December 6, 2006
Appendiceal Cancer and Peritoneal Carcinomatosis: A Report of 29 Cases/DISCUSSION
By Esquivel, Jesus; Merriman, Barry; Davis, Sallie; Manning, Darrell; Et al
JESUS ESQUIVEL, M.D., F.A.C.S., BARRY MERRIMAN, SALLIE DAVIS, M.D., DARRELL MANNING, M.D.
Peritoneal surface malignancies of appendiceal origin arise from a perforated neoplasm with gradual expansion of the tumor within the abdomen. We report our experience with 29 patients. Between February 2000 and November 2004, 29 patients were classified into one of three groups based on the features of their peritoneal dissemination. Group 1 included those with extracellular mucin with little cellular atypia (disseminated peritoneal adenomucinosis/low- grade mucinous adenocarcinomas). Group 2 included those with peritoneal mucinous carcinomatosis/high-grade mucinous adenocarcinomas, and Group 3 included those with nonmucinous carcinomatosis. There were 17 patients in Group 1, 9 in Group 2, and 3 in Group 3. The majority had cytoreductive surgery and intraperitoneal chemotherapy. There were no operative deaths. Mean follow-up was 21 months. Median survival for Groups 1 and 2 has not been reached. Group 3 patients were more likely to die than Group 1 patients, with a hazard ratio of 48.0 (P = 0.001), and Group 2 patients with a hazard ratio of 7.8 (P = 0.029). Median survival for Group 3 was 5 months. These data add to the growing evidence that supports cytoreductive surgery and intraperitoneal chemotherapy in a selected group of patients. Those with mucinous peritoneal dissemination are more likely to benefit from this approach. It appears that in patients with nonmucinous carcinomatosis, the biology of the tumor predicts their outcome.
PERITONEAL SURFACE MALIGNANCIES represent a spectrum of diseases characterized by a rupture of the primary tumor with wide dissemination in the intraperitoneal cavity. This dissemination is governed mainly by three factors: the flow of the peritoneal fluid, which is clockwise, results in frequent accumulations of tumor underneath the right hemidiaphragm. Another factor is the phagocytic activity of the greater and lesser omentums and the appendices epiploicae in the sigmoid colon. Accumulation of tumor in these anatomical sites gives rise to the classic omental caking associated with these types of tumors. The third factor, gravity, leads to tumor accumulation in the culde-sac region with subsequent pelvic outlet obstruction. The paradigm of peritoneal surface malignancies is represented by the rupture of an appendiceal adenoma. After the tumor ruptures, large amounts of mucus and tumor will redistribute throughout the entire abdomen, giving rise to the Pseudomyxoma peritonei syndrome with its characteristic "jelly belly."1 In the past, this term was used for any peritoneal dissemination of a gastrointestinal mucin-producing adenocarcinoma, a primary mucinous ovarian tumor, and even peritoneal carcinomatosis from nonmucinous tumors. In some of these cases, the peritoneal dissemination consists mostly of solid tumor and serous ascites, and their clinical presentation can vary from intestinal obstruction, intractable ascites, or even a manifestation of a hypercoagulable state like a deep vein thrombosis or a pulmonary embolus.
Pseudomyxoma peritonei was once treated with repeated operative debulking procedures with the goal being to evacuate as much tumor and mucus as possible. Even though it is a minimally aggressive tumor with limited capability of invasion, few patients lived beyond 5 years.2 Invariably, the tumor would continue to grow and the patients would succumb to intestinal obstruction. Sugarbaker et al.3 have previously reported greater than 80 per cent 5-year survival rates in patients with appendiceal adenomas with Pseudomyxoma peritonei syndrome treated with a comprehensive cytoreductive surgery and intraperitoneal hyperthermic chemotherapy. The use of peritonectomy procedures, better perioperative management, and strict selection criteria have allowed this systematic approach to be used for the treatment of high-grade appendiceal cancers and other mucinous and nonmucinous peritoneal surface malignancies of gastrointestinal origin. Long-term success with this particular approach has also been reported in patients with peritoneal dissemination from colorectal cancer. In a recent report, the median survival in patients with colorectal cancer with peritoneal dissemination in whom a complete cytoreduction was achieved was 32 months.4
The aim of this study was to report a detailed analysis of 29 patients with peritoneal dissemination from an appendiceal neoplasm evaluated by the Kaiser Permanente MidAtlantic Region Cancer Center.
