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Original Article |
Peritoneal Surface Malignancy Program, Washington Cancer Institute, Washington Hospital Center, 106 Irving Street, NW, Suite 3900N, Washington, DC 20010, USA
Correspondence: Address correspondence and reprint requests to: Dr. Paul H. Sugarbaker, MD; E-mail: Paul.Sugarbaker{at}medstar.net
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Methods: This prospective morbidity and mortality assessment was performed on 70 consecutive cytoreductive procedures with perioperative intraperitoneal chemotherapy for DMPM. Forty-seven adverse events by eight categories were rated from grades I to IV with increasing severity. Grade I morbidity was self-limiting; grade II required medical treatments; grade III required an invasive intervention; grade IV required returning to the operating room or intensive care management. Risk factors for grades III and IV morbidity were determined.
Results: The perioperative mortality rate was 3%. The grades III and IV morbidity rates were 27 and 14%, respectively. Primary colonic anastomosis (P = 0.028), more than four peritonectomy procedures (P = 0.015), duration of the operation of more than 7 h (P = 0.027) were the risk factors for grade IV morbidity. Survival analysis of these 70 patients was provided.
Conclusions: The morbidity and mortality results for cytoreductive surgery and perioperative intraperitoneal chemotherapy for patients with DMPM were within the acceptable range for major gastrointestinal surgery. Grade IV morbidity was associated with more extensive cytoreduction.
Key Words: Morbidity and mortality • Peritoneal mesothelioma • Asbestos • Cytoreduction • Perioperative intraperitoneal chemotherapy • Peritonectomy
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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The purpose of this study is to report the morbidity and mortality associated with the combined treatment for a single diagnosis, DMPM. The correlations of preoperative and operative factors with moderate to severe morbidity outcomes were sought to allow more knowledgeable patient selection. As a result of these data modifications in patient management and thereby a reduction in morbidity and mortality is expected.
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PATIENTS AND METHODS |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Patient Selection
This prospective database on morbidity and mortality for patients with peritoneal surface malignancies was maintained from January 1989 until October 2005. For this report, only patients with major cytoreductive surgeries that required peritonectomy procedures and/or visceral resections with heated intraoperative intraperitoneal chemotherapy were included. Procedures excluded were reoperative procedures with or without perioperative intraperitoneal chemotherapy, second look surgery, or ostomy closure. Also patients taken to the operating room for planned cytoreductive surgery combined with intra-peritoneal chemotherapy but having an "open and close" procedure were excluded. These eligibility requirements were designed to exclude patients with less extensive procedures from this assessment. In this database, there were 70 consecutive cytoreductive procedures with perioperative intraperitoneal chemotherapy which satisfied the inclusion and exclusion criteria.
Database
The database was designed specifically to evaluate patients treated for peritoneal surface malignancy. It consisted of 47 adverse events arranged within eight categories by organ system (Table 1
). For each adverse event, grades I–IV was assigned. In general, for a grade I adverse event, the diagnosis was established but no treatment was required. For grade II, the adverse event required medical treatment for resolution. For grade III, the adverse event was potentially serious but resolved conservatively with an invasive intervention. Often this consisted of a CT- or ultrasound-guided diagnostic or therapeutic procedure. For grade IV, the adverse event required a definitive urgent intervention, such as returning to the operating room or returning to the surgical intensive care unit (Table 2).
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Preoperative Management
All patients had preoperative physical examination and abdominal, pelvic and chest CT. Measurements of relevant tumor markers (e.g., CA 15-3, CA 19-9, CA 72-4, CA 125 and Carcino-embryonic antigen) were also obtained. Patients with good performance status were considered for surgery. Mechanical bowel preparation was performed in all patients. Oral antibiotics were not administered. Intrajugular or subclavian central venous catheters were inserted in all patients. Cefazolin 1 g every 4 h and metronidazole 500 mg every 4 h were began approximately 1 h prior to the surgical procedure and were continued throughout the cytoreduction.
Patients were positioned in lithotomy position with the legs extended in St. Mark’s leg-holders. The weight of the legs was directed to the soles of the feet by positioning on the footrests so that minimal weight was on the calf muscles. The calves were protected with foam padding to avoid possible myonecrosis and were then wrapped with alternating-pressure boots to prevent deep venous thrombosis. Shoulder braces were positioned so patients did not move on the table with steep Trendelenberg position.
Cytoreductive Surgery
The aim of cytoreductive surgery in these patients was to eradicate all macroscopic tumor deposits in the abdominal and pelvic cavities. The volume and extent of the tumor deposits were prospectively recorded in each of the 13 abdominopelvic regions using the peritoneal cancer index (PCI). It is an assessment combining lesion size (LS-0 to LS-3) with tumor distribution (AR-0 to AR-12), which quantifies the extent of disease as a numerical score (PCI-0 to PCI-39) (Fig. 1).24
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2.5 mm in diameter. CCR-2 indicated residual tumor nodule between 2.5 mm and 2.5 cm in diameter. CCR-3 indicated residual tumor modules >2.5 cm in diameter or a confluence of tumor nodules present at any site.
