J Gastrointest Surg DOI 10.1007/s11605-014-2477-5

ORIGINAL ARTICLE

Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy for Peritoneal Carcinomatosis: Outcomes from a Single Tertiary Institution Parissa Tabrizian & Brian Shrager & Ghalib Jibara & Ming-Jim Yang & Anya Romanoff & Spiros Hiotis & Umut Sarpel & Daniel M. Labow Received: 30 July 2013 / Accepted: 27 January 2014 # 2014 The Society for Surgery of the Alimentary Tract

Abstract Background Cytoreductive surgery (CRS) with heated intraperitoneal chemotherapy (HIPEC) is an effective but morbid procedure in the treatment of peritoneal carcinomatosis. We report our outcomes at a single tertiary institution. Method A total of 170 consecutive patients underwent CRS-HIPEC for peritoneal carcinomatosis between July 2007 and August 2012. The peritoneal cancer index (1–39) was used for peritoneal carcinomatosis (PC) staging. Mitomycin C (88.8 %) was administered intraperitoneally at 42 °C for 90 mins. Risk factors associated with major morbidities were analyzed. The KaplanMeier method was used for survival analyses. Results The mean age was 55.1 (±11.3) years, and the majority (77.1 %) of patients had complete cytoreduction (CC0-1). Tumor types included colorectal (n=51, 30.0 %), appendiceal (n=50, 29.4 %), pseudomyxoma peritonei (n=16, 9.4 %), and other (n= 53, 31.2 %). Factors associated with major complications were estimated blood loss (>400 ml), length of stay (>1 week), intraoperative blood transfusion, operative time (>6 h), and bowel anastomosis. Intraoperative blood transfusion was the only independent prognostic factor on multivariate analysis (p=0.031). Median follow-up was 15.7 months (±1.2). The recurrence rates for colorectal and appendiceal carcinoma at 1 and 3 years were 40 %, 53.5 % and 68 %, 79.1 %, respectively. The 1- and 3year overall survival for colorectal and appendiceal carcinomatosis was 74.0 %, 32.5 % and 89.4 %, 29.3 %, respectively. Intraoperative peritoneal cancer index (PCI) score (>16) and need for blood transfusion were factors independently associated with poor survival (p<0.05). Conclusion Our single institution experience of CRS/HIPEC procedures for peritoneal carcinomatosis demonstrates acceptable perioperative outcome and long-term survival. Optimal cytoreduction was achieved in the majority of cases. Intraoperative PCI>16 was associated with poor survival. This series supports the safety of CRS-HIPEC in selected patients. Keywords Hyperthermic intraperitoneal chemotherapy . Peritoneal carcinomatosis . Colorectal cancer . Outcome

P. Tabrizian (*) : M.
Introduction Peritoneal carcinomatosis (PC) has been traditionally regarded as the lethal endpoint of a variety of intra-abdominal tumors.1,2 Over the last several decades, with improved understanding of the disease, cytoreductive surgery (CRS) with heated intraperitoneal chemotherapy (HIPEC) has evolved into a novel treatment approach in selected patients with PC.1,3,4 For PC of colorectal and appendiceal origin specifically, this treatment has been shown to be beneficial in multiple large-scale retrospective studies.5–10 Thus far, only one randomized controlled trial has been conducted and demonstrated improved survival in patients undergoing CRS-HIPEC in the treatment

J Gastrointest Surg

of colorectal cancer PC compared to systemic chemotherapy alone.4 The procedure, however, is generally long and technically challenging, and the potential for major morbidity remains its main criticism. To date, multiple groups practicing the technique have assessed risk factors for procedure-related complications, with morbidity and mortality rates of 12–52 % and 0.9–5.8 % respectively reported.5–10 Among other variables, the lack of homogeneity in HIPEC administration regimens makes a comparison of results across studies difficult. Although with increasing experience, an improvement in morbidity has occurred in high-volume centers, the predictive factors for short-term outcomes remain unclear. Presented in this study are results from a tertiary center in the USA performing a high volume of CRS and HIPEC for carcinomatosis. The specific aim of this analysis was to investigate the perioperative outcomes of this approach in the treatment of PC from various primary tumor sites. The primary endpoint was major morbidity rate. The secondary endpoint was overall survival, with this portion of the analysis restricted to PC from colorectal and appendiceal primary tumors.

