Evaluation of Peritoneal Cancer Index as a Prognostic Marker in Primary Advanced Epithelial Ovarian Carcinoma Undergoing “Interval Cytoreductive Surgery” After Neoadjuvant Chemotherapy

Abstract

Background:

Peritoneal cancer index (PCI) has been validated in patients of primary advanced epithelial ovarian carcinoma (PAEOC) undergoing primary cytoreductive surgery (PCS) but not in patients undergoing interval cytoreductive surgery (ICS) after neoadjuvant chemotherapy (NACT).

Materials and Methods:

Patients with PAEOC undergoing NACT followed by ICS were included in the study. Inclusion criteria comprised patients with extrapelvic peritoneal metastases on imaging at presentation and high-grade serous histology. PCI score was calculated for every patient using the operative records. Effect of PCI on overall survival (OS), progression-free survival (PFS), and completeness of cytoreduction was evaluated.

Results:

One hundred thirty-eight patients were included in the study. High PCI (10–39) was associated with significantly higher chances of incomplete cytoreduction. The 3-year PFS for low PCI, high PCI, complete cytoreduction, and incomplete cytoreduction were 77.8%, 17.9%, 66.6%, and 27.5%, respectively. The 3-year OS were 89.6%, 35.9%, 79.3%, and 41.6%, respectively. PCI and stage at surgery were found to be independent predictors of OS on multivariate analysis.

Conclusion:

Post-NACT surgical PCI score can be used as a prognostic marker in cases of PAEOC undergoing ICS. Also, a higher PCI score portends an increased likelihood of incomplete cytoreduction. (J GYNECOL SURG 37:331)

Background

Malignant ovarian tumors comprise one of the commonest cancers in women. Worldwide, ovarian cancer is responsible for 4.4% of cancer-related mortality among females. The Indian picture is also grim. According to GLOBOCAN 2018,¹ age-standardized incidence rate of ovarian cancer among females is 5.5 per 100,000 in India. Malignant ovarian cancers are the second most common gynecologic cancer and overall third most common cause of cancer in Indian women after breast and cervical cancer. Ovarian carcinoma is generally diagnosed at an advanced stage, in >70% of cases. The International Federation of Gynecology and Obstetrics (FIGO) staging,² especially stage IIIC, for ovarian carcinoma encompasses a wide spectrum of disease and cannot quantitate the tumor burden and its distribution.

Peritoneal cancer index (PCI) score serves as a prognostic marker in peritoneal surface malignancies. It has been validated in cases of GI malignancies, as well as in primary advanced epithelial ovarian carcinoma (PAEOC) who have undergone primary cytoreductive surgery (PCS). However, the prognostic role of PCI in PAEOC has not yet been evaluated in post-neoadjuvant chemotherapy (NACT) setting, that is, in patients undergoing interval cytoreductive surgery (ICS).

Materials and Methods

This study seeks to evaluate the role of PCI score in patients of PAEOC undergoing ICS after NACT. This is an analysis of the clinical records of patients who were operated in the department of surgical oncology at All India Institute of Medical Sciences (AIIMS), New Delhi, between the years 2013 and 2018.

In our outpatient department, all patients suspected of ovarian malignancy were evaluated using standard investigations—chest X-ray, contrast-enhanced computed tomography (CECT) scan of abdomen and pelvis, CA-125, serum albumin, upper and lower gastrointestinal endoscopies, and other routine investigations. The cases were then discussed in a gynecology-oncology tumor board wherein the sequence of treatment, PCS or NACT followed by ICS, was decided. Generally, patients with gross ascites, pleural effusion, poor performance status at presentation, diffuse peritoneal deposits or deposits in regions precluding complete cytoreduction, or requiring multivisceral resection (over small bowel mesentery, hepatoduodenal ligament, celiac axis, behind porta hepatis, duodenum, pancreas, etc.) undergo NACT (paclitaxel and carboplatin, three cycles) after an image-guided core needle biopsy.