Materials and Methods
The research records of all the patients with peritoneal surface malignancies evaluated by the Kaiser Permanente MidAtlantic Region Cancer Center from February 2000 to November 2004 were reviewed. There were 57 patients with peritoneal surface malignancies. Of these, 29 patients had the diagnosis of a peritoneal surface malignancy of appendiceal origin. Four patients were excluded from the study because of the following reasons: two refused surgery, one had an appendectomy only, and one had not had surgery at the time of this report. An analysis of the remaining 25 patients constitutes the basis of the study. No patients were lost to follow-up.
All 25 patients were taken to the operating room with the intention of performing cytoreductive surgery and intraperitoneal hyperthermic chemotherapy. A completeness of cytoreduction score (Table 1) was assigned to each patient at the end of their surgical procedure. A summary of selected clinical and histopathological features regarding these 25 patients was gathered from the clinical records. An analysis of these features and their prognostic impact was performed using survival as an endpoint.
There were 15 men and 14 women. The mean age of presentation was 59 years. The most common presenting sign or symptom overall was increasing abdominal girth, with 34 per cent of the patients presenting this way. Fifty per cent of women presented with an ovarian mass (Table 2). There were 14 (56%) patients in Group 1 and the vast majority of those had disseminated peritoneal adenomucinosis. There were eight (32%) patients in Group 2 and there were three (12%) patients in Group 3 (Table 3). The standard surgical approach consisted of a very generous midline incision, usually removing the umbilicus. The peritoneum of the anterior abdominal wall was usually stripped to get access to the intraperitoneal cavity. Mechanical retraction was achieved with a Thompson retractor and the abdominopelvic regions were then evaluated. High-voltage electrosurgery with a 3-mm ball tip was used to perform the peritonectomy procedures necessary to remove as much tumor as possible. After all of the resections were done, the abdomen was prepped for the intraperitoneal hyperthermic perfusion with the open coliseum technique. The majority of patients (84%) had cytoreductive surgery, and 76 per cent of those patients had intraperitoneal chemotherapy with mitomycin C (12.5 mg/m^sup 2^ in men and 10 mg/m^sup 2^ in women) heated at 42 C for 90 minutes (Table 4). There were four (16%) patients that had only an exploratory laparotomy and were closed because a cytoreduction could not be performed because of the extensive involvement of the small bowel. There were no operative deaths. The overall morbidity was 32 per cent. Six (24%) patients had a Grade III complication and two (8%) patients had a Grade IV complication. There were 17 patients with no Grade III and no Grade IV complications (Table 5). Mean follow-up was 21 months. Cox Proportional-Hazards regression was used to measure and test the impact that a number of factors had on survival. Age, gender, and length of hospital stay were not statistically significantly related to survival. The completeness of cytoreduction score approached but did not reach statistical significance, with patients with a CC score of 3 being 7.9 times as likely to die as a patient with a CC score of 1 (P = 0.068). The group that a patient was in was statistically related to survival. Patients in Group 2 were 6.1 times more likely to die than patients in Group 1 (P = 0.028), and patients in Group 3 were 48.0 times more likely to die than patients in Group 1 (P = 0.001). Similarly, patients in Group 3 were 7.8 times more likely to die than patients in Group 2 (P = 0.029). Median survival for Group 1 and Group 2 has not yet been reached, but it is greater than the 22 months in Group 1 and greater than the 20 months but less than the 2 years in Group 2. Median survival for Group 3 patients was 5 months.
TABLE 1. Surgical Scoring
TABLE 2. Clinical Presentation
TABLE 3. Pathology
TABLE 4. CC-Scores
TABLE 5. Morbidity and Mortality
Cytoreductive surgery and intraperitoneal hyperthermic chemotherapy are playing an ever-increasing role in the treatment of patients with peritoneal carcinomatosis of gastrointestinal origin. Results of this treatment modality are being reported from centers around the world. In addition, the morbidity and mortality from this procedure has improved significantly and is no different than any other major gastrointestinal \or hepatobiliary operation for cancer.
This study reports the results of our peritoneal surface malignancy center treating peritoneal carcinomatosis of appendiceal origin. A critical review of our early experience warrants further discussion.