Methods Study Design All patients receiving CRS and HIPEC for PC between July 2007 and August 2012 were included. Analysis was conducted on patients undergoing initial CRS-HIPEC for the treatment of PC. Data for this retrospective analysis were retrieved from a prospectively maintained database. The main analysis included patients with PC from a multitude of primary tumor sites and had as its endpoint perioperative major morbidity.11 The secondary analysis was restricted to patients with PC from mucinous appendiceal tumors or nonappendiceal colorectal cancers and had as its endpoints long-term survival and recurrence. Diagnosis and Treatment Most patients were referred to our institution after a diagnosis of PC had been established at an outside hospital. After initial evaluation at our institution, a contrast-enhanced crosssectional imaging study (CT scan or MRI) of the chest, abdomen, and pelvis was done as a means of quantifying peritoneal disease burden and ruling out extra-abdominal spread. Nonresectable visceral hepatic metastases or thoracic metastases were contraindications to CRS and HIPEC. If tissue had been obtained at an outside hospital, review of the slides was performed to confirm diagnosis. With regard to aggressiveness of treatment, patients with PC from colorectal cancer (moderate or high grade) were typically treated with oxaliplatin- or irinotecan-based systemic chemotherapy, and a progression-free interval of at least

3 months was expected before a recommendation of CRS and HIPEC was made. However, patients with low-grade tumors and/or minimal residual disease amenable to complete cytoreduction were offered immediate CRS-HIPEC. An even more selective approach was applied to gastric origin PC, for which a sustained radiologic response of 6 months or more on systemic chemotherapy was generally required. Surgery commenced selectively with a diagnostic laparoscopy to assess the feasibility of thorough cytoreduction. If the disease burden was acceptable, a midline laparotomy was made and the patient was explored. The peritoneal cancer index was recorded.12 This index described by Jacquet and Sugarbaker is a widely used system of staging PC. It quantitatively determines the distribution and implant size of the cancer throughout 13 abdominopelvic regions. The lesion size of the largest implants is scored for each abdominopelvic region. The sum of each region’s numerical score results in the total peritoneal cancer index (PCI) score, which varies from 1 to 39. If not previously performed, the primary tumor was resected using oncological principles. Additional gross tumor debulking was then performed as dictated by the distribution of disease. This included resection of intra-abdominal organ(s) densely involved by tumor, omentectomy, and stripping of all parietal peritoneal surfaces affected, including those of the subdiaphragmatic spaces, the paracolic recesses, and the anterior abdominal wall. The completeness of cytoreduction was then recorded using the Jacquet/ Sugarbaker Classification System: CCR-0, no residual macroscopic disease; CCR-1, residual peritoneal deposits <2.5 mm; CCR-2, residual deposits between 2.5 mm and 2.5 cm; and CCR-3, residual deposits >2.5 cm or confluent tumors.12,13 The aim was a “complete cytoreduction”, defined as an eradication of all peritoneal nodules ≥2.5 mm in diameter (CCR 0–1). Following cytoreduction, HIPEC was then performed as previously described.14 The closed abdomen technique was used in all cases. Mitomycin C was the most common agent used in our series and was administered over two doses for a 90-min perfusion period with a target intraperitoneal temperature of 41–43 °C. A 40 mg dose was used and split between 30 mg for the first 60 min and 10 mg for the last 30 min. Cisplatin or other chemotherapeutic agents were used in 11.2 % of cases, where the tumor origin was a gynecologic malignancy or mesothelioma. Creation of gastrointestinal anastomoses was performed after the conclusion of the perfusion. Following surgery, patients were typically extubated and transferred to a telemetry unit for 24–48 h of initial monitoring. Major postoperative complications were defined according to the Clavien-Dindo Classification System (III–V) and included any complication requiring endoscopic, radiologic, or surgical intervention or any life-threatening postoperative condition requiring intensive care unit management. 11