Hyperthermic Intraoperative Intraperitoneal Chemotherapy
After the cytoreduction was complete, but prior to intestinal anastomoses or repair of seromuscular tears, the abdomen and pelvis was instilled with cisplatin (50 mg/m2) and doxorubicin (15 mg/m2) in the operating room at approximately 42 °C in 3 L of 1.5% dextrose peritoneal dialysis solution for 90 min.8 The hyperthermic intraperitoneal chemotherapy solution was manually distributed to facilitate maximal contact and penetration of the chemotherapy into residual cancer cells. Following the completion of heated intraoperative intraperitoneal chemotherapy, bowel anastomoses, plication of seromuscular tears and then abdominal closure were performed. All anastomoses and bowel closures were hand-sewn with two-layer sutures, except for colorectal anastomoses, which were performed with a circular stapler of 33-mm diameter.
Closed-suction drains remained in place postoperatively in all patients. One drain was placed beneath the right hemidiaphragm, another beneath the left hemidiaphragm, and two were left in the pelvis. A fifth closed-suction drain was placed within the subcutaneous space in the midline abdominal wound. Thoracostomy tubes were used whenever a patient had a subphrenic peritonectomy. The tubes were removed in the second postoperative week as drainage diminished.
Early Postoperative Intraperitoneal Chemotherapy
The tubes and drains positioned for the heated intraoperative intraperitoneal chemotherapy were preserved for early postoperative intraperitoneal chemotherapy with paclitaxel at 20 mg/m2 per day in 1 L of 1.5% dextrose peritoneal dialysis solution or 6% hetastarch solution from postoperative days 1 to 5.8,25–27 After instillation gravity distribution of the chemotherapy solution was achieved by turning the patient from the full right lateral position to the full left lateral position and back every 30 min for the first 6 h. Patients were flat in bed in order to minimize pooling of chemotherapy solution in the pelvis. The intraperitoneal chemotherapy was allowed to dwell for 23 h and was then removed by closed suction drains over the course of 1 h. When the abdomen was cleared of fluid as completely as possible, the next instillation was commenced.
In this clinical pathway, by the intention to treat principle all patients were to receive early postoperative intraperitoneal chemotherapy with paclitaxel. However, in selected patients postoperative chemotherapy was not possible.
Postoperative Management
No antibiotics were used postoperatively except to treat a specific organism causing clinically significant infection identified in follow-up. The prophylaxis for venous thrombosis and pulmonary embolus was limited to the use of sequential compression devices that were applied to the legs. These sequential compression devices were utilized throughout the hospitalization except when the patient was ambulating or up in the chair. No prophylactic anticoagulants were used; intravenous heparin was used to treat an identified venous thrombosis or pulmonary embolus. Filgastrim (Amgen, Thousand Oaks, CA, USA) was used if the total white blood cell count fell below 2,000. The treatment was with 400 mcg a day until neutrophil counts returned to normal. Granulocyte colony stimulating factors were not used prophylactically. No pre- or post-splenectomy vaccinations were ordered on any of these patients. All patients received postoperative total parental nutrition until their caloric intake was adequate. Patients were followed at 6-monthly intervals by CT to monitor their disease.
Statistical Analysis
The institutional review board granted permission to perform and analyze the clinical data on these patients with DMPM. Twenty-eight clinical and treatment-related factors were analyzed for an association with grades III and IV perioperative morbidity, respectively. Categorical variables were compared using the 
2 analysis or Fisher’s exact test where appropriate. All statistical analyses were performed using the Statistical Package for Social Sciences for Windows (Version 11.5; SPSS GmbH, Munich, Germany). A significant difference was defined as P < 0.05. Survival analysis was performed using the Kaplan–Meier method. Survival was determined from the time of cytoreductive surgery and perioperative intraperitoneal chemotherapy.
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RESULTS |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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demonstrates the patient characteristics.
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Morbidity
The mean operative duration was 8 + 2 h. The mean intraoperative blood loss was 590 + 730 cm3. The mean length of hospital-stay was 23 + 12 days. Table 4 demonstrated the extent of cytoreductive surgery and the type of perioperative chemotherapy treatments in these 70 patients. Forty-six of the 70 patients (66%) had both heated intraoperative intraperitoneal chemotherapy and early postoperative intraperitoneal chemotherapy as perioperative intraperitoneal chemotherapy. Early postoperative intraperitoneal chemotherapy with paclitaxel was withheld in 24 patients. Indications not to use postoperative chemotherapy included postoperative bleeding (n = 5); postoperative respiratory instability (n = 3); other grade IV postoperative complications (n = 2); chemotherapy agent not available (n = 9) and low leukocyte cell count related to extensive prior chemotherapy (n = 5). Overall 29 patients (41%) had no adverse events.
