Comparison of primary debulking surgery and neoadjuvant chemotherapy plus interval debulking surgery for epithelial ovarian cancer with extra-abdominal metastasis

doi:10.21203/rs.3.rs-2463011/v1

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Comparison of primary debulking surgery and neoadjuvant chemotherapy plus interval debulking surgery for epithelial ovarian cancer with extra-abdominal metastasis

https://doi.org/10.21203/rs.3.rs-2463011/v1

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Background

Primary debulking surgery (PDS) or neoadjuvant chemotherapy with interval debulking surgery (NACT-IDS) was the standard treatment for advanced ovarian cancer. Optimal cytoreduction is believed one of the most important factors for survival. However, in patients with extra-abdominal metastases which is impossible to achieve optimal cytoreduction around whole body, which treatment should be used is not clear yet.

Methods

Patients with stage IV epithelial ovarian cancer with extra-abdominal metastases who underwent primary treatment between January 1, 2015 and January 31, 2022 were identified. Data were retrospectively extracted. Each patient record was evaluated to subclassify stage IV disease according to the sites of metastases at the time of diagnosis. Kaplan-Meier plot and Log-rank test were used to analyze the difference between two groups. Univariate and multivariate Cox regression analysis were used to identify important prognostic factors.

Results

A total of 72 newly diagnosed stage IV epithelial ovarian cancer patients were included, in which 36 (50%) patients underwent PDS, 36 (50%) patients underwent NACT-IDS. The median overall survival was significantly longer in PDS group than NACT-IDS group (51.3 months vs. 36 months, p = 0.027). Patients receiving PDS has significantly longer progression-free survival than who received NACT-IDS (21.6 months vs. 14.3 months, p = 0.049). The rate of no residual disease was higher in patients with NACT-IDS versus PDS (61% vs. 44%). The complete response rate was significantly higher in PDS group than NACT group (83% vs. 67%, p = 0.013) after PDS/IDS and full course of chemotherapy. Women who received PDS had a trend toward a higher rate of grade III/IV postoperative complications than those who received NACT (25% vs. 6%, p = 0.046).

Conclusions.

PDS for epithelial ovarian cancer patients with extra-abdominal metastasis resulted in longer OS and PFS than NACT + IDS. Cytoreduction to no residual disease in the interval debulking surgery should be the goal in patients who receive NACT.

distant metastasis

epithelial ovarian cancer

primary debulking surgery

neoadjuvant chemotherapy

overall survival

progression-free survival

Epithelial ovarian cancer (EOC) is the third most common and the most lethal gynecologic cancer, with approximately 300,000 new cases and 185,000 deaths per year [1]. About 70% of patients are diagnosed with advanced-stage disease (stages III/IV), and fewer than 50% will survive more than 5 years [2]. FIGO stage IV OC patients with extra-abdominal metastasis (including malignant pleural effusion, visceral/lymph nodes metastases) have the worst prognosis. The current available treatments for these patients were primary debulking surgery (PDS) followed by adjuvant chemotherapy or neoadjuvant chemotherapy (NACT) followed by interval debulking surgery (IDS) depending on the general condition and tumor load of patients. PDS has been historically used as standard treatment for ovarian cancer, particularly in more earlier stages. However, throughout the past 20 years, NACT-IDS has been playing a more and more important role in patients with most advanced disease, especially those who cannot tolerate upfront surgery. A couple of powerful studies have suggested non-inferiority of NACT-IDS in advanced ovarian patients. These studies have also emphasized the importance of no residual disease in the abdomen (R0) in overall survival (OS) and progression-free survival (PFS) of patients.

An R0 resection of abdominal disease is one of the most important factors to achieve long-term survival for advanced ovarian cancer patients. Depending on whether an optimal debulking surgery could be performed, either PDS or NACT-IDS could be chosen as a definitive treatment. When there is a high possibility to resect all the macroscopic tumors (R0), primary debulking surgery is highly recommended. Otherwise, NACT would be the first choice if radiology (Suidan CT criteria) or laparoscopic exploratory surgery (Fagotti criteria) suggest difficulty to achieve R0. Currently, most therapeutic studies which focuses on advanced ovarian cancer included stage IV patients together with stage III patients. However, stage IV disease is biologically different from stage III, especially for those with extra-abdominal metastasis. Normally, neither PDS nor IDS would remove the extra-abdominal metastases, for example, those metastases in the mediastinum, bone, lung, etc, except for those superficial sites such as cervical or inguinal lymph nodes. Since the extra-abdominal metastases are usually unresectable, is it still important to strive for R0 at the cost of extended resection and consequent adverse events? Also, in this case, which treatment should we choose for these patients? Obviously, the treatment strategies for stage IV patients with extra-abdominal metastasis need not slavishly follow those set out for patients with stage III disease. Sadly, to date, we’ve seen no study comparing the effect and safety of PDS vs. NACT-IDS for this special group of patients.

