World Journal of Surgery

, Volume 40, Issue 5, pp 1075–1081 | Cite as

Where Oncologic and Surgical Complication Scoring Systems Collide: Time for a New Consensus for CRS/HIPEC

  • Kuno Lehmann
  • Dilmurodjon Eshmuminov
  • Ksenija Slankamenac
  • Benedict Kranzbühler
  • Pierre-Alain Clavien
  • René Vonlanthen
  • Philippe Gertsch
Original Scientific Report

Abstract

Introduction

Morbidity and mortality rates after cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) are important quality parameters to compare peritoneal surface malignancy centers. A major problem to assess postoperative outcomes among centers is the inconsistent reporting due to two coexisting systems, the diagnose-based common terminology criteria for adverse events (CTCAE) classification and the therapy-oriented Clavien-Dindo classification. We therefore assessed and compared both reporting systems.

Patients and Methods

Complications after CRS/HIPEC were recorded in 147 consecutive patients and independently graded by an expert board using both systems. In a next step, a group of residents, experienced surgeons, and medical oncologists evaluated a set of twelve real complications, either with the Clavien-Dindo or CTCAE classification.

Results

The postoperative complication rate after CRS/HIPEC was 37 % (54/147), 6.8 % (10/147) were reoperated, and three (2 %) patients died. The most frequent complications were intestinal fistula or abscess, pulmonary complications, and ileus. Grading of complications with the CTCAE classification resulted in a significantly higher major morbidity rate compared to the Clavien-Dindo classification (25 vs. 8 %, p = 0.001). Evaluating a set of complications, residents, surgeons, and oncologists correctly assessed significantly more complications with the Clavien-Dindo compared to the CTCEA classification (p < 0.001). In addition, all participants evaluated the Clavien-Dindo classification as more simple. Residents (p < 0.001) and surgeons (p < 0.01) required less time with the Clavien-Dindo classification; there was no difference for oncologist.

Conclusion

In conclusion, our data indicate that there is a different interpretation of severity grades of complications after CRS/HIPEC between the two classifications. There is a need for a common language in the field of CRS/HIPEC, which should be defined by a new consensus to compare surgical outcomes.

Abbreviations

CTCAE

Common terminology criteria for adverse events

CRS

Cytoreductive surgery

HIPEC

Hyperthermic intraperitoneal chemotherapy

PC

Peritoneal carcinomatosis

PCI

Peritoneal Cancer Index

CC-Score

Completeness of cytoreduction scoring

Introduction

Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) opened a door to a potentially curative treatment in patients with peritoneal carcinomatosis. In recent series, five-year survival rates of up to 50 % were possible in patients with limited colorectal carcinomatosis [1, 2]. In contrast, only limited outcomes are reported with systemic chemotherapy only [3, 4]. An important argument for many physicians against CRS/HIPEC is the reported, high rate of major complications, ranging between 25 and 60 % [5, 6]. Considering the biology of a malignant disease and quality of life issues, some physicians argue that the reported complication rates of CRS/HIPEC are too high to integrate CRS/HIPEC in a multimodal therapy concept. Yet, there is a major confounding factor in the reporting and interpretation of postoperative outcomes, due to the use of an uncommon classification system in the surgical field. To standardize reporting of complications after CRS/HIPEC, the Common Terminology Criteria for Adverse Events (CTCAE) grading system was proposed in a consensus conference in Milan in 2006 [7]. The CTCAE classification has a long tradition in reporting medication toxicity and adverse effects, and includes 310 specific types of complications and five severity grades [8]. The rationale to use the CTCAE classification for complication grading after CRS/HIPEC was the better comparability with adverse events of systemic chemotherapy. Nowadays, most experts would agree that CRS/HIPEC and systemic chemotherapy are rather complementary than in direct competition [9]. In contrast to the diagnosis-related CTCAE classification, the Clavien-Dindo classification (supplementary Table 1) is therapy-oriented and was developed to report surgical complications [10]. This classification was used and validated in many fields of surgery, including general [10] and orthopedic surgery [11], urology [12], and transplantation [13]. A potential drawback is that most studies report the highest-grade complication only, and complications like mild hematotoxicity or transient nephrotoxicity may not appear in the postoperative scoring. The major problem to compare postoperative outcomes in the field of CRS/HIPEC today is inconsistent reporting due to the confusing use of these two coexisting systems. We therefore performed this study to analyze and specify postoperative morbidity, and to compare the two classification systems.

