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ORIGINAL ARTICLES |
From the Colorectal Service, Department of Surgery (ATC, ADB, JGG, WDW, PBP), the Division of Medical Oncology, Department of Medicine (SS, LBS, GKS, EMO, DHI, NEK, DPK), Memorial Sloan-Kettering Cancer Center, New York, New York, and the Lucille P. Markey Cancer Center (AMC), University of Kentucky.
Correspondence: Address correspondence and reprint requests to: Philip B. Paty, MD, Colorectal Service, Department of Surgery, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021; Fax: 212-717-3678; E-mail: patyp{at}mskcc.org
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Methods: Patients having surgical debulking and IP 5-fluoro-2'-deoxyuridine (FUDR) plus leucovorin (LV) for peritoneal metastases from 1987 to 1999 were evaluated retrospectively.
Results: There were 64 patients with a mean age of 50 years. Primary tumor sites were 47 in the colon and 17 in the appendix. Peritoneal metastases were synchronous in 48 patients and metachronous in 16 patients. Patients received IP FUDR (1000 mg/m2 daily for 3 days) and IP leucovorin (240 mg/m2) with a median cycle number of 4 (range, 1–28). The median number of complications was 1 (range, 0–5), with no treatment related mortality. Only six patients (9%) required termination of IP chemotherapy because of complications. The median follow-up was 17 months (range, 0–132 months). The median survival was 34 months (range, 2–132); 5-year survival was 28%. Lymph node status, tumor grade, and interval to peritoneal metastasis were not statistically significant prognostic factors for survival. Complete tumor resection was significant on multivariate analysis (P = .04), with a 5-year survival of 54% for complete (n = 19) and 16% for incomplete (n = 45) resection.
Conclusions: Surgical debulking and IP FUDR for peritoneal metastases from colon cancer can be accomplished safely and has yielded an overall 5-year survival of 28%. Complete resection is associated with improved survival (54% at 5 years) and is the most important prognostic indicator.
Key Words: Colon cancer • Appendix cancer • Intraperitoneal chemotherapy • Cytoreduction
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Intraperitoneal (IP) delivery of chemotherapy offers a potential therapeutic advantage over systemic chemotherapy by producing high regional concentrations of drug while simultaneously minimizing systemic toxicities.3–6 Hyperthermic perfusion of the peritoneal cavity with a heated (42°C) solution containing either cisplatin or mitomycin has been performed in colorectal cancer patients. The perfusion is typically performed in the operating room under general anesthesia for 60 to 90 minutes. Pharmacological studies indicate that a 5- to10-fold higher drug concentration can be achieved in peritoneal fluid compared with systemic drug levels.7 However, penetration of drug into established tumors is limited, and use of peritoneal perfusion is generally restricted to patients for whom complete or near-complete surgical debulking can be accomplished.8,9 Sugarbaker and Sugarbaker et al.7,8,10–16 have reported a large experience with aggressive cytoreductive surgery combined with heated IP perfusion with mitomycin for metastatic colon and appendix cancers. The published data indicate a mortality risk of 1.5% to 5% and a perioperative morbidity of 27% to 35%. Major causes of mortality and morbidity are enteric fistula, pancreatitis, postoperative bleeding, hematological toxicity, and anastomotic leak.
An alternative approach is infusional IP chemotherapy in which the drug is infused after surgery via an indwelling IP catheter. The principal advantages of this method are a longer duration of drug exposure and the ability to give multiple cycles of treatment. The safety and efficacy of IP cisplatin have been well studied in ovarian cancer patients. In colon cancer patients, safety and pharmacokinetic data are available for IP 5-fluorouracil (5-FU) and IP 5-fluoro-2'-deoxyuridine (FUDR). After IP administration of FUDR, peak drug levels are 100- to 10,000-fold higher in peritoneal fluid compared with plasma.17 Moreover, peritoneal drug levels remain higher than plasma for >6 hours. Area under the curve calculations of regional drug exposure indicate a profound pharmacological advantage for IP delivery.17 Several centers have reported giving IP FUDR or 5-FU as a component of postoperative adjuvant therapy for patients with stage II and III colon cancer.18–21 However, there are few published data that describe the use of surgical debulking and infusional IP therapy for patients presenting with established peritoneal metastases.
