CA-125: an inaccurate surveillance tool immediately after cytoreductive surgery and hyperthermic intraoperative chemotherapy (CRS-HIPEC)?

Abstract

Objective: This study seeks to evaluate pre and post-operative CA-125 in patients undergoing complete cytoreduction surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC), and understand the time frame before values normalise allowing use as a surveillance tool to resume.

Methods: A retrospective review was carried out of 94 patients undergoing CRS-HIPEC to compare pre-operative CA-125 values, measured within one week prior to surgery to post-operative readings within the first 30 d. Raised CA-125 was defined using as a value >35 U/ml.

Results: Of 63 (67%) patients with normal pre-operative CA-125, 22 (35%) had raised post-operative CA-125, and consisted of patients with colorectal (n = 8), appendiceal (n = 6), ovarian (n = 4) or other (n = 4) cancers. The average peak CA-125 was 80 U/ml occurring on median 10th post-operative day (POD) (range 7–30). The median day of normalisation for patients with normal pre-operative and raised post-operative CA-125 was 57 (range 28–115). The median day of normalisation for patients with raised pre-operative CA-125 was POD 41 (range 1–114). Notably 10 patients had initial normalisation (median POD 1, range 1–6), followed by subsequent raised value (median POD 10, range 5–40) and re-normalisation (median POD 47, range 19–104).

Discussion: For patients with raised pre-operative CA-125 an immediate post-operative CA-125 within 3 d may be useful to assess normalisation following surgery. Aside from immediate measurement CA-125 is misleading and should not be measured post-operatively within the first 3 months after surgery following which its use as a surveillance marker can resume.

Keywords:

• Regional perfusion cancer chemotherapy
• cytoreduction surgical procedures
• peritoneal neoplasms
• tumour biomarkers

Introduction

Tumour markers such as carcinoembryonic antigen (CEA), cancer antigen 19-9 (CA-19-9) and cancer antigen 125 (CA-125) can be used in oncology for disease detection, monitoring of response to therapy or detection of post-treatment recurrence [1–7]. Pre-operatively raised levels, persistently elevated post-operative or long time to normalisation in response to chemotherapy or surgical resection may correlate with poor prognosis.

There are currently no guidelines on when to measure tumours markers after cytoreductive surgery and hyperthermic intraoperative chemotherapy (CRS/HIPEC) and their role in management of patients after surgery. We have previously reported on the measurement and use of tumour markers after CRS/HIPEC [13]. Among patients with raised pre-op TM, the median time to normalisation was 7 d for CEA, 90 d for CA125 and 6 d for CA 19-9. Patients with raised pre-operative CEA or CA19-9 which did not normalise post-operatively had worse overall survival (hazard ratio 1.48 and 1.8, respectively) although the converse was seen for CA125 (hazard ratio 0.78). Given the established reliability of CEA and CA-19-9 and potential for non-specific post-operative increases in CA-125 we chose to focus on CA-125 in this article.

Raised pre-operative and persistently raised post-operative CA-125 are thought to be associated with poorer prognosis [8,9]. However, early studies on the use of CA-125 reported significant post-operative increases in patients undergoing abdominal surgery for ovarian cancer, other types of cancer and for benign disease (Table 1).

Table 1. Previous studies comparing pre and post-operative CA-125 levels.

Study	Cohort	Relevant findings
[10]	873 patients undergoing abdominal surgical treatment for benign disease and cancer	Raised in 62% of patients with normal pre-operative CA-125 Maximum levels of CA-125 seen 2–4 h after operation with elevations persisting up to 3 months
[12]	Patients undergoing second-look laparotomy in ovarian cancer (n = 28), radical hysterectomy in cervical cancer (n = 42) or aortic surgery for atherosclerotic occlusive disease or aneurysm (n = 14)	Rising CA-125 seen in 82% regardless of primary diagnosis, type of operation or sex Highest levels during second week after operation normalised 8 weeks post-surgery
[15]	Patients with ovarian cancer (n = 50), uterine cancer (n = 60), gastrointestinal cancers (n = 20) and benign gynaecological diseases (n = 40)	Significant increases in CA-125 for ovarian (18%), uterine (30%), and gastrointestinal (75%) cancers, and for benign gynaecological diseases (23%)
[16]	17 patients with ovarian cancer	Increased CA-125 in 5 patients (29%) Increased CA-125 observed after initial postoperative fall in 9 patients (53%)
[17]	Patients undergoing abdominal surgery (n = 19) vs. patients undergoing extra-abdominal surgery (n = 21)	Increased CA-125 in 53.5% of patients undergoing peritonectomy vs. 16.7% of patients undergoing extra-peritoneal surgery (p < 0.03)
[11]	94 patients undergoing hysterectomy for benign gynaecological conditions	No change in CA-125 at 24 h after operation