The patients were then re-evaluated using CECT to assess feasibility of surgery. If deemed operable by the surgeon, these patients underwent ICS; otherwise, they underwent further three cycles of NACT and re-evaluated. A standard ICS comprised exploratory laparotomy, total abdominal hysterectomy with bilateral salpingo-oophorectomy, greater and lesser omentectomy, pelvic and para-aortic lymphadenectomy, disease-specific peritonectomy, and visceral resections with an aim to achieve complete cytoreduction. Those who achieved complete cytoreduction were thereafter kept on surveillance after completion of the remainder of total six cycles of chemotherapy. Those with inoperable or residual disease were treated as per the decision of tumor board.

Our study included patients who presented upfront (had not earlier received treatment for the disease), had extrapelvic peritoneal metastases on imaging at the time of presentation, had high-grade serous histology, received NACT at our center, and underwent surgery with an intent of ICS. The patients who had undergone debulking surgery before receiving NACT, harboring distant metastases (FIGO IV B), or having a recurrent disease were not included in the study. PCI score was calculated for every patient using the operative records by application of principles described by Sugarbaker.³ Therefore, only the cases with operative records deemed informative enough by the two lead investigators (B.B. and M.R.) were included in the study.

Ethics

This is a noninterventional and nonrandomized study that required evaluation of records of patients who underwent treatment for ovarian carcinoma in the past. The patients were informed at time of treatment that in future their clinical records may be anonymized and used for purpose of clinical research. The study was conducted after approval of institutional ethics committee and research board.

Statistical analysis

The clinical and radiologic data gathered for this study were summarized and analyzed using MS Excel 2016 and STATA (version 14) software. Data were tested for normality using Kolmogorov–Smirnov test. For establishing association, the chi-square or Fisher's exact test was used. The survival curves were established using the Kaplan–Meier method and comparisons were undertaken using the log-rank test and Cox regression. A value of p < 0.05 is considered to represent statistical significance of the study.

Results

A total of 152 patients of PAEOC meeting the inclusion criteria underwent ICS between the years 2013 and 2018. Of whom the operative records of 138 patients were found fit to be included in the study.

The patient characteristics are mentioned in Table 1. The average age was 50.8 years. Majority of patients were postmenopausal (67.4%) and had good performance status (71%). 42.8% had anemia and 13% had low albumin levels at presentation. Fifty-eight percent had clinical ascites at presentation (shifting dullness or fluid thrill). Thirty-six patients (26.1%) had pleural effusion, of whom 15 (10.9%) turned out to be positive on cytology (FIGO IV A).

Table 1.

Clinico-Pathologic and Surgical Characteristics and Their Relation to Operative Peritoneal Cancer Index