Therefore, the main purpose of our study was to retrospectively compare the survival outcomes of PDS followed by adjuvant platinum-based chemotherapy to NACT-IDS for EOC patients with extra-abdominal metastases. We also designed subgroup analysis to compare the safety of two treatments and explored whether R0 has an important role in the survival of EOC patients with extra-abdominal metastases.

2.1 Patients

This study followed the Declaration of Helsinki and was approved by the Committee at Obstetrics and Gynecology Hospital of Fudan University (IRB number 2021-93). All participants provided written informed consent.

We reviewed the medical records of women diagnosed with epithelial ovarian, tubal and peritoneal cancer who was admitted by our hospital in the past 6 years (between January of 2015 and January of 2022). The patients who had extra-abdominal metastasis were then selected, including those with positive pleural cytology, biopsy or pathology-proved visceral metastatic tumor or enlarged lymph nodes outside the abdomen. Our inclusion criteria were that patients had (1) a pathology report suggesting EOC and (2) had extra-abdominal metastasis which was confirmed by biopsy or pathology and (3) received PDS followed by adjuvant chemotherapy or NACT-IDS. Patients were removed from the study if they (1) had a previous history of other malignancies, or (2) were diagnosed as mucinous adenocarcinoma or low-grade adenocarcinoma, or (3) received only chemotherapy but no surgery or received no treatment. The decision to perform PDS or IDS was based on surgeons’ judgement. The PDS or IDS was performed by gynecologic oncologists with or without assistance of general surgeons. Pre- and postoperative chemotherapy was based on platinum and paclitaxel with or without bevacizumab according to surgeons’ determination. PARP inhibitor was the first choice of maintenance therapy in selected patients according to surgeons’ evaluation.

2.2 Data collection and follow up

The information was mainly collected from the medical history database of Obstetrics and Gynecology Hospital of Fudan University. The information of patients who received chemotherapy or surgery at other hospital was collected from their discharge summaries provided by the hospital. The patients' information included each patient's age, stage, treatment, symptoms, numerical value of CA-125, maximal diameter of tumor before any treatment, amount of pleural effusion, amount of ascites, cycles of chemotherapy pre- and after the surgery, duration of surgery, contents of operation, time of hospitalization, pathology and residual disease. The follow-up information was collected by telephone. When the time of death was not accessible, the last follow-up was defined as the endpoint.

2.3 Data analysis

SPSS version 23 and Prism 9 was used for computation and plotting. Comparisons between categorical variables were performed using χ2 and t-tests as appropriate. Fisher’s exact test was used in the conditions where number of patients < 5. P-value less than 0.05 was considered statistically significant, and all reported P values were two-sided.

The OS was defined as the interval from the start of treatment (primary surgery for PDS or first course for NACT) to the time of death or the last follow-up. The PFS was defined as the interval from start of treatment to the time of first relapse or death. The OS and PFS was analyzed with the Kaplan-Meier method and log‐rank tests. Several clinicopathological factors that could have an association with OS or PFS were analyzed in the univariate analyses, based on the Cox proportional hazard model. The factors with a p-value < 0.2 and other factors which are reported to be important prognostic factors were then analyzed in a multivariate Cox regression analysis to test jointly the relative importance as predictors of OS and PFS.

The clinically relevant factors we selected for univariate analysis include treatment (PDS or NACT), patients’ age, maximal diameter of tumor, level of CA125, presence or absence of malignant pleural fluids, enterostomy, sites of metastasis (IVA vs IVB), and residual disease after surgery. The residual disease was recorded as either no macroscopic abdominal disease (R0), < 10 mm (R1) or > 10 mm (R2) residual disease in the abdomen.