Patients and methods

Patients for CRS/HIPEC

Data of consecutive patients from the department of Visceral and Transplantation Surgery, University Hospital Zürich (2009–2013) were entered in a prospective database. Patients for CRS/HIPEC were presented in an interdisciplinary tumor board prior to surgery. Preoperative management included intravenous hydration and bowel preparation. During surgery, patients were hydrated and cooled down 1 h prior to HIPEC; coagulation factors and albumin were substituted proactively. Patients were extubated in the operation room if possible and recovered in the intensive care unit for the first night. Severity grades of complications were determined after consensus in a weekly, interdisciplinary morbidity meeting. The term “major” complication was used only after grading with the Clavien-Dindo for grades IIIb and IV and for the CTCAE grades III/IV to group severe, non-lethal events. The study was approved by the local ethic review board.

Participants of the survey

Fifty-four residents, thirty experienced attending surgeons, and 28 medical oncologists were contacted and randomized to evaluate a set of complications with either the CTCAE or the Clavien-Dindo classification. Participation was voluntary and no reimbursement was provided. The participants received a brief introduction and the tables for the Clavien-Dindo or CTCAE classification. Residents had no experience with both classifications. Some surgeons had experience with the Clavien-Dindo classification, but none with the CTCAE. Respectively, all medical oncologists had experienced with the CTCEA classification but none with the Clavien-Dindo classification. Up to three reminders were sent to participants per e-mail or phone, if there was no response. A small group of study nurses (n = 4) trained in the Clavien-Dindo classification evaluated the same set of complications. No such personal was available for the CTCEA classification.

Questionnaire

A questionnaire including a set of twelve real complications after CRS/HIPEC was designed. Either the CTCAE classification or the Clavien-Dindo classifications were randomly attached anonymously without defining the name of the classification to the questionnaire. Fluency in English was prerequisite, thus the classifications were provided only in English. The raters reported also simplicity, certainty, and time for the two complication systems.

Statistical analysis

Statistical analysis was performed using STATA (version 12, Stata Corp., College Station, Texas). To test the reproducibility of ratings, intraclass correlation coefficients (ICC) were calculated, an ICC of 0.7 was expected to indicate sufficient reliability. For all results, p values ≤ 0.05 were considered significant.

Results

Demographic data

Overall, 147 patients were operated for peritoneal carcinomatosis, and the treatment was potentially curative in 72 % (106/147) of patients. Palliative HIPEC was indicated in 14 cases with symptomatic ascites, where no complete CRS was possible. The majority of patients had carcinomatosis from appendix tumors or colon carcinoma. Further demographic details are shown in Table 1.
Table 1

Demographic data: DPAM: disseminated peritoneal adenomucinosis

Parameters

n = 147

Age (years, range)

53 (13–73)

Gender

 Male

64 (43 %)

 Female

83 (57 %)

Primary tumor

 Appendix tumors

70 (48 %)

 DPAM

32

 PMCA

15

 Signet ring

9

 Adenocarcinoma

11

 Adenocarcinoid

2

 Colon carcinoma

43 (29 %)

 Mesothelioma

13 (9 %)

 Gastric carcinoma

5 (3 %)

 Ovarian carcinoma

7 (5 %)

 Other tumors

9 (6 %)

Surgery

 PCI (median)

14.6

 HIPEC performed

120 (81 %)

 Potentially curative treatment

106 (72 %)

 Operation time (minutes)

557 (60–1020)

ICU stay (days, median, range)

1 (0–19)

Hospital stay

16 (5–118)

PMCA peritoneal mucinous carcinomatosis, PCI peritoneal cancer index, CC-score completeness of cytoreduction, ICU intensive care unit

Morbidity and mortality by patients

The majority of the patients, 63 % (93/147), had no postoperative complication, 37 % (54/147) patients had at least one complication. In a first step, the highest-grade complication per patient, which is commonly reported in the literature, was graded in a consensus meeting with the two classifications, the diagnosis-oriented CTCEA classification and the therapy-oriented Clavien-Dindo system, as shown in Table 2. The major complication rate, defined as ≥ IIIb in the Clavien-Dindo or ≥ 3 in the CTCAE classification, was significantly higher if the CTCAE classification was used (8.1 vs. 25.1 %, p = 0.0001). Even if grade IIIa in the Clavien-Dindo was considered as a major complication, the difference was still significant (p = 0.02). The mortality rate was 2 % (3/147).
Table 2

Postoperative morbidity and mortality (highest grade): The highest-grade complication was assessed for each patient in a morbidity and mortality conference