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Morbidity by grade
The overall grade III morbidity rate was 27%. Thirty grade III adverse events were found in 19 patients. In some patients there was more than one grade III adverse event (Fig. 2). Low hemoglobin level (between 6.5 and 7.9) was responsible for 26% of the grade III adverse events. Central line sepsis was responsible for 17% of grade III adverse events. Urinary tract infection with elevated temperature and leucocytes accounted for 13% of the grade III adverse events. Respiratory distress requiring endotracheal intubation, dehydration requiring intravenous therapy and delirium each accounted for 7% of the grade III adverse events. Other grade III adverse events included stroke (n = 1), pleural effusion (n = 1), thrombocytopenia (n = 1) and pulmonary embolism (n = 1). The grade III pulmonary embolism was a result of central venous catheter-related thrombosis, which required removal of the central venous catheter.
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). Postoperative bleeding requiring urgent return to the operating room represented 38% of grade IV adverse events. Respiratory failure requiring orotracheal intubation was responsible for 22% of grade IV adverse events. Pulmonary embolism, anastomotic leak, pancreatic leak, duodenal leak and bile leak each contributed 8% of grade IV adverse event. The patient with grade IV pulmonary embolism was hemodynamically unstable and required a return to the intensive care unit.
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shows the influence of the clinical factors on grades III and IV morbidity. There were no clinical factors significantly associated with either grade III or IV morbidity.
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shows the influence of the treatment-related factors on grades III and IV morbidity. Three treatment-related factors were identified as significant risk factors for grade IV morbidity. They were primary colonic anastomosis (P = 0.028), more than four peritonectomy procedures (P = 0.015), and duration of operation of more than 7 h (P = 0.027).
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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We are pleased at these results that show that DMPM can be treated as other peritoneal surface malignancies with cytoreductive surgery and perioperative intraperitoneal chemotherapy. The mortality of 3 and 14% grade IV morbidity in patients who underwent major cytoreductive surgery and perioperative intraperitoneal chemotherapy (reoperative surgery and exploratory laparotomy were excluded) compare favorably to reports on other diseases treated in a similar manner. The cytoreduction in these patients was extensive as shown in Table 4
, and heated intraoperative intraperitoneal chemotherapy was utilized in all patients. Forty-six patients had intraoperative plus early postoperative intraperitoneal paclitaxel. As shown in Table 6, addition of early postoperative intraperitoneal chemotherapy for the first five postoperative days did not increase morbidity when it was used selectively. Taken in the context of the results of other studies assessing survival outcomes with the combined treatment in patients with DMPM,4,6–13 this study suggests that this approach is a feasible option in selected patients treated at a high-volume center.
Cytoreductive surgery in DMPM patients required a large number of peritonectomy procedures and visceral resections. The extent of the surgery was correlated with grade IV morbidity. Also, the duration of surgery was correlated with grade IV morbidity. In our study as in previous reports the extent of tumor involvement and a requirement for a prolonged surgery caused an increased incidence of grade IV morbidity.2,4,15
Often the small bowel, colon and mesentery are so extensively involved that only option is to perform a bowel resection rather than to cytoreduce individual tumor nodules. However intestinal anastomosis is a high-risk procedure because intraperitoneal chemotherapy inhibits wound healing and the surgery removes the peritoneum, which is the primary defense barrier for infection. Especially in a primary colonic anastomosis there is an increase risk of anastomotic leak and sepsis. These adverse events in the setting of immune suppression as a result of intraperitoneal chemotherapy can be lethal. It is sometimes necessary to avoid an unprotected primary colorectal anastomosis in patients receiving perioperative intraperitoneal chemotherapy and consider ostomy construction with closure at a later time.
The relationship of the surgical procedures to subsequent morbidity may not be completely straightforward. For example, there was grade III morbidity in 9 of 25 patients having a colectomy with a low colorectal anastomosis; also, seven of the patients with grade IV morbidity had a low colorectal anastomosis (Table 6). In Fig. 3, it is shown that there is only a single colorectal anastomotic leak. One is forced to conclude that colectomy with primary colorectal anastomosis has an adverse effect on morbidity over and above its specific relationship to anastomotic leak. These grade IV adverse events associated with colectomy and anastomosis may be related to more extensive cytoreductive surgery and prolonged operative duration.