	Total (n = 138)	Operative PCI
		Low PCI	High PCI	p
		0–9 (n = 90)	10–39 (n = 48)	p
Age (mean ± SD)	50.8 ± 9.7	51.7 ± 9.9	49.0 ± 9.3	0.314
Menopause
Pre/perimenopausal	45 (32.6%)	27 (30.0%)	18 (37.5%)	0.371
Menopausal	93 (67.4%)	63 (70.0%)	30 (62.5%)
Comorbidities	49 (35.5%)	31 (33.3%)	18 (37.5%)	0.721
Hypertension	23 (16.7%)
Diabetes	14 (10.1%)
Hypothyroidism	13 (9.4%)
Coronary artery disease	3 (2.2%)
Asthma	2 (1.4%)
ECOG performance status
PS 0 or 1	98 (71.0%)	60 (66.7%)	38 (79.2%)	0.123
PS 2 or 3	40 (29.0%)	30 (33.3%)	10 (20.8%)
Anemia (Hb <10 g/dL) at presentation	59 (42.8%)	41 (45.6)	18 (37.5%)	0.362
Low albumin (<3.5 g/dL) at presentation	18 (13.0%)	9 (10.0%)	9 (18.8%)	0.146
Ascites
At presentation (clinical)	80 (58.0%)	51 (56.7%)	29 (60.4%)	0.671
Intraoperative	48 (34.8%)	28 (31.1%)	20 (41.7%)	0.214
CA-125 elevation (>40)
At presentation	122 (88.4%)	81 (90.0%)	41 (85.4%)	0.423
Post-NACT	63 (45.7%)	45 (50.0%)	18 (37.5%)	0.160
FIGO stage at presentation
III B or III C	123 (89.1%)	82 (91.1%)	41 (85.4%)	0.509
IV A	15 (10.9%)	8 (8.9%)	7 (14.6%)
FIGO stage at surgery
0, I or II	33 (23.9%)	33 (36.7%)	0 (0%)	-
III or IV	105 (76.1%)	57 (63.3%)	48 (100%)
PCI
Mean ± SD	7.7 ± 5.3	3.9 ± 2.2	14.8 ± 4.1	-
Median (range)	6 (0–25)	4 (0–9)	13 (10–25)
Complete cytoreduction	103 (74.6%)	82 (91.1%)	21 (43.8%)	<0.001
Operative time (in minutes; mean ± SD)	242.0 ± 79.0	237.1 ± 52.5	251.3 ± 114.3	0.772
Complete cytoreduction	272.1 ± 60.5	248.5 ± 36.1	360.0 ± 52.0
Incomplete cytoreduction	150.0 ± 54.1	120.0 ± 54.8	159.2 ± 52.5
Visceral resection^a	37 (26.8%)	14 (15.5%)	23 (47.9%)	<0.001
Appendix	17 (12.3%)	5 (5.5%)	12 (25.0%)
Colon	11 (8.0%)	4 (4.4%)	7 (14.6%)
Rectum	7 (5.1%)	3 (3.3%)	4 (8.3%)
Small intestine	8 (5.8%)	3 (3.3%)	5 (10.4%)
Stomach	2 (1.5%)	0 (0.0%)	2 (4.2%)
Spleen ± pancreatic tail	10 (7.2%)	3 (3.3%)	7 (14.6%)
Gall bladder	7 (5.1%)	3 (3.3%)	4 (8.3%)
Discharge after surgery (days)	7.2 ± 3.2	6.7 ± 2.3	8.0 ± 4.5	0.063
Perioperative morbidity (CTCAE Grade 3/4)	25 (18.1%)	16 (17.8%)	9 (18.8%)	1.000
Perioperative mortality	1 (0.7%)	0	1	-

Bold values indicate significant p-values.

Resection of any abdominal viscera other than uterus and ovary.

CTCAE, common terminology criteria for adverse events; FIGO, International Federation of Gynecology and Obstetrics; NACT, neoadjuvant chemotherapy; PCI, peritoneal cancer index; PS, performance status; SD, standard deviation.

CA-125 was elevated in 88.4% of patients at presentation and in 45.7% after chemotherapy. 34.8% had free fluid intraoperatively. The mean PCI was 7.7% and 74.6% underwent complete cytoreduction (no gross residual disease). 23.9% of patients did not have any extrapelvic disease at surgery, of whom 12 patients (8.7%) achieved complete response. Twenty-five patients (18.1%) suffered perioperative major morbidity (common terminology criteria for adverse events Grade 3 or 4) such as urinoma, biliary fistula, chylous fistula, bedsore, and vesicovaginal fistula. One patient died due to pulmonary embolism.

A receiver operating characteristic curve plotted the PCI score and overall survival (OS) to find an ambient cutoff point for the analysis (Fig. 1). A cutoff value of 9 was determined to be clinically meaningful (area under curve = 0.81; 95% confidence interval = 0.73–0.89; sensitivity = 70.83% and specificity = 84.4%). The clinico-surgical parameters are sorted into low and high PCI groups in Table 1. Complete cytoreduction was achieved more often in the low PCI group (PCI = 0–9; 91.1% vs. 43.8%; p ≤ 0.001). Multivisceral resection was more common in the high PCI group (PCI = 10 and above; 47.9% vs. 15.5%; p ≤ 0.001). Other parameters did not differ significantly.

FIG. 1.

ROC curve of PCI score regarding OS. OS, overall survival; PCI, peritoneal cancer index; ROC, receiver operating characteristic.