Clavien-Dindo classification

CTCAE classification

Grade

n = 147

%

Major

Grade

n = 147

%

Major

p

I

3

2

 

I

6

4.1

  

II

27

18.4

 

II

8

5.4

  

IIIa

9

6.1

 

III

24

16.3

25.1 %

 

IIIb

6

4.1

8.1 %

.0001

IVa

5

3.4

IV

13

8.8

IVb

1

0.7

 

V

3

2

 

V

3

2

  

Total

54

46.7

  

54

46.7

  

Major complications were graded as defined ≥ IIIb in the Clavien-Dindo, and ≥ 3 in CTCAE classification

Morbidity and mortality by specific complications

In a next step, multiple complications (n = 86) were analyzed in those 54 patients with a complicated course, and separately analyzed and graded with the two systems (Table 3). Since all complications were evaluated, this table represents the frequency or risk of a specific complication for a patient after CRS/HIPEC. Most frequent, patients suffered from intestinal complications, e.g., anastomotic insufficiency, fistulas or abscess, pulmonary complications, or prolonged intestinal passage problems. The majority of complications (76 %) were managed conservatively and represented by the complication grades I-IIIa of the Clavien-Dindo classification, (Table 3A). Twenty-one percent of the complications required an intervention under general anesthesia, reoperation, or referral to the intensive care unit, graded as Clavien-Dindo grades IIIb-IVb. In detail, redo-surgery was required in 10 (6.8 %) of patients for gastrointestinal complications, anastomotic insufficiency, fistulas, or abscess. Readmission to the intensive care unit was indicated for dialysis and cardiac events, or in case of sepsis and multiorgan failure after reoperation. Overall, three patients died; one patient from mass bleeding, secondary to a pancreas fistula, another patient developed pulmonary failure, and one patient becomes septic after repeated laparotomy for a duodenal fistula. Remarkably, the 27 patients who had advanced disease at explorative laparotomy and underwent no CRS/HIPEC, showed a high major complication rate (7.4 %, 2/27) and one death (3.7 %, 1/27), highlighting the complexity of advanced disease. The CTCAE classification provides the same number and types of complications but the interpretation of severity grades is different and more difficult without a clinical context (Table 3B).
Table 3

Grading of specific complications (cumulative): assessment of multiple complications per patient revealed 86 complications in 54 of 147 patients

(A) Clavien-Dindo grade

Intestinal

Bile Pancreas

Ileus

Dialysis

Pulmonary

Other

Total

% of compl.

I

    

1

3

4

4.7

II

4

4

11

 

2

23

44

51.2

IIIa

3

2

1

 

11

 

17

19.8

IIIb

9

1

1

 

2

1

14

16.3

IVa

   

3

 

1

4

4.7

IVb

        

V

1

   

1

1

3

3.5

Total (n)

17

7

13

3

17

29

86

100.0

% of complications

19.7

8.1

15.1

3.5

19.8

33.7

  

(B) CTCAE Grade

Intestinal

Bile pancreas

Ileus

Dialysis

Pulmonary

Other

Total

% of compl.

I

 

2

  

1

3

6

7.0

II

2

2

  

5

10

19

22.1

III

6

2

11

3

8

11

41

47.7

IV

8

1

2

 

2

4

17

19.8

V

1

   

1

1

3

3.5

Total (n)

17

7

13

3

17

29

86

100.0

% of complications

19.7

8.1

15.1

3.5

19.8

33.7

  

Complications were graded according to the (A) Clavien-Dindo classification or the (B) CTCAE classification. “Intestinal” complications include anastomotic insufficiency, fistulas, abscess formation; “bile/pancreas” includes biliary or pancreatic fistulas; “ileus” was defined as prolonged intestinal paralysis requiring reinsertion of a gastric tube, prolonged parenteral nutrition, or more; “pulmonary” complications include effusions, pneumothorax, pneumonia, and ARDS; “other” includes nonsurgical infections, cardiac arrhythmias, wound problems, thrombosis and pulmonary embolism, or bleeding. Percentages of the total number of complications (n = 86) are given for types and severity of complications