There were four (16%) patients that were opened and closed, and only 56% of the patients (14/25) were able to have the cytoreductive surgery and the intraperitoneal hyperthermic chemotherapy. These numbers represent a combination of inadequate patient selection criteria and that cytoreductive surgery with intraperitoneal hyperthermic chemotherapy is a complex procedure with a very steep learning curve. None of those four patients that were opened and closed survived 24 months.
In Group 1, there were 8 of 14 (57%) patients with complete cytoreductions, CC-1. Five of those 8 patients had a massive cytoreductive surgery (operating room time greater than 10 hours) with intraperitoneal hyperthermic chemotherapy. All five patients are alive and four of five (80%) are with no evidence of disease at a follow-up greater than 24 months. It is important to mention that of the four patients that were excluded from the study because they did not have surgery, three had the diagnosis of a low-grade mucinous adenocarcinoma and were still alive at the time this article was written. The other patient had a high-grade mucinous adenocarcinoma and died 4 months after diagnosis.
Also, recurrence of low-grade mucinous adenocarcinomas of the appendix even after a complete cytoreduction is not an uncommon event.5 This relapse has been correlated with a number of clinicopathological parameters, including extent of initial disease, histology, adequacy of cytoreduction, the use of intraperitoneal chemotherapy, and other factors. Still, the ability to inhibit mucin reaccumulation would transcend all of these prognostic factors. As pointed out by O'Connell et al.,6 they can think of no setting more appropriate for new translational approaches than that offered by Pseudomyxoma peritonei where MUC2 is the clear target and is the cause of the disease's morbidity and mortality.
Our current approach for patients with low-grade mucinous adenocarcinomas of the appendix is to perform the best ostomy- sparing cytoreductive surgery with intraperitoneal hyperthermic chemotherapy followed by systemic chemotherapy if gross disease was left behind. However, sometimes the only way to achieve an adequate cytoreduction will be to perform a total abdominal colectomy with an end ileostomy.
When it comes to high-grade mucinous and nonmucinous appendicial cancer, our current review shows that we were able to achieve a complete cytoreduction in only two of eight patients in Group 2. At a mean follow-up of 21 months, these were the only two patients from Group 2 that were alive. In Group 3, all patients had only surgical debulking and no intraperitoneal hyperthermic chemotherapy because of bulky disease left behind. None of these patients lived more than 9 months. It is clear that this group of patients did not benefit from our surgical procedure.
As a result of these experiences, we have refined our selection criteria, making every possible effort to take patients with high- grade tumors of the appendix to the operating room only if we think that an adequate cytoreduction can be achieved. That has decreased our open and close rate for peritoneal carcinomatosis from appendicial cancer to 3 per cent in our latest 33 cases.
Also, there has been significant improvement of the armamentarium with systemic chemotherapy. The combination of cytotoxic chemotherapy with biological agents has resulted in a median survival of more than 20 months in patients with metastatic colorectal cancer.7 Unfortunately, there is no data regarding the use of these therapeutic combinations in the treatment of peritoneal carcinomatosis from appendicial cancer. Whether these new regimens should be used in a neoadjuvant or adjuvant setting in asymptomatic patients with high-grade appendicial cancer warrants further evaluation.
In summary, it appears that the prognosis of patients and the responses to cytoreductive surgery and intraperitoneal hyperthermic chemotherapy depend on the histology, the degree of malignant transformation that is present in the appendiceal tumors, and the adequacy of the cytoreductive surgery, and only with a continuous interaction between medical and surgical oncologists will we be able to identify the right sequence of our therapeutic treatment modalities.
1. Esquivel J, Sugarbaker PH. Clinical presentation of the Pseudomyxoma peritonei syndrome. Br J Surg 2000;87:1414-8.
2. Gough DB, Donohue JH, Schutt AJ, et al. Pseudomyxoma peritonei. Long-term patient survival with an aggressive regional approach. Ann Surg 1994;219:112-9.
3. Sugarbaker PH, Chang D. Results of treatment of 385 patients with peritoneal surface spread of appendiceal malignancy. Ann Surg Oncol 1999;6:727-31.
4. 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 multi-institutional study. J Clin Orthod 2004; 22:3284-92.
5. Esquivel J, Sugarbaker PH. Second-look surgery in patients with peritoneal dissemination from appendiceal malignancy. Analysis of prognostic factors in 98 patients. Ann Surg 2001;234: 198-205.