The median follow-up period of the cohort is 32.6 months (2–86 months). Ten patients were lost to follow-up. Sixty-three patients progressed and 48 patients died during the follow-up period. The 3-year progression-free survival (PFS) for low PCI, high PCI, complete cytoreduction, and incomplete cytoreduction were 77.8%, 17.9%, 66.6%, and 27.5%, respectively. The 3-year OS were 89.6%, 35.9%, 79.3%, and 41.6%, respectively.

The median OS and PFS were 66.27 and 40.4 months, respectively. Upon log-rank analysis, both PCI and complete cytoreduction were found to have a significant impact on OS and PFS (p < 0.01). The Kaplan–Meier curves are depicted in Figure 2.

FIG. 2.

Kaplan–Meier curves. (A) OS in patients with low (0–9) and high (10 and above) PCI score; (B) OS in complete and incomplete cytoreduction; (C) progression-free survival in patients with low and high PCI score; (D) progression-free survival in complete and incomplete cytoreduction. CRS, cytoreduction.

Upon univariate Cox regression analysis PCI, complete cytoreduction, pleural effusion at presentation, stage at presentation, and at surgery were found to have a significant impact on PFS, whereas PCI, complete cytoreduction, albumin at presentation, stage at presentation, and at surgery impacted OS. Multivariate analysis excluded completeness of cytoreduction from analysis as it has significant association with PCI. PCI and pleural effusion at presentation were found to significantly impact PFS, whereas PCI and stage at surgery were independent predictive factors for OS (Table 2).

Table 2.

Univariate and Multivariate Analysis of Progression-Free Survival and Overall Survival

Factor	Progression-free survival			Overall survival
Factor	HR	95% CI	p	HR	95% CI	p
Univariate analysis
Age (≤50 vs. >50)	0.75	0.46–1.23	0.256	0.77	0.44–1.37	0.378
ECOG PS (0–1 vs. 2–3)	1.87	0.87–3.10	0.116	1.19	0.65–2.18	0.570
Menopause	1.17	0.67–2.02	0.571	0.81	0.43–1.52	0.512
Anemia	0.65	0.39–1.09	0.109	1.00	0.56–1.79	0.989
Albumin	1.88	0.99–3.53	0.052	2.55	1.31–4.97	0.036
Comorbidity	0.98	0.59–1.63	0.950	0.62	0.33–1.15	0.128
CA-125 at presentation	2.16	0.78–5.98	0.136	1.70	0.61–4.78	0.310
Ascites at presentation	0.88	0.53–1.44	0.605	0.58	0.33–1.02	0.062
Pleural effusion at presentation	2.69	1.62–4.51	0.002	1.44	0.79–2.63	0.238
Stage at presentation (III vs. IV)	3.66	2.07–6.50	<0.001	2.07	1.03–4.18	0.040
CA-125 after NACT	1.13	0.65–1.96	0.675	0.84	0.44–1.56	0.580
Ascites—intraoperative	1.39	0.84–2.28	0.197	1.57	0.89–2.77	0.121
PCI (0–9 vs. 10–39)	6.63	3.83–11.5	<0.001	7.29	3.88–13.7	<0.001
Complete cytoreduction	3.85	2.31–6.40	<0.001	3.78	2.12–6.71	<0.001
Stage at surgery (0–2 vs. 3–4)	3.64	1.73–7.66	0.001	6.17	2.20–17.3	0.001
Discharge after surgery (≤5 vs. >5 days)	0.86	0.52–1.41	0.557	0.81	0.45–1.47	0.493
Perioperative morbidity	0.72	0.40–1.32	0.296	0.59	0.28–1.26	0.174
Multivariate analysis
PCI	4.88	2.78–8.52	<0.001	6.57	3.41–12.6	<0.001
Pleural effusion at presentation	2.07	1.24–3.47	0.005	—	—	—
Stage at surgery	2.13	0.98–4.62	0.054	3.86	1.36–10.9	0.011

Bold values indicate significant p-values.

CI, confidence interval; HR, hazard ratio.