3.1 Patient characteristics

We reviewed the data of 342 women diagnosed with stage IV epithelial OC in our institute from Jan. 1st, 2015 to Jan. 31st, 2022. Among them, 190 women had extra-abdominal metastasis. Patients who had mucinous adenocarcinoma or low-grade adenocarcinoma were not included in these patients. Among 190 patients, 110 patients who had metastasis identified only by radiology (such as CT and PET/CT) but not pathology were excluded. Five patients who received only chemotherapy or never received any therapy were excluded. Three patient who received surgery at other hospitals was excluded because of missing medical records. Finally, 72 eligible patients were left for analysis (Fig. 1). Ovarian, tubal, or peritoneal cancer were confirmed by pleural cytology, lymph node biopsy or post-PDS pathology in all the included patients. Their baseline characteristics were summarized in Table 1.

Table 1 Baseline characteristics of patients. Data are median (range) or n (%). PDS, primary debulking surgery. NACT-IDS, neoadjuvant chemotherapy followed by interval debulking surgery.

Baseline characteristic	PDS (n = 36)	NACT-IDS (n = 36)	P value
Age (years), median (range)	51 (32–76)	53 (37–74)	0.82
Maximal size of tumor (mm), median	70	58	0.65
CA125, IU/ml
0-500	11	5
500–1000	12	7
1000–5000	11	16
> 5000	2	4*	0.04
Metastasis site outside of abdomen**, n
Malignant pleural effusion	22	25
Lung Lymph nodes Inguinal Clavicular Axillary Cervical Subcutaneous	1 10 2 0 2 1	0 5 5 1 0 0	0.22
Pathology, n
High grade serous carcinoma	32	35
Endometrioid adenocarcinoma	2	0
Mixed	2	0	0.14
Pathological origin, n
Ovarian	22	13
Tubal	2	7
Peritoneal	2	1
Mixed (ovarian + tubal)	10	15	0.09
BRCA mutation, n	5/12	7/10

*The value of CA125 of 4 patients were missing.

**Some patients have more than one site of cytology/biopsy/pathology proved metastasis.

Overall, there were 36 (50%) patients in the PDS group and 36 (50%) patients in the NACT group. From Jan. 2015 to Dec. 2018, a total of 24 patients were included, in which 13 (54%) patients underwent PDS, while 11 (46%) patients underwent NACT. From Jan. 2019 to Jan. 2022, a total of 48 patients were included, in which 23 (48%) patients underwent PDS, while 25 (52%) patients underwent NACT. Overall, 46 (64%) patients were categorized as having stage IV disease with extra-abdominal metastasis because of positive pleural cytology. Metastasis to the lymph nodes outside the abdomen was found in 24 (34%) patients. One (1%) patient had parenchymal lung metastasis, while another (1%) patient had subcutaneous metastasis. The median age of diagnosis was 52 years old in our study. There were more patients in NACT group with higher serum CA-125 quantification at diagnosis. 56% of patients in the NACT group had serum CA-125 higher than 1000 IU/ml, compared to 36% of patients in the PDS group.

Among the most advanced ovarian cancer patients with extra-abdominal metastasis, the most common initial symptom was abdominal distention or pain, which was complained in 62.5% of patients. Chest tightness, dyspnea and shortness of breath was the second most common symptoms in 26.4% of patients, followed by anorexia which was complained in 15.3% of patients. Other symptoms or signs included weak and fever, compressive symptoms such as change in bowel habit and lower limb swelling. Vaginal bleeding could also be the first symptoms in some patients. Note that 19.4% of patients had no symptom but only had unexplained palpable lumps or found by accident or routine physical examination (Table supplementary 1).

Table 2 summarizes the contents, outcomes, and complications of PDS/IDS. Overall, 34 out of 72 (47%) patients received laparoscopy, while 37 (51%) patients received open surgery. One patient died after two cycles of neoadjuvant chemotherapy and did not receive interval debulking surgery. We defined aggressive surgery as those include a small or large bowel resection, diaphragm resection, liver resection or splenectomy. Around the whole cohort, 8 (22%) patients in PDS group the and 5 (14%) patients in the NACT group received aggressive surgery (p=0.54). Eight (22%) patients in the PDS group and ten (28%) patients in the NACT group around whole cohort (p=0.54) had upper abdominal procedures, which included tumor resection around diaphragm, paracolic sulci, hepatorenal recess, surface of liver, surface of stomach, and surface of transverse colon. Nine (13%) out of all patients had enterotomy followed by anastomosis or ostomy. The rate of enterotomy was higher in the PDS group than NACT group (17% and 8% in each group, respectively). 39% of patients in the PDS group versus 25% of patients in the NACT group received blood transfusion. The duration of surgery in the PDS group was not significantly different from NACT group. The mean time of surgery in both groups was around 230-240 minutes. However, patients who received PDS stay 3 more days in average in the hospital after surgery than whose who received NACT+IDS. Patients in the PDS group are more likely to spent at least one day in intensive care unit than NACT group (19% vs. 6%). The rate of optimal debulking was higher in NACT group. 61% patients in the NACT group had no residual disease after IDS, compared to 44% patients with no residual disease in the PDS group. The proportion of patients with less than 1cm residual tumor (R0 and R1) was 83% in the PDS group and 92% in the NACT group, respectively.