The time course for post-operative increase has been reported with conflicting evidence. Levels have been reported to reach a maximum at 2–4 h post-operatively, [10] to show no changes in the first 24 h, [11] and to be highest during the second week after operation. [12] Normalisation after initial increase has been reported take up to 2–3 months post-operatively [10,12].

CA-125 was noted to be raised in many of our patients after CRS/HIPEC despite some of these patients having normal pre-operative readings, and we hypothesise that similar to previous studies assessing CA-125 after abdominal surgery, CRS/HIPEC has an effect on the peritoneum resulting in a reactive rise in CA-125 in the immediate post-operative period. This study seeks to evaluate the values of pre and post-operative CA-125 in patients with complete cytoreduction and HIPEC, and understand the time frame before normalisation of these values, that would allow for CA-125 to be used as a surveillance tool again in these patients.

Materials and methods

Patients

A prospectively maintained, IRB-approved database of all patients who underwent CRS/HIPEC for peritoneal-based malignancies at the National Cancer Centre Singapore from April 2001 through to March 2016, was retrospectively reviewed. Demographics including age, gender, race and tumour type were included in the database and are reported.

Patients considered for CRS/HIPEC had to be of Eastern Cooperative Group (ECOG) performance status 0 or 1, with no distant metastases. All patients were recommended for CRS/HIPEC after evaluation in a multidisciplinary tumour board. The extent of disease in the abdomen and pelvis was examined on CT scan and the absence of extra-abdominal disease either via thorax CT or positron emission tomography (PET)-CT scan was determined.

CRS/HIPEC proceeded according to previously published techniques. Complete cytoreduction was attempted whenever possible. Chemotherapy was infused via a hyperthermia pump (Belmont) into a closed abdomen at a target temperature of 41–42 °C for 60 min. The chemotherapeutic agent used was determined by the primary surgeon and medical oncologist on the basis of primary malignancy.

Thirteen patients underwent a second CRS/HIPEC procedure during the study period and one of these patients also underwent a third CRS/HIPEC procedure. Data were analysed at the procedural level in order to increase the generalisability of results to include patients who underwent multiple procedures. In these instances, listed patient characteristics are representative of the patient’s state at the time of each included operation.

Pre-operative values, measured within one week prior to surgery, were assessed for all optimally cytoreduced patients (completeness of cytoreduction score, CC =0, no visible nodules) and compared to post-operative readings within the first 30 days. Normal CA-125 was defined as a value <35 U/ml. Raised CA-125 was defined using as a value >35 U/ml. Raised (persistent) was defined as a value >35 U/ml that failed to normalise (return to a value <35 U/ml).

Statistics

Continuous variables were expressed as mean ±1 standard deviation (normally distributed data) or medians with interquartile ranges (nonparametric data) and categorical data as proportions throughout the article.

Clinical variables or surgical outcomes and grouping status were compared using Chi-square, Fisher’s exact or ANOVA with Tukey post-hoc testing, as appropriate. A multivariable logistic regression model was used to assess independence of gastrectomy and outcomes. p < 0.05 was considered statistically significant. All statistical analyses were performed using R 3.2.3 [14] (Vienna, Austria).

Results

Baseline characteristics of study population

From April 2001 through to February 2016, a total of 214 CRS/HIPEC were performed on 201 patients. Baseline demographics of 85 patients with complete cytoreduction (no visible tumour), CA-125 measurement within one week prior to surgery (pre-operative) and repeat measurement within 30 d of surgery (post-operative, median 2 readings, range 1–5) are summarised in Table 2. Initial post-operative measurements were taken on median post-operative day 4 (range 1–30) with 51 patients having a second reading on median POD 5 (range 2–27). The majority of patients had primary tumours that were ovarian (31%), colorectal (31%) or appendiceal (16%). All CRS procedures included HIPEC. 43 (51%) of the HIPEC regimen included Mitomycin C, 40 (47%) used cisplatin, 2 (2%) used oxaliplatin. Overall rates of incomplete cytoreduction (0%), serious morbidity (16%) and 60-day mortality (0%) were comparable to previously reported data.