Discussion

The FIGO system is universally used to prognosticate cases of carcinoma ovary. The FIGO stage IIIC encompasses a wide spectrum of disease—ranging from a single deposit >2 cm anywhere in the extrapelvic peritoneal cavity to a peritoneum studded with disease. Also, it is well established that the optimality of cytoreduction has a considerable impact on outcomes; however, the FIGO system does not include any such variable. Therefore, a need is felt to validate a tool that can objectively quantify the tumor burden, its distribution, and the residual disease.

Jacquet and Sugarbaker,³ in 1996, described the PCI score for gastrointestinal malignancies. It has been validated as a prognostic marker for colorectal carcinoma with peritoneal metastases. Sugarbaker⁴ in a prospective study of 100 patients demonstrated that patients with lower PCI had a better prognosis for survival. Elias⁵ in a retrospective study of 64 patients found that patients with a PCI <16 had better survival rates. Glehen et al.⁶ evaluated its significance in gastric cancer and Schaub et al.⁷ in malignant peritoneal mesothelioma.

Tentes et al.⁸ first evaluated the role of PCI in ovarian carcinoma. Sixty patients of PAEOC were retrospectively included in study and underwent PCS. 68.3% received platinum-based adjuvant chemotherapy. PCI cutoff of 10 was used for the study. On univariate analysis, both PCI and CC score were found to be impact survival. Tentes et al.⁹ in another study validated PCI and CC score in patients of carcinoma ovary undergoing cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy for primary or recurrent disease.

Lampe et al.¹⁰ concluded that PCI more precisely defined the heterogenous group of patients with FIGO stage III primary ovarian carcinoma, provided objectivity and reproducibility and a prognostic indicator of resectability, that is, CC score.

Gasimli et al.¹¹ retrospectively enrolled 80 patients of primary advanced ovarian carcinoma who underwent PCS with complete cytoreduction to assess the prognostic value of PCI independent of completeness of cytoreduction score. Patients who received NACT were excluded from the study. Higher PCI was associated with poor OS (PCI ≥18) and PFS (PCI ≥13) on univariate analysis. However, on multivariate analysis, the association remained significant only for PFS and not OS. Llueca et al.¹² in a similar cohort found PCI >15 to be associated with poorer overall and disease-free survival.

Elzarkaa et al.¹³ conducted the only prospective study on this subject. Only patients with PAEOC (stage IIIB–IVA) who underwent PCS were included. A PCI score cutoff value of 13 was calculated. Higher PCI was associated with worse survival on univariate analysis. Suboptimal cytoreduction was the only independent factor predictive of recurrence and death.

NACT in PAEOC is associated with higher optimum debulking rate with reduced postoperative morbidity and improved quality of life.¹⁴ The patients undergoing ICS have no significant difference in OS or PFS vis-à-vis those undergoing PCS for PAEOC.^15,16

To the best of our knowledge, no study has yet evaluated the prognostic role of PCI score in patients having received NACT and undergone ICS. In our study, we evaluated records of patients with extrapelvic peritoneal metastases (Stage IIIB–IV A) at presentation with high-grade serous histology, having received NACT and undergone ICS.

The mean PCI is 7.7 and the cutoff determined is 9, which is slightly lower than that in other studies.^8–13 This is because our study is conducted in a post-NACT setting, which would decrease the tumor bulk and consequently the PCI score. The higher PCI score in our study was associated with higher rates of incomplete cytoreduction. Both PCI and completeness of cytoreduction were found to significantly affect disease progression and OS. These findings are in consonance with other studies, which were conducted for patients of PAEOC undergoing PCS or recurrent ovarian carcinoma undergoing secondary cytoreduction for carcinoma ovary. PCI and stage at surgery were independent prognostic factors affecting OS.

The limitation of our study is that it is retrospective in nature and PCI was calculated using the operative records. This could have resulted in errors in calculation of PCI despite best of efforts.

Conclusion

We conclude from our study that PCI score has a prognostic significance in patients of PAEOC undergoing ICS after NACT. Patients with PCI score >9 have a significantly poor prognosis than those with lower scores. PCI also has a significant association with completeness of cytoreduction in these patients. The clinical applications of PCI score in cases of ICS should be assessed in future studies.

Footnotes

Author Disclosure Statement

No competing financial interests exist.

Funding Information

No funding was received for this article.

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