J Gastrointest Surg Table 1 Clinicopathologic and operative data of 170 patients undergoing CRS-HIPEC for peritoneal carcinomatosis

Table 1 (continued) Variable

Variable Clinicopathologic data Male gender (%) Age (mean±SD) Comorbidities Hypertension Chronic lung disease Cardiovascular disease Diabetes mellitus Chronic renal insufficiency Chronic liver disease Primary tumor site, n (%) Colorectal Appendiceal Pseudomyxoma peritonei Gastric Ovarian Others ASA score, n (%) 1 2 3 4 Systemic chemotherapy prior to CRS-HIPEC Previous surgery, n (%) None Partial debulking Operative data Operative time (minutes, mean) (±SD)a Estimated blood loss (ml) Mean (±SD) Median (SE) Blood transfusion, n (%) Intraoperative PCI score, n (%) ≤16 >16 Mean (±SD) Post-CRS PCI, mean (±SD) ΔPCI, mean (±SD) CC score (Jacquet), n (%) CCR 0–1 CCR 2–3 CC score (Lyon), n (%) R0 R1 R2 Chemotherapeutic agents Mitomycin C, n (%) Cisplatin/others

n=170

n=170

76 (44.7) 55.1 (±11.3) 40 (23.5) 7 (4.1) 14 (8.2) 14 (8.2) 1 (0.6) 5 (2.9) 51 (30) 50 (29.4) 16 (9.4) 12 (7.1) 11 (6.5) 30 (17.6) 0 27 (15.9) 123 (72.4) 20 (11.8) 109 (64.1) 42 (24.7) 35 (20.6) 366.3 (±132.6) 750.9 (±1014.5) 400 (78.9) 52 (38.5) 90 (52.9) 78 (45.9) 16.0 (±9.0) 3.5 (±4.0) 12.3 (±6.9) 131 (77.1) 34 (20.0) 62 (36.5) 46 (27.1) 32 (18.8) 151 (88.8) 19 (11.2)

Peritonectomy procedures, mean (SD) Number of organs resected, median (range)b Number of bowel anastomoses, n (%)

115 (67.6) 4.0 (0–10)

0 1 ≥2 Intraoperative complications, n

69 (40.6) 73 (42.9) 28 (16.5) 0

PCI peritoneal cancer index, CRS cytoreductive surgery a

Including HIPEC (90 min)

b

Multiple resections possible

Perioperative mortality was defined as any death within 30 days of surgery or during the same hospitalization.

Table 2 Perioperative outcomes of 170 patients undergoing CRS-HIPEC for peritoneal carcinomatosis Variable

n=170

Hospital stay [days], mean (± SD) ICU admission, n (%) Reoperations (30 days) Reoperation (90 days) 30 day outcome

11.9 (±15.5) 36 (21.2) 19 (11.2) 33 (19.4)

Morbidity, n (%) None Clavien-Dindo I–II Clavien-Dindo III–IV Ileus Intraabdominal abscess/leak/fistula Wound complications Pneumonia/pleural effusion Respiratory failure Pulmonary embolism/DVT Cardiac complications Bleeding Hematologic toxicity Diarrhea/UTI Others Mortality (Clavien-Dindo V), n (%) 90-day outcome Morbidity (n, %) None Clavien-Dindo I–II Clavien-Dindo III–IV Mortality (Clavien-Dindo V) (n, %)

77 (45.3) 54 (31.8) 35 (20.6) 22 (12.9) 24 (14.1) 17 (10) 16 (9.4) 10 (5.8) 12 (7.0) 6 (3.5) 4 (2.3) 18 (10.5) 13 (7.6) 2 (1.2) 4 (2.4)

71(41.8) 52(30.6) 35(20.6) 12 (7.1)

ICU intensive care unit, UTI urinary tract infection, DVT deep venous thrombosis

J Gastrointest Surg Fig. 1 Overall recurrence of 101 patients undergoing CRS-HIPEC for PC in the treatment of colon (n=51) and appendiceal (n=50) cancer

Surveillance

Statistical Analysis

Surveillance consisted of a physical examination, complete blood count, serum chemistry, CEA level if appropriate, and contrast-enhanced CT scan (or MRI) of the chest, abdomen, and pelvis every 3 months for the first 2 years, and then every 6 months thereafter. Diagnosis of recurrence was generally established by radiographic means, with tissue biopsy in select circumstances. For isolated peritoneal recurrence after a disease-free interval of 6 months or more, consideration was given to repeat CRS and HIPEC.