The grade III morbidity rate was 27%; more knowledgeable postoperative care may decrease this statistic. Low hemoglobin level of 6.5–7.9 represented 26% of grade III adverse events. This is often a hemodilution effect, in that patients were given a large volume of intravenous fluid during the administration of intraperitoneal chemotherapy in order to avoid renal toxicities. In addition, absorption of intraperitoneal chemotherapy carrier solution will contribute. More timely blood transfusion and less intraoperative fluid will decrease this grade III morbidity. Central line sepsis was responsible for 17% of grade III adverse events. This is related to the long-term administration of total parental nutrition in patients with immune suppression from chemotherapy. Improved central line access with Per Q Cath (Bard, Salt Lake City, UT, USA) and the routine use of Bio-patch (Johnson and Johnson, Somerville, NJ, USA) have been initiated. Urinary tract infection caused 13% of the grade III adverse events. In patients with pelvic peritonectomy, a Foley catheter was required for at least 10 days; this increased the likelihood of urinary tract infection. More adequate emptying of the Foley catheter tubing may reduce urine stasis in the bladder. In the univariate analysis, no risk factors were identified to be significantly associated with grade III morbidity.
Although this is the largest series of morbidity/ mortality in patients with DMPM the number of patients is limited. It is difficult and sometimes impossible to see the relationship between the clinical factors and the treatment-related morbidity. Surgical judgments regarding the management of these patients may be facilitated by this study but certainly not all the questions can be answered. For example, in these patients would it be more prudent to avoid a low colorectal anastomosis and avoid the increased morbidity that goes with this procedure? One would do this realizing that some disease would be left behind in the pelvis. This would work to diminish morbidity and mortality, but may concomitantly have an adverse effect on long-term survival.
It is appropriate for the surgeon to attempt to use these date regarding morbidity and mortality to better select patients to be treated by combined cytoreductive surgery and perioperative intraperitoneal chemotherapy. Our approach involves 7–12 h in the operating room, chemotherapy in the operating room, chemotherapy in the early postoperative period and a long hospitalization requiring multiple tubes and drains and prolonged use of central venous lines for parenteral feeding. Not measured in this study, but an important issue is the time to full recovery and return to work. One of the surgeons important pre-operative responsibilities is to determine the patients overall physical and mental condition, to estimate the morbidity/mortality for the individual patient, and the benefits likely to be achieved by these treatments. A part of the judgment to move ahead with the combined treatment involves the possible benefits from alternative treatments such as systemic chemotherapy or best supportive care. If a treatment is considered to have curative intent the risks tolerated are greater than if there is palliative intent. This manuscript cannot complete the balance of this surgical equation. It does establish that this approach is associated with mortality (3%) and a life-threatening morbidity (14%) requiring urgent intervention with return to the operating room or intensive care. It does show that the most common grade IV events were postoperative hemorrhage and respiratory failure. These data suggest that patients with a hemorrhagic diathesis or a requirement for continuous anticoagulation should be excluded from extensive peritonectomy. Patients with compromised pulmonary function should be excluded. In some patients who are thought to present a greater risk, limitations of the extent of surgery should be considered because the requirement for an anastomosis, extent of peritonectomy and duration of operation were the risk factors for grade IV morbidity.
The relationship of the morbidity and mortality for the treatment of peritoneal mesothelioma is favorable when compared to that for other peritoneal surface malignancies. Elias and colleagues in 2001 reported 64 patients treated for colorectal carcinomatosis who had a 65% morbidity and a 9.3% mortality.16 Also, Verwaal et al.20 in reporting on 102 colorectal carcinomatosis patients had a 35% morbidity and a 7.8% mortality. Our morbidity and mortality data and the accompanying survival would suggest that cytoreductive surgery with perioperative intraperitoneal chemotherapy is a reasonable treatment option for DMPM.
There are now Food and Drug Administration-approved treatment protocols using systemic pemetrexed plus cisplatin.28–30 A recent nonrandomized study demonstrated a median survival of 13 months and 1-year survival of 66% in 66 DMPM patients treated with systemic pemetrexed and cisplatin, versus 9 months and 0% in the respective survival for 32 DMPM patients treated with systemic pemetrexed alone.28 From the limited data, it is difficult to extrapolate any definitive conclusions regarding the efficacy of this combined systemic treatment, but further research is warranted. It is likely that systemic chemotherapy for this disease may show additional benefit. With the data currently available the median survival of 13 months for this disease using systemic chemotherapy as compared to 40–90 months using combined cytoreductive surgery plus perioperative intraperitoneal chemotherapy calls for this comprehensive approach to be considered as option. Patient selection is as always an important issue. This manuscript may help to match the patient with a treatment of appropriate risk.
In conclusion this study showed that the perioperative outcomes of cytoreductive surgery and perioperative intraperitoneal chemotherapy for patients with DMPM were within acceptable range for major gastrointestinal surgery. Primary colonic anastomosis, more than four peritonectomy procedures and more than 7 h of surgery were associated with grade IV morbidity.
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ACKNOWLEDGMENTS |
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Received for publication July 3, 2006. Accepted for publication July 4, 2006.
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REFERENCES |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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