Evaluation by residents, surgeons, and medical oncologists

To test the practicability of the Clavien-Dindo and CTCAE classifications residents, surgeons,, and medical oncologists assessed a selected set of twelve complications. The response rates among residents, surgeons, and oncologists were 74 % (40/54), 70 % (21/30), and 75 % (21/28), respectively. Residents and surgeons required less time using the Clavien-Dindo classification, which was not the case for oncologists (Fig. 1). In contrast to residents and oncologists, surgeons felt less certain using the CTCAE classification (Fig. 2a). Consistently, all three groups evaluated the Clavien-Dindo classification as more simple compared to the CTCAE classification (Fig. 2b). Remarkably more complications were correctly assessed with the Clavien-Dindo classification compared to the CTCAE classification, and this finding was consistent in all three groups; residents (62 vs. 32 %, p < 0.001), surgeons (66 vs. 28 %, p < 0.001), and oncologists (74 vs. 31 %, p < 0.001). There was no difference between surgeons and oncologists in the rate of correct answers. The inter-rater reliability was good for the Clavien-Dindo classification among residents (0.67, p < 0.001), surgeons (0.72, p < 0.001), and oncologists (0.82, p < 0.001), but only moderate for the CTCEA classification (residents: 0.34, p < 0.001, surgeons: 0.45, p < 0.001, and oncologists: 0.39, p < 0.001).
Fig. 1

Time requirement to evaluate a specific set of complications: a questionnaire including twelve real complications after CRS/HIPEC was given to residents, surgeons, and oncologists to evaluate the two classifications. Residents (8 ± 4 min vs. 22 ± 10 min, p < 0.001) and surgeons (9 ± 5 vs. 19 ± 7, p = 0.006) required less time to complete the Clavien-Dindo classification compared to the CTCAE classification. There was no difference in time requirements for oncologists (16 ± 11 vs. 23 ± 15, p = 0.4)

Fig. 2

Subjective assessment of simplicity and certainty: a surgeons felt significantly more certain using the Clavien-Dindo classification compared to the CTCAE classification (8.4 ± 0.9 vs. 5 ± 2.7, p = 0.005). Residents (6.2 ± 1.9 vs. 5.4 ± 1.5, p = 0.2) and medical oncologists (7.5 ± 1.2 vs. 6 ± 1.8, p = 0.1), however, did not feel more certain with one of the classifications compared to other. b Consistently, residents (7.1 ± 2.2 vs. 4.5 ± 2.3, p < 0.001), surgeons (8.4 ± 0.8 vs. 4.1 ± 2.9, p = 0.001), and oncologists (8 ± 1.5 vs. 5 ± 2.1, p = 0.03) rated the Clavien-Dindo classification as more simple

Four study nurses, trained in the Clavien-Dindo classification, correctly assessed 98 % (47/48) of the vignettes. This rate was significantly higher compared to specialists and residents (p < 0.001), indicating that independent, specially trained personal may improve the correct assessment of complications.

Correlation with hospital stay

We questioned whether the Clavien-Dindo and CTCAE classifications correlate with hospital stay after CRS/HIPEC. Both classifications showed a similar moderate correlation with hospital stay (Clavien-Dindo r = 0.65 vs. CTCAE r = 0.63).

Discussion

Our data demonstrate that CRS/HIPEC can be performed with morbidity and mortality rates that are not higher compared to other fields of major abdominal surgery. The incidence of complications requiring redo-surgery and/or readmission to the intensive care unit is low, and the majority of complications can be managed conservatively. CRS/HIPEC, however, is a complex intervention and requires standardization and a high level of expertise for all contributing disciplines [14, 15]. Dedicated and experienced centers can prevent, or at least attenuate the risk of major morbidity. For example, the incidence of renal failure is low with adequate hydration prior to surgery and a careful intraoperative fluid management [15]. Fatal outcomes after anastomotic or pancreatic leakage can also be prevented or attenuated by adequate intraoperative and postoperative management, e.g., placement of protective ileostomies, adequate drainage, and early revision if necessary. It should be highlighted that explorative laparotomy in patients with advanced peritoneal disease is already a procedure with significant morbidity, often due to postoperative ileus, pulmonary aspiration, or development of intestinal fistula.