Table 2

The contents, outcomes, and complications of PDS/IDS.
Types		Initial symptoms & signs	N (%)
Constitutional symptoms		Weak	1 (1.4)
Constitutional symptoms		Fever	3 (4.2)
Thoracic symptoms		Chest tightness, dyspnea or shortness of breath	19 (26.4)
		Cough or expectoration	8 (11.1)
		Chest pain	2 (2.8)
Abdominal symptoms		Abdominal distention or pain	45 (62.5)
Abdominal symptoms		Anorexia	11 (15.3)
Compressive symptoms		Backache	1 (1.4)
		Constipation or slender stool	3 (4.2)
		Frequent defecation	5 (6.9)
		Lower limb swelling	2 (2.8)
Vaginal bleeding	Postmenopausal bleeding or prolonged menstruation		3 (4.2)
No symptom	Palpable lumps		7 (9.7)
No symptom	Found by accident or routine physical examination		7 (9.7)

*Para-diaphragmatic: tumor resection around diaphragm, paracolic sulci, surface of liver, surface of stomach, and surface of transverse colon

**According to Clavien classification of surgical complications.

***Primary treatment means PDS followed by 6–8 cycles of postoperative chemotherapy, or NACT followed by IDS and corresponding cycles of postoperative chemotherapy.

All patients included in this study received full course of platinum- and paclitaxel-based chemotherapy combined with or without bevacizumab during primary treatment. In the PDS group, patients were given 6–8 cycles of chemotherapy after primary debulking surgery. In the NACT group, IDS was performed after 2–5 cycles of preoperative chemotherapy, followed by 2–5 cycles of postoperative chemotherapy of the same regimen. The total chemotherapy received by patients in the NACT group was 6–8 cycles. In both groups, patients started chemotherapy at 16 days in average after the PDS/IDS. After full course of PDS plus postoperative chemotherapy or neoadjuvant chemotherapy followed by IDS and postoperative adjuvant therapy, significantly more patients in the PDS group achieved complete response than NACT group (83% vs 67%, respectively, p = 0.013). There were significantly more patients with progression disease in the NACT group than PDS group (31% vs. 6%, respectively). In 22 patients who had genetic test after full course of primary treatment, 10 patients were BRCA1/2 wild type and 12 patients had BCRA1/2 mutation. The BRCA1/2 mutation rate in the PDS group and NACT group in this study was 42% and 70%, respectively.

3.2 Survival analysis

The median follow-up time was 22.2 months (ranged from 1.6–67 months). Patients were analyzed according to treatment group. The median OS was 51.3 months for PDS group and 36 months for NACT group (p = 0.027). The median PFS was 21.6 months in the PDS group and 14.3 months in the NACT group (p = 0.049) (Fig. 2).

By the end of the last follow-up, a total of 32 out of 72 (44%) patients died. The number of patients who died in the PDS group and NACT group was 14 (39%) and 18 (50%), respectively. No one died of post-operative acute complications. The patient with shortest OS (1.6 months) was in the NACT group. She died of deep vein thrombosis after 2 cycles of NACT. The patient with the second shortest OS (3 months) was in the PDS group. Her general condition was extremely poor after the PDS and she died after one cycle of postoperative chemotherapy. Two patients (one in the PDS group and another in the NACT group) died during postoperative chemotherapy. The rest 68 patients all finished PDS/IDS and full courses of pre- and post-operative chemotherapy.