Continuous variables were presented as mean±standard deviation and compared using the Student’s t test. Categorical variables were expressed as valid percentages and compared using the chi-square test or Fisher’s exact test as appropriate. Recurrence and survival outcomes were calculated using the Kaplan-Meier method and compared with the log-rank test. Incomplete cytoreduction (CCR 2–3) was considered an immediate recurrence. A univariate analysis of multiple clinicopathological variables was performed to determine the variables

Fig. 2 Overall survival of 101 patients undergoing CRS-HIPEC for PC in the treatment of colon (n=51) and appendiceal (n=50) cancer

J Gastrointest Surg

associated with major morbidity. A similar analysis was performed with survival as the endpoint; however, this analysis was restricted to patients with a primary tumor of the appendix or nonappendiceal colon/rectum. Those factors deemed significant in univariate analyses were entered into multivariate analyses using logistic and Cox regression models. A p value of <0.05 was considered significant. Statistical analysis was carried out using SPSS 20.0 (Chicago, IL).

Results During the study period, 185 consecutive combined procedures were performed on a total of 170 patients for PC. The clinicopathologic data of the group are summarized in Table 1. The two most common tumor types were colorectal (30.0 %) and appendiceal (29.4 %) cancer. The operative outcomes are outlined in Table 1. Overall, 64.1 % of patients underwent systemic chemotherapy prior to CRS-HIPEC. Patients with PC from appendiceal or colorectal cancer origin with moderate- or high-grade tumors and/or extensive peritoneal disease (72.7 %) were treated with neoadjuvant systemic chemotherapy as compared to patients with low-grade and/or minimal disease (27.3 %) who were offered immediate CRS-HIPEC. All patients with pseudomyxoma peritonei in whom complete debulking (n=15) was feasible were offered immediate CRS-HIPEC. Neoadjuvant chemotherapy was given to all (100 %) patients with PC of gastric, gallbladder, and recurrent ovarian cancer origin. Diagnostic laparoscopy was attempted and completed in 95 patients with no associated morbidity. Based on the laparoscopic evaluation, 78 (82.1 %) patients were deemed amenable to CRS-HIPEC and completed the treatment. CRS-HIPEC was aborted (17.9 %) mainly based on extensive tumor burden (mean PCI 14.3±7.8 vs. 22.9±4.6). Complete cytoreduction (CCR 0–1) was achieved in overall 77.1 % of patients. The overall perioperative (30 days) complication rate was 52.4 %. The most common surgical morbidities (grades III–IV) were bowel complications (Table 2). Reoperative rate was 11.2 % at 30 days. Factors associated with poor outcome were analyzed. Age, tumor type, extent of cytoreduction (ΔPCI), and intraoperative PCI>16 did not predict development of major complications. Intraoperative blood transfusion was the only independent prognostic factor on multivariate analysis (hazard ratio (HR) 3.74; 95 % CI 1.1– 12.4; p=0.031). Mortality rate at 30 days was 2.4 %. The cause of death was multiorgan system failure secondary to sepsis in three patients and respiratory failure in one patient. Mortality rate at 90 days was 7.1 %. The cause of death was multiorgan system failure secondary to sepsis in six patients, disease progression in four patients, respiratory failure in one patient, and acute myocardial infarction in one patient.