There is an ongoing controversy whether complications after CRS/HIPEC should be assessed by the surgical and therapy-oriented Clavien-Dindo classification, or the CTCAE classification, which is traditionally used by oncologists. The current agreement, the 2006 consensus in Milano [7], to use the CTCAE classification to report complications after CRS/HIPEC created some difficulties, as shown by our data, to compare CRS/HIPEC to other major procedures. At that time, CRS/HIPEC was considered as an alternative to systemic chemotherapy, and therefore, adverse events were assessed in the same way as a new cytostatic regimen. Nowadays, CRS/HIPEC is the surgical part of a multimodal therapy regimen, comparable to other complex oncological diseases, like liver metastases or esophageal cancer [16, 17]. Compared to these major surgical procedures, the use of the CTCAE classification over-grades complications for CRS/HIPEC, making it difficult to compare perioperative outcomes in the surgical fields. For example, rating of complications with the CTCAE classification results in a rate of major (grade III/IV) complications of 25 %, similar to the expert center in Lyon, who reported a rate of 24 % [18]. However, if we assess complications with the Clavien-Dindo score the rate of major complications (IIIb/IV) is 8.1 %, comparable to other fields of major abdominal surgery. The collision of the two scoring system becomes evident with an example: For instance, symptomatic ileus requiring intravenous replacement or parenteral feeding for more than 24 h is regarded as a Grade 3 (major complication) in the CTCAE classification; according to the Clavien-Dindo classification, it is a Grade II (minor complication) [10]. After CRS/HIPEC, postoperative intestinal paralysis requiring parenteral feeding should not be regarded as a complication, unless reoperation or an intervention took place. The difficulty to define an adverse event, which does not require a specific treatment after such a complex procedure does also explain the probably too low rate of grade I complications in the present study. In an individual patient, it is very difficult or not possible to differentiate perioperative complications into purely surgical or HIPEC-related, due to the complex nature of the procedure. For example, postoperative renal insufficiency or hematological toxicities can be due to anesthetic or volume management, drug related side effects, e.g., metamizol, sepsis, or finally, HIPEC.

The CTCAE classification has a long history over the last 30 years, after its development by the National Cancer Institute (NCI) to report medication toxicity and adverse effects [8, 19], and its value in clinical trials comparing different oncologic treatments is undisputable. The Clavien-Dindo classification system was developed in 1992 and updated in 2009 [20, 21]. An international working group later selected the classification for the World Health Organization’s Safe Surgery Saves Lives program to report postoperative complications [22]. Our results demonstrate that the Clavien-Dindo is more convenient and reproducible, compared to the CTCAE classification. Indeed, we were surprised about the low inter-rater reliability for the CTCAE, even among experienced oncologists. In contrast, residents and oncologists without exposure to the Clavien-Dindo classification consistently assessed complications. A simple explanation for this is the large volume of the 71-page CTCAE manual required to describe the severity of a diagnosis, compared to the one table Clavien-Dindo classification which defined the therapy-based grading. An important drawback is that this classification usually reports the highest-grade complication only. Particularly in a clinical trial, mild hematotoxicity or nephrotoxicity may not appear in the postoperative complication scoring with the Clavien-Dindo score if no treatment was necessary. A practical solution to maintain the benefits of both classifications, the simplicity and reproducibility of the Clavien-Dindo and the sensitivity of the CTCAE system, would be to introduce the Clavien-Dindo classification, but to keep the CTCAE for the assessment of critical parameters, e.g., nephrotoxicity or hematotoxicity. Compared to previous studies, we observed a lower rate of complications that were correctly assessed [21]. The vignettes presented in the survey included real and complex cases after CRS/HIPEC with sometimes multiple complications. Particularly in such patients complication grading can be difficult. Reporting of all complications may here be more sensitive and better reflect the complexity of a complicated course, as suggested in a recent publication introducing the so called “comprehensive complication index” [23].

In conclusion, our data indicate that there is a different interpretation of severity grades of complications after CRS/HIPEC, which impairs the comparison of quality data if the two systems are inconsistently used among centers. Independent of a potential advantage or disadvantage of one system, there is a need for a common language in a field involving surgery and medical oncology. A potential solution could be to define specific complications to be assessed by the CTCAE, in addition to the Clavien-Dindo classification. This could be a topic of a future consensus conference to clarify the use of the two classification systems, and to remove the tower of Babel in the common language of surgeons and oncologists in the field of CRS/HIPEC.

Supplementary material

268_2015_3366_MOESM1_ESM.docx (12 kb)
Supplementary material 1 (DOCX 12 kb)

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Copyright information

© Société Internationale de Chirurgie 2015

Authors and Affiliations

  • Kuno Lehmann
    • 1
  • Dilmurodjon Eshmuminov
    • 1
  • Ksenija Slankamenac
    • 1
  • Benedict Kranzbühler
    • 1
  • Pierre-Alain Clavien
    • 1
  • René Vonlanthen
    • 1
  • Philippe Gertsch
    • 1
  1. 1.Klinik für Viszeral- und TransplantationschirurgieUniversitätsspital ZürichZurichSwitzerland

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