10.1245/s10434-006-9186-6
Annals of Surgical Oncology 13:1627-1632 (2006)
© 2006 Society of Surgical Oncology
Toxicity and Quality of Life after Cytoreductive Surgery Plus Hyperthermic Intraperitoneal Chemotherapy
Todd M. Tuttle, MD, MS1,
Yan Zhang, MS2,
Edward Greeno, MD3 and
Amy Knutsen, MD1
1 Division of Surgical Oncology, University of Minnesota Medical Center, 420 Delaware Street SE, Minneapolis, MN 55455, USA
2 Biostatistics Core, University of Minnesota Cancer Center, 420 Delaware Street SE, Minneapolis, MN 55455, USA
3 Division of Hematology, Oncology, and Transplantation, University of Minnesota, Minneapolis, MN, USA
Correspondence: Address correspondence and reprint requests to: Todd M. Tuttle, MD, MS; E-mail: tuttl006{at}umn.edu
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ABSTRACT
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Background: The purpose of our study was to determine the toxicity and quality of life for patients with peritoneal metastases after cytoreductive surgery (CS) plus hyperthermic intra-peritoneal chemotherapy (HIPC).
Methods: From 2001 to 2005, 35 consecutive patients with peritoneal metastases enrolled in a prospective trial approved by the University of Minnesota Institutional Review Board. Their primary cancer sites included the appendix (19 patients), colon (7), mesothelioma (3), stomach (2), small bowel (2), gallbladder (1), and unknown (1). We performed CS in an effort to remove all or nearly all peritoneal tumor nodules. Using a closed technique, we administered hyperthermic mitomycin C into the peritoneal cavity for 90 min. Before treatment and then at 4-month postoperative intervals, we used the functional assessment of cancer therapy-colon subscale (FACT-C) instrument to assess the patients’ quality of life.
Results: The median hospital stay was 9 days; 12 patients were hospitalized at least 30 days or required readmission within 30 days after treatment. The postoperative mortality rate was 0%; adverse events occurred in 18 (51%) patients. As of December 2005, 20 patients were alive; 14 had died of progressive disease and 1 of an unrelated cause. The median survival time was 21.4 months. Quality of life measurements, including trial outcome index (TOI), FACT-colon, and FACT-general, returned to baseline 4 months after treatment and were significantly improved at 8 and 12 months.
Conclusions: Despite early toxicity, CS plus HIPC may prolong the overall survival rate of patients with peritoneal metastases and improve quality of life measurements.
Key Words: Peritoneal metastases • Cytoreductive surgery • Hyperthermia • Intraperitoneal chemotherapy • Quality of life
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INTRODUCTION
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Usually, cancer patients with peritoneal metastases die within a few months after diagnosis, have a poor quality of life, and are debilitated by bowel obstruction, malignant ascites, dyspnea, and pain. For patients with peritoneal metastases from gastrointestinal malignancies, the outcomes of systemic chemotherapy have been unsatisfactory. Thus, some investigators have recently combined two modalities: (1) cytoreductive surgery (CS), a systematic attempt to remove all or nearly all peritoneal tumor nodules, and (2) hyperthermic intraperitoneal chemotherapy (HIPC) administered immediately after CS to treat residual microscopic disease. The results from non-randomized single- and multi-center studies suggest that this aggressive regional treatment – CS plus HIPC – may improve the survival rate for selected patients with peritoneal metastases.1–4 A recent prospective randomized trial from The Netherlands demonstrated that CS plus HIPC with mitomycin C improved the survival rate of patients with peritoneal metastases from appendiceal and colorectal cancer.5 Despite the potential survival benefit, the combination of CS plus HIPC is currently associated with significant morbidity and with mortality rates as high as 12%.6 Complications include enteric fistula, intraabdominal abscess, pneumonia, small bowel obstruction, pancreatitis, and neutropenia. As a result, hospital stay is often prolonged and overall recovery may require several months. Thus, any survival benefit must be measured against early and late morbidity of the treatment. The morbidity rates from recent retrospective studies were reported to be about 25%.3,6–8 However, the actual morbidity rates may be substantially higher in prospective studies. For instance, in prospective clinical trials conducted at The Netherlands Cancer Institute, Verwaal et al.9 reported that 65% of patients developed grade 3, 4, or 5 toxicity. Such toxicity can cause significant impairment in short- and long-term quality of life. The specific aims of our study were: (1) to determine prospectively the morbidity and mortality rates of CS plus HIPC, and (2) to determine prospectively the overall quality of life after CS plus HIPC.