For more than a decade at our institution, selected patients with established peritoneal metastases from colorectal cancer have been treated with surgical debulking and postoperative infusional IP FUDR and leucovorin (LV). We have retrospectively reviewed this experience and present the patient characteristics, results, and implications of our data.
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SUBJECTS AND METHODS |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Patients were evaluated before surgery by both a medical oncologist and a surgeon and judged to be potential candidates for IP chemotherapy. Consent for surgical debulking and placement of the IP port was obtained before surgery by the attending surgeon. Final patient selection for port placement was made in the operating room on the basis of the operative findings. The IP port consisted of an implanted device with a subcutaneous titanium reservoir and an IP single-lumen 14.3F silastic catheter (Bard Port®, product No. 0603006, Bard Access Systems, Salt Lake City, UT). The port was accessed transcutaneously with noncoring needles and was flushed with heparinized saline after each use. The timing, dose, and schedule of IP chemotherapy were selected by the medical oncologist.
Eight patients who had an IP port placed for metastatic colon cancer were not included in this review. Two patients had received IP etoposide rather than FUDR. Also excluded were six patients who had an IP port placed at the time of surgical debulking but who did not subsequently receive IP chemotherapy.
Complications
Complications were identified by chart review and recorded as reported in the medical record by the treating physicians. All complications related to surgical debulking and port placement were recorded. Complications that occurred after removal of the IP port were not included in this analysis.
Survival Analysis
Outcome data were obtained from medical records, clinical databases, and, when appropriate, patient interviews. Because date and sites of recurrence could not be reliably determined, no attempt was made to evaluate disease-free survival or patterns of recurrence. Survival interval was calculated from the date of initial IP port placement. Linear regression was used to evaluate association of patient and treatment variables with survival. Both univariate and multivariate analyses were performed. Survival curves were plotted with the Kaplan-Meier method,22 and differences were assessed by the log-rank test. The Cox proportional hazards model was used to determine the relative influence of covariates. Statistical analyses were performed by using SPSS software (SPSS Inc., Chicago, IL). A P value of 
.05 was considered significant.
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RESULTS |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Surgery
Before IP chemotherapy was started, all patients underwent surgical resection of primary large-bowel cancer and placement of an IP port. In 21 cases (33%) the IP port was placed at the initial surgery for removal of the primary colon or appendix cancer. In 43 cases (67%), the primary cancer had been resected at a previous operation. Table 3 lists the spectrum of procedures performed concurrently with IP port placement. The most common additional procedure was colon resection to remove either primary, locally recurrent, or metastatic disease involving the colon. A variety of procedures were performed to achieve tumor debulking, the most frequent being excision of peritoneal mass, omentectomy, hysterectomy, and small-bowel resection. Fulguration of peritoneal nodules was used as an adjunct surgical technique in nine patients.
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Chemotherapy
After tumor debulking, all patients received IP FUDR and LV. Treatment was generally initiated during the same hospitalization as port placement, most often on the second postoperative day (range, 1–10 days). Criteria for initiating treatment included a stable surgical closure of the abdominal fascia with adequate initial wound healing and an uneventful postoperative recovery.
The standard doses of FUDR and LV most often used were 1000 mg/m2 and 240 mg/m2, respectively. The drugs were mixed together in 1000 or 2000 ml of sterile saline, depending on body surface area, and given by gravity infusion through the IP port over approximately 1 hour. To promote drug distribution, patients were encouraged to remain supine for one or two additional hours and to shift position intermittently. The drugs were administered daily by IP infusion for three consecutive days, and each 3-day treatment constituted one cycle. Subsequent cycles were given every 2 weeks. The median number of administered cycles of IP chemotherapy was 4 (range, 1–28). Treatment was well tolerated; no patient had early termination of chemotherapy because of toxicity. Nausea and abdominal discomfort were the most common patient complaints. Fifty percent of patients received systemic intravenous (IV) chemotherapy either concurrently or after IP chemotherapy.
Complications
There were no deaths attributable to surgery or IP chemotherapy. Thirty-five patients (54%) had no documented complications. Overall, there were a total of 44 complications in the remaining 29 patients. Seventeen patients (27%) had one complication, nine patients (14%) had two complications, and three patients (5%) had three complications. Documented complications are listed in Table 4.
