneal surface malignancy, mucinous appendiceal tumor can be treated successfully, achieving a 5-year survival of 81%. The large volume of such tumor does not equate to poor survival. Because of its minimally invasive and non-metastasizing characters, no matter how much tumor is present intraperitoneally at the beginning of cytoreduction, all tumor can be eradicated, and with perioperative intraperitoneal chemotherapy, a good long term disease-free survival can be expected. However, this is in contrast to more invasive colorectal cancer, where a complete cytoreduction is hard to achieve with large volume of peritoneal carcinomatosis. This means that prompt diagnosis and treatment of colorectal peritoneal carcinomatosis is important. We suggest that patients with low-volume of colorectal peritoneal involvement, found at the time of 115

8 Yan T.D. et al. primary tumor resection, should have no delay to receive cytoreduction and perioperative intraperitoneal chemotherapy in an experienced center for treating peritoneal surface malignancies. Sugarbaker (22) identified three important requirements for an optimal prognosis in treating colorectal carcinomatosis: 1) PCI 10; 2) the ability to achieve a complete cytoreduction; 3) the ability to achieve thorough distribution of intraoperative intraperitoneal mitomycin C and early postoperative intraperitoneal 5-fluorouracil. An international registration that accumulated 506 patients with colorectal peritoneal carcinomatosis, treated by the combined treatment modality of cytoreductive surgery and perioperative intraperitoneal chemotherapy, with a curative intent from 28 institutions has been finalized (12). From these data the oncology community must consider a role for this novel therapeutic approach in treating colorectal carcinomatosis. Of course, there are questions still to be answered, such as the optimal choice of chemotherapy treatment. In additional, work needs to be done to refine the selection criteria for patients who may benefit from this comprehensive treatment strategy. It is interesting that new evidence suggests that peritoneal carcinomatosis, sarcomatosis and peritoneal mesothelioma may occur without systemic dissemination. It is also thought that many peritoneal seeding is a result of improper surgical handling during the primary tumor resection. The combined treatment modality of cytoreductive surgery and perioperative intraoperative chemotherapy, pioneered by Sugarbaker, targets directly such disease process. The surgical procedure is technically and physically demanding and may be associated with high morbidity and mortality. The centripetal surgery with electroevaporative device can greatly facilitate tumor eradication and reduce blood loss and fistula formation. It is imperative to have a complete cytoreduction in order for patients to receive the maximal benefit from perioperative intraperitoneal chemotherapy, but at the same time adequate small intestine length must be preserved. The changes have been made in the mode of chemotherapy delivery and these have translated to good prognosis. Chemotherapy is given intraperitoneally, rather than intravenously, so that maximum surface exposure to the chemo-therapeutic agents is achieved. It is also given in the early postoperative period before adhesion forms, which may greatly diminish chemotherapy distribution. In summary, this review emphasizes the importance of patient selection for such comprehensive treatment and describes the current standardized treatment strategies and their rationale for the non-gynecological peritoneal surface malignancies of mucinous appendiceal tumor, mesothelioma, colorectal cancer, gastric cancer, and abdomino-pelvic sarcomas. References 1. Savalgi RS. 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