Table 2. Patient demographics.

Category	Parameter	Mean ± SD	Range	Median
Patient characteristics	Age (years)	51 ± 11	19–75	52
	Gender	15 Male (18%)	70 Female (82%)
Intra-operative parameters	Duration (h)	460 ± 150	200–800	460
	PCI score	12 ± 7.5	0–31	10
Surgical procedures	40 sub-diaphragmatic stripping (47%), 46 Colectomy (54%), 23 small bowel resection (27%), 18 cholecystectomy (21%), 19 splenectomy (22%), 21 THBSO (25%), 4 gastrectomy (4.7%), 2 bladder/ureteric resection (2.4%) and 52 Others (61%)
Primary	26 ovarian (31%), 26 colorectal (31%), 14 appendiceal (16%), 8 primary peritoneal (9.4%), 3 mesothelioma (3.5%) and 8 other (9.4%)
Short-term post-operative outcomes	Serious morbidity	14 (16%)
	60 d mortality	0 (0%)
	Incomplete cytoreduction	0 (0%)
	SICU stay	1.3 ± 2.2	0–16	1
	Total hospital stay	19 ± 18	6–77	14

Patterns of CA-125 before and after CRS-HIPEC

The CA-125 measurements of 85 patients with both pre- and post-operative readings and are summarised in Tables 3 and 4. The average change in CA-125 to peak post-operative value was an increase of 28.6 U/ml (range −17.1 to +193) in patients with normal pre-operative CA-125, and -277 U/ml (range −5573 to 91.6) in patients with raised pre-operative CA-125.

Table 3. Number of patients with normal or raised pre- and post-operative CA-125 (>35 U/ml). normal = CA-125 < 35 U/ml, raised = CA-125 > 35 U/ml that subsequently normalised, raised (persistent)=CA-125 > 35 U/ml that failed to normalise.

	Pre-operative		Post-operative reading when normal pre-operative			Post-operative reading when raised pre-operative
	Normal	Raised	Normal	Raised	Raised (persistent)	Normal	Raised	Raised (persistent)
Appendiceal	9 (64.3%)	5 (35.7%)	3 (33.3%)	5 (55.6%)	1 (11.1%)	1 (20%)	1 (20%)	3 (60%)
Colorectal	22 (84.6%)	4 (15.4%)	14 (63.6%)	6 (27.3%)	2 (9.1%)	1 (25%)	1 (25%)	2 (50%)
Ovarian	11 (42.3%)	15 (57.7%)	7 (63.6%)	3 (27.3%)	1 (9.1%)	2 (13.3%)	5 (33.3%)	8 (53.3%)
Mesothelioma	3 (100%)	0 (0%)	2 (66.7%)	0 (0%)	1 (33.3%)	na	na	na
Primary Peritoneal	6 (75%)	2 (25%)	5 (83.3%)	1 (16.7%)	0 (0%)	0 (0%)	0 (0%)	2 (100%)
Others	6 (75%)	2 (25%)	4 (66.7%)	1 (16.7%)	1 (16.7%)	0 (0%)	1 (50%)	1 (50%)
Total	57 (67.1%)	28 (32.9%)	35 (61.4%)	16 (28.1%)	6 (10.5%)	4 (14.3%)	8 (28.6%)	16 (57.1%)

Table 4. Average pre- and post-operative CA-125 reading in (n = 85 patients total).

	Pre-operative		Post-operative		Pre- to post-operative change
	Average CA-125	Range	Average CA-125	Range	Average change in CA-125	Range
Appendiceal	36.8	6.3–109	39.2	6.7–64.7	+2.4	−88.9–+44.9
Colorectal	29.9	3–178	40.4	8.6–217.0	+10.5	−120.9–+193.0
Ovarian	353.0	11.9–6131	55.4	13.1–275.7	−297.6	−5.855.3–+35.0
Mesothelioma	8.9	5.5–11.4	40.9	6.0–102.0	+32.1	−3.7–+90.6
Primary Peritoneal	38.9	5.7–149	24.6	6.9–52.6	−14.3	−112.0–+13.9
Others	18.8	0.7–63.4	42.3	11.4–122.4	+23.5	+5.9–+59.0
Overall	128.9	0.7–6.131	43.5	6.0–275.7	−85.4	−5.855.3–+193.0