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Twenty-six complications occurred in 13 patients (20%) during subsequent IP chemotherapy. There were eight bowel obstructions requiring hospitalization, but only five required surgical intervention (lysis of adhesions). Six operations for IP port revisions were performed for various indications (inability to access catheter, angulation with poor flow, or occlusion). These were subcutaneous operations under local anesthesia, and in four cases the problems were successfully corrected. Three ports were removed because of occlusion (two cases) or infection (one case). Thus, overall four patients (6%) had premature termination of IP therapy as a result of a technical complication. The percentage of patients requiring reoperation for any reason was 23% (15 of 64), but the rate of repeat laparotomy was only 11% (7 of 64).
Survival Analysis
Median follow-up for the entire study group was 17 months. Sixteen patients (25%) were disease free, 21 patients (33%) were alive with disease, and 27 patients (42%) were dead at time of the analysis. All deaths were related to progressive disease. The survival curve for all patients is shown in Fig. 1. Median survival after placement of the IP port was 34 months, with an actuarial 5-year survival of 28%. On univariate analysis, complete resection was the only statistically significant variable (P = .04). Lymph node status, interval to peritoneal metastasis (synchronous vs. metachronous), location (appendix vs. colon), presence of liver or ovarian metastases, diagnosis of pseudomyxoma peritonei, duration of IP therapy, and concurrent or subsequent IV systemic chemotherapy were not significant factors for survival on univariate analysis (Table 5). On multivariate analysis, complete tumor resection was associated with significantly improved survival (P = .04). Patients who had an incomplete resection had a 2.5-fold higher hazard rate of dying from disease progression as compared with patients who had complete resection.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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The rationale for IP chemotherapy is to expose the peritoneal cavity to higher concentrations of cytotoxic drugs for longer durations than are possible with IV delivery.7 For tumors that will remain largely confined to the peritoneal cavity for most of their natural history, IP treatment could increase efficacy and reduce toxicity. These theoretical advantages have been well studied for cisplatin in the treatment of epithelial ovarian cancer. IP cisplatin has been studied as primary treatment in stage III disease, as consolidation therapy after primary treatment with IV cisplatin regimens, and as salvage therapy in both cisplatin-sensitive and cisplatin-resistant relapse. A survival advantage and reduced toxicity have been demonstrated in front-line treatment of stage III ovarian cancer in two randomized trials.25 For patients who have responded to front-line IV cisplatin but have small-volume residual disease, consolidation therapy with IP cisplatin has shown significant response rates (40% to 50%), and comparisons with historical controls suggest a survival benefit.26,27 As salvage therapy for IP recurrence of ovarian cancer treated initially with IV cisplatin, small studies have suggested a benefit for IP cisplatin only when the disease was sensitive to initial cisplatin therapy and when the disease could be surgically debulked to 1 cm or less residual disease.28
In this article, we have retrospectively evaluated our institutional experience with surgical debulking and infusional IP chemotherapy with FUDR and LV for patients with established metastatic spread of colon or appendix cancer to the peritoneal cavity. Although a survival advantage for this approach has never been documented in a prospective trial, our favorable experience with IP FUDR/LV used as a component of adjuvant therapy for resected primary colon cancer18 and the frequent failure of systemic treatment for peritoneal metastases prompted us to offer IP treatment to selected patients. It should be emphasized that the patients analyzed in this review were only those with established peritoneal metastases who were treated by surgical debulking and IP FUDR/LV for stage IV disease. Patients who received IP FUDR/LV in the adjuvant setting were not included in this review.
In this study, 80% of patients received IP FUDR/LV as a component of their initial cancer therapy. Our survival results, therefore, largely reflect the outcomes for colon cancers that are previously untreated and chemotherapy naive. Most peritoneal metastases were encountered synchronously with locally advanced primary large-bowel cancers, and spontaneous shedding of cancer cells into the peritoneal cavity from the primary tumor seemed to be the dominant route of spread. Ovarian metastases were extremely common (26 of 43 women; 60%), and this suggests that transperitoneal spread to the ovary contributed to development of ovarian metastases. Six patients with pseudomyxoma peritonei were included in the study group. Although these tumors represent a group with more indolent biology and favorable survival, because of their small number and relatively short follow-up they did not significantly influence the outcome of the entire study population. Median survival was unchanged when such patients were excluded from analysis. Finally, it is important to emphasize that patients included in this series seem to have a limited peritoneal tumor burden that was amenable to aggressive debulking. Although it was not possible in retrospect to quantify the extent of peritoneal disease, we did observe that 19 of 64 patients were completely debulked of all gross disease, and 63 of 64 patients had residual disease of <2 cm maximal diameter. In summary, our survival figures reflect a highly selected patient population with metastatic adenocarcinoma of the appendix or colon treated with up-front IP FUDR as a component of therapy.