There was no significant difference between stage IVA (i.e. patients with only hydrothorax) and IVB patients (those with extra-abdominal visceral or lymph node metastasis) in OS and PFS (p = 0.89 and 0.93, respectively) (Fig. 3). The median OS was 43.2 and 42.9 months for IVA and IVB patients, respectively. The median PFS of IVA and IVB patients was 17.4 and 17 months respectively. Metastasis to different sites (pleural versus lymph nodes) is not associated with significantly different survival outcomes (p = 0.58) (Fig. 3).

Different residual diseases (R0/R1/R2) did not show a significant role in progression-free survival and overall survival (p = 0.53 and 0.96, respectively) when analyzing all 72 patients as a whole (Fig. 4). Further analysis which dividing the whole cohort into just two groups (R0 and non-R0) did not make the difference significant. Even in each group (PDS/NACT), there was no evidence that different residual diseases may influence PFS or OS in advanced EOC patients with extra-abdominal metastases.

In the univariate Cox regression analysis, the variables with P-value < 0.2 included treatment and diameter of largest tumor at diagnosis. These two variables were considered the potential prognostic factors and proceeded to multivariate analysis. Considering the importance of age at diagnosis, serum CA125 level, and residual diseases as many studies have indicated, we also included these factors in the multivariate Cox regression analysis (Table 3). Our result shows that treatment (PDS/NACT) was an independent prognostic factors for OS (p = 0.047).

Table 3

The univariate and multivariate cox regression analysis of variables which may have an influence on the survival of patients. Eight variables were included in the univariate analysis, among which only treatment and diameter of largest tumor at diagnosis had p value lower than 0.2. Considering the importance of age at diagnosis, serum CA125 level, and residual diseases, we also included these factors in the multivariate Cox regression analysis. Finally, only treatment was suggested as the significant important prognostic factor for survival (p = 0.047).
Variable	Univariate		Multivariate
	Risk ratio (95% CI)	P value	Risk ratio (95% CI)	P value
Treatment
NACT	1.00 (reference)		1.00 (reference)
PDS	0.471 (0.215–1.032)	0.06	0.369 (0.138–0.988)	0.047
Age at diagnosis
<55 years	1.00 (reference)		1.00 (reference)
≥55 years	0.941 (0.428–2.071)	0.881	1.168 (0.467–2.923)	0.740
Diameter of largest tumor at diagnosis
<65 mm	1.00 (reference)		1.00 (reference)
≥65 mm	2.087 (0.877–4.966)	0.096	2.591 (0.976–6.878)	0.056
CA125 serum level
< 600 IU/ml	1.00 (reference)		1.00 (reference)
≥ 600 IU/ml	1.197 (0.499–2.869)	0.687	1.049 (0.361–3.050)	0.930
Positive pleural cytology
No	1.00 (reference)		-	-
Yes	1.56 (0.618–3.936)	0.347	-	-
Enterostomy
No	1.00 (reference)		-	-
Yes	0.731(0.171–3.127)	0.672	-	-
Sites of metastasis
Pleura (IVA)	1.00 (reference)		-	-
Lymph nodes or parenchyma (IVB)	0.825 (0.376–1.809)	0.631	-	-
Residual disease
R0	1.00 (reference)		1.00 (reference)
R1/R2	0.985 (0.453–2.139)	0.969	1.174 (0.486–2.835)	0.722

In this retrospective research, primary debulking surgery followed by chemotherapy was compared with neoadjuvant chemotherapy followed by interval debulking surgery in ovarian cancer patients with extra-abdominal metastasis. We found that overall survival and progression-free survival after primary debulking surgery followed by chemotherapy was significantly better than survival after neoadjuvant chemotherapy followed by interval debulking surgery.

The superiority of PDS and NACT for metastatic OC has been discussed over the years and has not reached an agreement. In 2010, the EORTC trial launched by Vergote I et al randomly assigned 670 OC patients with stage IIIC or IV to PDS and NACT, which came to the conclusion that NACT + IDS was not inferior to PDS [3]. The median PFS and OS for patients who received PDS were 12 months and 29 months, respectively. Meanwhile, they emphasized the importance of R0 whenever the debulking surgery was performed. In 2015, the CHORUS trial launched by Sean K et al supported this opinion with shorter median PFS and OS results (10.7 months and 22.6 months for PDS group, respectively) [4]. In 2020, the SCORPION trial launched by Fagotti A et al also suggested the similar efficacy of PDS and NACT on advanced epithelial OC and a higher score of quality of life in patients who received NACT [5]. However, there were other studies suggesting the different efficacy between the two groups. In 2012, Dennis S Chi et al retrospectively analyzed the survival of patients who received PDS in Memorial Sloan-Kettering Cancer Center [6]. The median PFS and OS reported in their article were 17 months and 50 months, respectively. Besides, over 70% of patients had residual disease less than 1cm. They insisted that only patients who cannot tolerate surgery or who were deeded not candidate for an R0 surgery or in the absence of professional surgical team can consider NACT. Barry R et al reported a dramatic difference in seven-year overall survival between the PDS group and NACT group (41% vs. 8.6%; p < 0.00001), strongly suggesting the benefits of PDS [7]. In the PDS group of their study, patient who reached R0 had significantly higher 7-year survival rate than who did not reached R0 (73.6% vs 21%).