Raised post-operative CA-125 in patients with normal pre-operative reading

Of patients with normal pre-operative CA-125, 22 (35%) had raised post-operative CA-125 and are summarised in Supplementary Table 1. A raised CA-125 was seen for patients with appendiceal (n = 6, 67%), ovarian (n = 4, 36%), colorectal (n = 8, 35%) and other (mesothelioma and primary peritoneal) primary cancers (n = 4, 27%). The average peak CA-125 was 80 U/ml (average increase of +63 U/ml) in these patients. For all patients where early post-operative CA-125 was measured (n = 16), the initial values were not raised. The peak value of the raised post-operative CA-125 was noted to be at a median 10 post-operative day (POD) (range 7–0).

Normalisation of raised post-operative CA-125

Of these 22 patients (Supplementary Table 1), 3 (14%) had raised CA-125 persisting beyond 30 d that normalised by POD 59, 75 and 92, respectively. Other patients had normalised by the next CA-125 reading on median POD 49 (range POD 28–115), or had no further CA-125 readings (n = 8, 35%).

The median day of normalisation for patients with normal pre-operative CA-125 and raised post-operative CA-125 was 57 (range 28–115). The median day of normalisation for patients with raised pre-operative CA-125 was POD 41 (range 1–114). Notably 10 patients with raised pre-operative CA-125 had an initial normalisation of CA-125 (median POD 1, range 1–6), followed by a subsequent raised value (median POD 10, range 5–40) and then re-normalisation (median POD 47, range 19–104) (Supplementary Table 2).

Discussion

Early studies on the use of CA-125 reported significant post-operative increases in patients undergoing abdominal surgery for ovarian cancer, other types of cancer, and for benign disease. Although there was no clear consensus as to when this non-specific increase occurs, renormalisation has been reported to take as long as 2–3 months. Our study investigates this non-specific increase in the setting of CRS/HIPEC.

In our cohort of patients undergoing CRS/HIPEC, raised pre-operative CA-125 was most commonly seen in patients with ovarian cancer (57.7%), and is a less common occurrence in other cancer types (0–35.7%). Despite a normal pre-operative CA-125 in the remaining patients, a significant proportion (27–67%) of these have a raised post-operative value with an average change of +28.6 U/ml after surgery.

For patients with normal pre-operative values, raised post-operative CA-125 occurred by POD 10 (range 5–30) despite CA-125 levels remaining normal up to and on post-operative day 5 (range 1–6). In these patients, re-normalisation occurred by a median of POD 49 (range POD 28–115).

A similar non-specific increase in post-operative CA-125 was seen in patients with raised pre-operative CA-125 who experienced an initial normalisation by POD 1 (range 1–6), followed by non-specific increase by POD 10, range 5–40). In these patients, re-normalisation occurs at a similar time course (median POD 47, range 19–104).

The main limitation of the study is the inability to assess the role that HIPEC plays in addition to CRS as we did not assess CA-125 levels in a CRS alone group control group for comparison. The study is also limited by its relatively small sample size and retrospective nature, without systematic measurement of post-operative CA-125 and limited resolution of a time curve beyond POD 10. However, we have been able to demonstrate a delayed non-specific increase in CA-125 after CRS/HIPEC and suggest a time course for renormalisation in keeping with the literature from earlier studies into post-operative changes in CA-125.

Conclusion

It is well established that a significant proportion of patients will have raised post-operative CA-125 after abdominal surgery including non-gynaecological cancers, and benign conditions. Similar increases are seen in patients undergoing CRS-HIPEC with 27–67% having raised post-operative CA-125 up to a month after CRS-HIPEC despite a normal pre-operative value.

For patients with raised pre-operative CA-125 in whom post-operative normalisation can play a role in prognosis, an immediate post-operative CA-125 reading should be taken within 3 d, during which any initial normalisation is seen (POD1, range 1–6). Subsequent non-specific increases in CA-125 seen by POD10 limit the utility of this marker in the later post-operative time period.

In view of the sustained non-specific increase in CA-125 seen after CRS-HIPEC, aside from an immediate post-operative reading the marker should not be measured in the first three months after surgery, following which its use as a surveillance marker can resume.

Disclosure statement

No potential conflict of interest was reported by the authors.