Treatment was remarkably well tolerated. No patient died as a result of treatment, and the 18 perioperative complications consisted largely of minor infections. There was one anastomotic leak with a secondary IP port infection. The only complications leading to termination of IP therapy were one perioperative port infection, two late port malfunctions, and one late port infection. Therefore, only four patients (6%) were unable to continue IP therapy as a result of complications. Side effects from IP chemotherapy infusion were mild and self-limited. Our complication rates compare favorably with data reported for heated IP perfusion. Jacquet et al.29 have reported a 5% perioperative mortality, a 35% morbidity, and a 10% anastomotic leak rate.
The median survival of 34 months seen for all patients in this series is superior to that reported for stage IV colon cancer treated by systemic chemotherapy; this ranges from 8 to 15 months.23,24 In our patient population with metastatic disease largely confined to the peritoneal cavity, patient selection undoubtedly contributed to the prolonged median survival observed in this study. The younger age of patients included in the study may also have contributed to prolongation of survival. It is therefore not possible to determine accurately the extent to which treatment influenced the increased median survival. Because three 5-year survivors were seen in the incompletely resected group, it can be speculated that IP chemotherapy contributed to tumor control and survival in a subset of patients. Complete surgical removal of all gross disease was, however, the only factor identified on multivariate analysis that predicted an improved median and 5-year survival. We believe that the benefit of complete tumor removal may have at least three components: less extensive and less biologically aggressive metastatic disease at presentation, maximal cytoreduction of cancer cells, and increased efficacy of IP chemotherapy. Tumor location, lymph node status, duration of IP chemotherapy, and addition of systemic chemotherapy did not significantly influence overall survival. We believe that patients who appear on imaging studies or at operation to have peritoneal disease that is amenable to complete resection are the best candidates for this treatment approach.
Our survival results are similar to those presented for surgical debulking and heated IP chemotherapy with mitomycin reported by Sugarbaker.8 Although the rate of complete resection in that study was not reported, the overall treatment results (5-year survival, 40% for complete and 3% for incomplete resection) seem similar to our results. Although the median survival rates in these retrospective analyses are encouraging, long-term cure rates are low. In our study, there were seven 5-year survivors, but only three have no evidence of cancer (Table 6).
In considering the appropriate use of IP therapy for colon and appendiceal cancer, it is important to emphasize that our analysis indicates that such an approach will probably benefit only patients with minimal residual disease. It is clearly this population in which randomized trials evaluating IP and systemic chemotherapy are warranted. However, until data from such trials are available, it is not possible to define the role of IP chemotherapy for patients with large-bowel cancer. Our recommendation would be that patients with IP disease amenable to aggressive surgical debulking should be placed in appropriately designed clinical trials to further study the role of complete resection of peritoneal disease in combination with IP chemotherapies.
In the absence of a clinical trial, our current practice is to use combined systemic and IP chemotherapy. The sequencing of chemotherapy depends on the clinical presentation. For patients who are referred with peritoneal metastases that have been identified by imaging studies or at a previous operation, we recommend initial treatment with systemic chemotherapy. Surgical debulking and IP therapy are reserved for patients whose disease is stable or responsive to systemic chemotherapy. For those patients whose peritoneal disease is discovered at their initial operation and who have had both optimal tumor debulking and placement of an IP port, we favor a course of IP chemotherapy in the immediate postoperative period. After completion of three to six cycles of IP chemotherapy, patients then receive systemic chemotherapy.
In conclusion, the safety profile and survival data observed in this study are encouraging. We recommend further evaluation of the role of surgical debulking and IP therapy in appropriately designed clinical trials. Availability of other novel agents for IP use may also be a promising arena for development of this approach.
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Footnotes |
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Received for publication March 16, 2001. Accepted for publication July 3, 2001.
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REFERENCES |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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