Of the 170 patients undergoing CRS-HIPEC in this study, the origin of the tumor was colorectal and appendiceal cancer in 59.4 %. The median follow-up for all patients diagnosed with PC of colorectal or appendiceal origin was 15.7 months (±1.2). The median time to recurrence for colorectal and appendiceal PC was 12.4±1.8 months. Overall recurrence rate for colorectal/appendiceal PC combined at 1 and 3 years was 46.9 and 73.9 %, respectively. The 1- and 3-year overall survival for colorectal and appendiceal carcinomatosis was 74.0 %, 32.5 % and 89.4 %, 29.3 %, respectively (Fig. 1). Of the 86 (50.6 %) patients with recurrent disease, repeat CRS/ HIPEC was offered to 15 (17.4 %) patients with a 3-year survival rate of 66.5 % after recurrence. Overall survival for colorectal/appendiceal PC combined at 1 and 3 years was 81.6 and 30.6 %, respectively. The 1- and 3year overall survival for colorectal and appendiceal carcinomatosis was 74.0 %, 32.5 % and 89.4 %, 29.3 %, respectively (Fig. 2). Factors associated with poor survival were analyzed (Table 3). Intraoperative PCI score >16 and need for intraoperative blood transfusion were factors independently associated with poor survival (Fig. 3).

Table 3 Univariate and multivariate analyses of factors associated with poor survival in patients undergoing CRS-HIPEC for PC in the treatment of colorectal (n=51) and appendiceal (n=50) cancer, n=101 Variable

Univariate analysis

Median survival (months) Intraoperative PCI scorea ≤10 > median 11–16 29.7 (5.2) >16 15.8 (3.0) CCR score 0–1 31.4 (2.5) 2–3 13.3 (2.6) RR score R0 > median R1 27.8 (4.1) R2 15.1 (5.5) Blood transfusiona Yes 14.6 (2.5) No 31.4 (3.0) Number of organs resected ≤4 33.4 (3.3) >4 20.6 (4.6) ΔPCI ≤12 31.4 (NA) >12 21.8 (4.1)

Multivariate Cox regression analysis p value

HR

p value

0.001

– 2.79 10.23

0.040 0.118 0.011

3.37

0.009

0.002

0.006

<0.001

<0.001

0.047

PCI peritoneal cancer index a

Retained significant on multivariate analysis

J Gastrointest Surg Fig. 3 Overall survival of 101 patients undergoing CRS-HIPEC for PC in the treatment of appendiceal and colorectal cancer according to intraoperative PCI score

CRS-HIPEC was performed in 12 (7.1 %) and 11 (6.5 %) selected patients with PC from gastric and ovarian cancer, respectively. At 3 years, two (16.6 %) patients with gastric cancer and two (18.2 %) patients with ovarian cancer were still alive.

Discussion Once viewed as an untreatable disease, the management of peritoneal carcinomatosis is becoming more aggressive.1–4 As the approach of cytoreductive surgery and HIPEC becomes standard for the treatment of PC in select cases, it is essential to improve both its safety and long-term survival benefits. We present the initial experience at our center and identify the factors associated with impaired perioperative and longterm outcomes. Our findings will help to improve patient selection for the application of this aggressive modality. A morbidity rate of 52.4 % reported in the present study is comparable to those reported elsewhere in the literature.2,15–20 Lack of a standardized technique among centers makes a comparison of morbidity rates difficult. These limitations notwithstanding, our results seem in line with those reported by Chua and colleagues, who reviewed the experiences of 24 treatment centers and reported morbidity rates of 12–52 %.2 Although not insignificant, these results are similar to those of major operations, such as pancreaticoduodenectomy or major hepatectomy, procedures now considered routine at referral