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METHODS
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Our phase II study, approved by the Institutional Review Board at the University of Minnesota, included 35 patients with peritoneal metastases. For each patient, the presence of peritoneal metastases was determined by computed tomography (CT) findings or by a tissue diagnosis. None of the patients had undergone previous abdominal radiation or intraperitoneal chemotherapy; none of them had uncontrolled cardiovascular disease. They were otherwise healthy with no radiographic evidence of extraabdominal metastatic disease. All patients had a Karnofsky score of >80%. Additional inclusion criteria were granulocyte count >1,500, platelet count >100,000, serum bilirubin <1.5, serum creatinine <1.5, and serum albumin >3.0. All 35 patients underwent CS to remove all or nearly all peritoneal nodules. Peritonectomy procedures, performed according to Sugarbaker’s guidelines, included resection of least one of the following organs: stomach, small bowel, large bowel, liver, omentum, spleen, gallbladder, uterus, or ovary.10 We evaluated the effectiveness of CS by the completeness of cytoreduction (CC) scale, as described by Sugarbaker; CC-0, no residual peritoneal tumor nodules are seen; CC-1, residual tumor nodules <2.5 mm; CC-2, residual tumor nodules between 2.5 mm and 2.5 cm; CC-3, residual tumor nodules >2.5 cm or a confluence of unresectable tumor nodules at any site.1 After CS, patients were prepared for HIPC. Two inflow catheters were placed in the upper quadrants; two outflow catheters, in the lower quadrants and pelvis. Inflow temperature probes were inserted in the upper abdomen; outflow temperature probes in the lower abdomen. The skin was then closed with a running nylon suture. Once the peritoneal temperatures reached 40 °C, mitomycin C was infused over 90 min through the ViaCirq (ThermaSolutions, Canonsburg, PA, USA) peritoneal perfusion unit. For our first 16 patients, we administered a fixed dose of mitomycin C (30 mg). For the remaining 19 patients, we based the dose of mitomycin C on body surface area (35 mg/m2); this amended protocol prescribed doses of mitomycin C higher than 30 mg (mean, 61 mg). Throughout the perfusion, we rotated the operating table every 10 min and the abdomen was agitated, in order to allow even exposure of peritoneal surfaces to the heated chemotherapy. After the infusion and irrigation with 2 l of normal saline, we completed the anastomoses. We identified and recorded all adverse events prospectively. Hospital readmission for any reason was considered an adverse event. About 2 weeks after their hospital discharge and then every 4 months after treatment, patients came in to our clinic for checkups. Every 4 months, they underwent abdominal and pelvic CT. The relationships of age, gender, operative time, preoperative ascites, number of resected solid organs, and mitomycin C dose to the occurrence of adverse events were evaluated using logistic regression. The final model containing the most significant predictors for adverse events was determined using the stepwise selection method. Before treatment and at 4-month postoperative intervals, we used the functional assessment of cancer therapy-colon subscale (FACT-C) (version 4) instrument.11 The FACT-C includes five subscales: physical well being (PWB), social and family well being (SWB), emotional well being (EWB), functional well being (FWB), and a colon cancer subscale (CCS). Higher scores indicate a higher quality of life. The trial outcome index (TOI) is calculated by adding PWB+FWB+CCS; the FACT-general (FACT-G) score, by adding PWB+FWB+SWB+EWB; the FACT-C score, by adding PWB+FWB+SWB+ EWB+CCS. The effects of time on these scores were evaluated using single-factor repeated-measures models. The multiple pairwise comparisons at four-time intervals were performed using the Tukey’s method.12 In addition, the relationships of age, gender, diagnosis (appendiceal malignancy versus non-appendiceal), CC scores (0–1 vs. 2–3), operative time, preoperative ascites, mitomycin C dose, number of resected organs, and the occurrence of adverse events to the changes in total FACT-C scores between 12 months and baseline were evaluated using the Spearman correlation coefficients. SAS Version 9.1 (SAS Institute, Cary, NC, USA) was used for statistical analyses. A test result with a p value of less than 0.05 was considered statistically significant.
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RESULTS
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Patient characteristics are listed in Table 1
. The median operative time was 423 min; median estimated blood loss, 300 cm3; median hospital stay, 9 days (mean, 13.9 days). Of the 35 patients, 12 were hospitalized at least 30 days or required readmission within 30 days after treatment. The treatment-related mortality rate was 0%. Adverse events occurred in 18 (51%) patients (Table 2). Using univariant regression models, we evaluated age, gender, operative time, preoperative ascites, number of resected solid organs, and mitomycin C dose each as a potential predictor of the occurrence of adverse events (Table 3). Mitomycin C dose >30 mg was the only variable significantly associated with the occurrence of adverse events in the final logistic regression model. Patients treated by mitomycin C dose >30 mg were significantly more likely to have adverse events then those treated by mitomycin C dose <30 mg (odds ratio: 8.4; 95% CI: 1.8 38.6; p=0.0062). The higher dose of mitomycin C induced bone marrow suppression in a significant number of patients (data not shown) which may have contributed to higher rates of adverse events. The overall median survival time was 21.4 months after CS plus HIPC. As of December 2005, 20 patients are alive; 14 had died of progressive disease and 1 of an unrelated cause. Quality of life scores measured at baseline and 4, 8, and 12 months after treatment are summarized in Table 4. Except for SWB, quality of life scores had significant or close-to-significant increases across the four measuring time points. At 4 months after treatment, most scores had returned to preoperative levels, but then increased at 8 and 12 months. The occurrence of an adverse event correlated with significantly smaller increases in the FACT-C scores from baseline to 12 months after treatments (Spearman correlation coefficient = –0.64, p=0.0352). Other factors such as age, gender, diagnosis (appendiceal malignancy versus non-appendiceal), CC scores (0–1 vs. 2–3), operative time, number of organs resected, and preoperative ascites were not associated with FACT-C scores.
Received for publication June 8, 2006.
Accepted for publication June 14, 2006.
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ABSTRACT
INTRODUCTION