6. O'Connell JT, Tomlinson JS, Roberts AA, et al. Pseudomyxoma peritonei is a disease of MUC2-expressing goblet cells. Am J Pathol 2002;161:551-64.
7. Hurwitz H, Fehrenbacher L, Novotny W, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 2004;350:2335-42.
Presented at the Annual Scientific Meeting and Postgraduate Course Program, Southeastern Surgical Congress, Lake Buena Vista, FL, February 18-21, 2006.
Address correspondence and reprint requests to Jesus Esquivel, M.D., F.A.C.S., Surgical Oncology, St. Agnes Hospital, 900 Caton Avenue, Baltimore, M.D. 21229.
EDWARD A. LEVINE, M.D. (Winston-Salem, NC): This paper represents an initial experience with cytoreductive surgery and intraperitoneal hyperthermic chemotherapy for peritoneal carcinomatosis from an appendiceal primary.
The absence of mortality is quite impressive with this initial experience of 25 patients undergoing this arduous procedure. Distributions of patients with low-grade versus high-grade tumors is quite similar to that of larger centers, and the major morbidity rate of 32 per cent is quite reasonable for operative procedures of this magnitude. However, the rate of complete, or nearly complete, CC-1 cytoreduction was only 40 per cent, which is significantly lower than that seen in other centers.
I have several questions for the authors. First, in the paper, the authors describe limiting cytoreductive procedures to perform the "best ostomy sparing cytoreduction." Having worked for some time in this field and having spent significant efforts in trying to quantify quality of life in these patients, I certainly understand the desire to avoid a stoma. However, the adverse impact of a stoma pales in significance to unsalvageable recurrent peritoneal disease. How are patients chosen for resection mandating a stoma or a stoma sparing procedure?
Second, the authors seem to suggest that only with CC-1 procedures was the intraperitoneal chemotherapy delivered. We, and others, have wrestled with perfusion of selected patients with R2a, or as the author calls them, low-volume CC-2 disease. Our patients with residual disease less than 5 mm in size are perfused and not simply observed. How much residual disease will the authors tolerate and continue with the chemoperfusion?
Finally, the authors suggest, and I would agree, that systemic therapy is needed for patients with high-grade lesions whether mucinous or not. Although patients with appendiceal tumors treated with cytoreductive surgery and intraperitoneal hyperthermic chemotherapy have survivals three times that of those with colorectal cancers, the high-grade lesions behave very much like colorectal adenocarcinomas in this setting. That being the case and with the recent improvements in systemic chemotherapy for colorectal carcinomas with the availability of agents such as oxaliplatin, irinotecan, and avastin, I ask the authors: would procedures be best performed before or after initial systemic therapy?
Dr. Esquivel and his colleagues bring significant experience to this vexatious problem, and I look forward to their responses.
JESUS ESQUIVEL, M.D. (Clarksville, MD; Closing Discussion): Regarding the first question, what we are currently doing for patients with low-grade mucinous tumors is to try to perform what we call "The Boss," the Best Ostomy-Sparing Surgery. That is only for patients with a true pseudomyxoma. We have been able to spare many of the right colon resections for pseudomyxoma. We do not believe that a right colectomy is necessary for patients with pseudomyxoma. We have been able to remove the peritoneum from the right colon and the pelvic peritoneum, including the cul-de-sac in patients who have small-volume disease in these regions. If the patient has disease that is extensive, there is no way to remove that peritoneum. Previously, our approach was to do a resection, and some of those patients ended up with an ostomy, whether it was temporary or permanent. Now, we try very hard to eliminate the tumor without having to do an ostomy. For high-grade tumors, there is no way you can remove the cul-de-sac and remove the pelvic peritoneum without having to do a resection.
Regarding the second question of when do we decide to do a perfusion, in our most recent review, we had about 97 per cent perfusion rate for appendicial cancer on our last 33 cases in Baltimore.
In terms of whether you should do systemic chemotherapy before or after, I do not know the answer to th\at. I think that if the patient presents to us with a very large abdomen and having repeated paracenteses, preparing the patient for the best systemic chemotherapy will be a more reasonable approach rather than giving the patient, who is not even able to eat, a combination of cytotoxic and biologic agents.
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