centers.21,22 Similar to our series, common postoperative complications reported included sepsis (0–14 %), fistula (0–23 %), abscess (0–37 %), ileus (0–86 %), anastomotic leak (0–9 %), hematologic toxicity (0–28 %), deep venous thrombosis/ pulmonary embolus (0–9 %), and renal insufficiency (0– 7 %).2 The rates of reoperation ranged from 0 to 23 %, and these are comparable to our findings (11.2 %).2 Whether these complications are a consequence of the debulking or the chemoperfusion remains unclear and need to be investigated. The perioperative mortality rate of 2.4 % in our series was also comparable to that of published series;2,16–20 patients in our group died from sepsis secondary to multiorgan system failure. Identifying patients with higher operative risk is essential. In our series, blood transfusion was the only predictor of major morbidity. This is a finding echoed in the surgical literature and certainly not specific to peritoneal surface malignancy surgery.23,24 This result reinforces the importance of sound intraoperative judgment and technique in treating patients with PC. Surprisingly, age, peritoneal tumor load, completeness of cytoreduction, number of gastrointestinal anastomoses, number of resected viscera, and chemotherapy dosage were not factors that we found to be independently associated with major morbidity in our patients. This contrasts the findings of other investigators.2,16–20 Barrati et al., for example, observed an increased morbidity rate of up to 65.7 % in patients who had at least two of the following factors: PCI> 30, more than five visceral resections, and poor performance

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status.20 Franko et al. confirmed the impact of viscera resected and extent of peritonectomy on morbidity rate.25 When analyzing the long-term survival of the subgroup of patients with appendiceal tumors or nonappendiceal colorectal cancers, our analysis yielded similar results (median survival of 22.8 months) as that reported by Verwaal and colleagues (median survival of 22.2 months).4 Both transfusion and peritoneal tumor load (PCI>16) were independent predictors of poor long-term survival. It is clear that despite a high complete cytoreduction rate of 77.1 %, long-term survival is affected by the tumor burden, and careful patient selection is warranted. Since high peritoneal tumor load affects not only perioperative morbidity but also overall survival, it is critical to predetermine patients at high risk. This study and other published series highlight the value of preoperative cross-sectional imaging and initial laparoscopy to assess for prohibitively high peritoneal tumor load.26–28 All of the patients in this series received highresolution imaging before or during initial clinical evaluation. In addition, surgery commenced selectively with laparoscopy to assess tumor burden and feasibility of cytoreduction. As our experience progressed, we became more refined in our selection of only patients with a reasonable quantity of peritoneal disease (PCI≤16). Although exploratory laparotomy remains the gold standard in scoring PCI, authors Esquivel and Chua have published data that CT-PCI, interpreted by dedicated radiologists and surgical oncologists, may be able to support patient selection for CRS and HIPEC with a clinical accuracy rate of up to 88 %.26,27 In a recent series published by Iversen and colleagues, the use of diagnostic laparoscopy was valuable in excluding patients with high tumor burden.28 In our series, the use of laparoscopy prevented 17.9 % open explorations associated with higher morbidity. Similar to any major procedure, the “learning curve” of the technique is essential. Smeenk and colleagues evaluated the learning curve after 10 years of combined-modality treatment of PC at a single center.29 They demonstrated a decrease in the extent of disease and perioperative morbidity; congruently, the rates of complete cytoreduction and survival increased. Although statistical power limited our analysis in this regard, we too likely experienced a progressive reduction of transfusion requirement, duration of operation, and length of intensive care unit stay over the course of our experience. The most important concept we have learned is that it is essential to carefully select patients, both during the initial visit and at surgery. All patients referred to our institution are first evaluated by a multidisciplinary team where we consider pathologic features, response to chemotherapy, and tumor burden on imaging studies, as well as the patient’s overall health including nutritional status, ECOG performance score, and number of comorbidities. We only proceed with surgery in patients in whom a complete cytoreduction is considered feasible. The use of neoadjuvant therapy, particularly in patients with moderate- to high-grade tumors, has also allowed us to better

select candidates with favorable disease biology. In addition, if a patient is considered for HIPEC, we have made it our standard practice to begin with diagnostic laparoscopy. We have observed that current imaging studies underestimate the extent of disease. The use of diagnostic laparoscopy provided some benefit in selecting candidates for CRS-HIPEC and preventing unnecessary explorations in those with high tumor burden. Finally, because achieving complete cytoreduction is essential to improving the patients’ outcome, we have learned to promptly abort cases where unresectable disease is found upon exploration.

Conclusion In summary, we report here our first analysis of the perioperative and long-term results of CRS-HIPEC at our center. We have discovered several important criteria for patient selection and demonstrated acceptable perioperative outcomes, validating the safety of the approach.

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