To date, most of the studies combined stage III or stage IV ovarian cancer patients, and most studies emphasized the importance of no residual disease in prognosis. It seemed that the superiority of PDS or NACT has not reached an agreement yet. However, in our clinical practice, we did observe the superiority of PDS in patients who had extra-abdominal metastasis. These patients were deemed not R0 candidate for PDS, and their performance status were usually bad, but we still observed longer PFS and OS in patients who received PDS, and our results proved our observation. In our study, the median PFS (21.6 months vs. 14.3 months) and OS (51.3 months vs. 36 months) of patients who received PDS were significantly higher than NACT. The results of PFS and OS in the PDS group in our study were longer than the common 20–49 months for OS and 10–14 months for PFS reported in the previous studies [3–7]. We assumed the reason for this is because the maximal effort to reach R0 and cooperation of professional surgical team and oncological team in our hospital. The long mean duration of surgery (around 240 mins in both groups) enables complete resection and careful operation to maximally reduce residual diseases and complications. Our high proportion of aggressive surgery (in 36% of patients) reflected our goal to achieve R0 in every patient. Indeed, we have to admit that there were limitations that may cause bias to our results. For example, the small number of patients included in this hospital may bring bias to the survival results. Besides, 40 out of 72 (56%) patients in this study were admitted by our hospital in the last 2 years (from 2020 Jan. to 2022. Jan). Only less than half of patients died by the end of observation. The short follow-up time of these patients may result in a relatively high rate of censoring and potential overestimation of OS in our study. Another difference between our study and previous studies is the higher proportion of patients using maintenance therapy. Since the accessibility of PARP inhibitors and promotion of bevacizumab as maintenance therapy, the survival of advanced ovarian cancer has been significantly prolonged than 10 year ago. However, our result is still statistically significant to support the viewpoint that PDS is associated with longer PFS and OS than NACT for OC patients with extra-abdominal metastasis.

Meanwhile, our study raised doubts in the importance of R0 as the basic requirement for PDS/IDS and as the most important prognostic factor for OC patients with extra-abdominal metastasis. In our study, the rate of R0/R1/R2 was consistent with the rate reported in other articles [3–7], but we did not observe a significant influence of residual disease on PFS or OS as expected. In addition, even though patients in NACT group had higher R0 rate, they did not get longer PFS or OS. In fact, due to the setting of our inclusion criteria, even though the patients achieved abdominal R0, there would still be extra-abdominal tumors left. These residual tumors may erase the survival benefit brought by achieving abdominal R0 and explains why different residual disease resulted in similar survival in our study. On the other hand, maximal efforts to perform R0 surgery often comes with higher risk of complications, such as enterotomy, time-related anesthetic accidents and coagulation disorders. Patients are more prone to ICU admission and longer hospitalization as our study indicated. Since our results found no significant relationship between abdominal residual disease and survival, whether we can reduce aggressive procedures and shorten surgery time in selected patients to reduce complications and improve their quality of life? For example, leaving small nodules on the surface of the small intestine for postoperative chemotherapy may be better than stripping the nodules which may lead to lethal intestinal damage. What’s more, in the current standard preoperative evaluation, most surgeons would delay surgery when R0 cannot be achieved. Because of the obscure role of R0 and probably better prognosis of PDS as our study suggested, whether we can perform surgery and brings better survival for those patients who are deemed not candidates for PDS? Obviously, the exact role of abdominal residual disease in OC patients with extra-abdominal metastasis need further investigation. More studies are needed to clarify the significance of maximal efforts to achieve abdominal R0 to help the surgeons balance benefits and complications in the future.

Previously, only few articles explored the reason for why NACT was associated with shorter survival. Here, we assumed several reasons to answer this question. First, in our study, the complete response rate was significantly higher in PDS group than NACT group (83% vs. 67%, p = 0.013) after PDS/IDS and full course of chemotherapy. There were significantly more patients with progression disease in the NACT group than PDS group (31% vs. 6%). The lower complete response rate and higher progression disease rate strongly indicated weaker efficacy of NACT. Secondly, some studies suggested an increased risk of platinum resistance in patients who received NACT [8 9 10]. After neoadjuvant chemotherapy, the occurrence of fibrosis makes identification and complete resection of macroscopic disease more difficult [3]. What’s more, since most sensitive tumor cells were killed after neoadjuvant chemotherapy, the residual tumors tend to be resistant clones, with may develop to recurrent tumors. Additionally, NACT applies chemotherapy when the tumor load is still high. The regional drug concentration is consequently decreased under same drug dose compared to PDS. Thirdly, the general condition of patients who received NACT tends to be worse. This may cause bias in the baseline characteristics and survival outcomes may be influenced.

Difference in complications and quality of life between NACT group and PDS group were the common discussion in most studies. Lower risk of death and higher quality of life were once the most persuasive advantages of NACT [???????], but with the development of professional surgical teams in these years, these advantages are fading. In our study, NACT was not associated with a significantly higher minimally invasive surgery compared to PDS group as expected. None of the patients died within 3 months after PDS. By contrast, one patient died of deep vein thrombosis after 2 cycles of NACT. Shorter operation time and lesser upper abdominal procedures/aggressive procedures were also believed to be advantages of NACT. However, in our study, the mean operation time (around 240 minutes) was similar between two groups. The rate of upper abdominal procedures/aggressive procedures was comparable between two groups. These results suggested that some advantages of NACT were not prominent in advanced EOC patients, especially those with extensive distant metastases. The surgeons should comprehensively take survival benefits and postoperative complications into consideration when deciding treatment for this special group of patients.

There were other findings of our study. For example, we found evidence to support the conclusion of other studies that division into IVA/IVB did not affect overall survival [11 12 13]. For example, in the SCORPION trial, CA125 was identified as a significant prognostic factor for progression-free survival and overall survival [4], but our results disagree with the association between CA125 and overall survival. However, restricted by our small population of patients, these findings should be tested in larger populations.

In conclusion, the overall survival and progression-free survival after primary debulking surgery followed by chemotherapy was significantly longer than survival after neoadjuvant chemotherapy followed by interval debulking surgery. Our study is the first retrospective research comparing primary debulking surgery followed by chemotherapy versus neoadjuvant chemotherapy followed by interval debulking surgery in ovarian cancer patients with extra-abdominal metastasis. Although the population of patients was limited, our study presented the maximal effort to manage advanced ovarian cancer in a national gynecological cancer center with huge surgery volume. More prospective studies with larger population is needed in the future to clarify the difference of PDS and NACT-IDS in the management of advanced epithelial ovarian cancer patients with extra-abdominal metastasis.

EOC, epithelial ovarian cancer; PDS, primary debulking surgery; NACT, neoadjuvant chemotherapy; IDS, interval debulking surgery; OS, overall survival; PFS, progression-free survival

Ethics approval and consent to participate: This study followed the Declaration of Helsinki and was approved by the Committee at Obstetrics and Gynecology Hospital of Fudan University (IRB number 2021-93). Written informed consent was obtained from individual or guardian participants.

Consent for publication: Not applicable.

Availability of data and material: All data generated or analyzed during this study are included in this published article.

Competing interests: The authors declare that they have no competing interests.

Funding: not applicable.

Authors' contributions: QJ and RZ participated in literature research, data collection, analyzing, writing and editing; MC participated in reviewing; LY and YB facilitated data acquisition; LY participated in conception of the study. All authors read and approved the final manuscript.

Acknowledgements: not applicable.

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No competing interests reported.

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Comparison of primary debulking surgery and neoadjuvant chemotherapy plus interval debulking surgery for epithelial ovarian cancer with extra-abdominal metastasis

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Abstract

Background

Methods

Results

Conclusions.

Figures

1 Background

2 Materials And Methods

2.1 Patients

2.2 Data collection and follow up

2.3 Data analysis

3 Results

3.1 Patient characteristics

3.2 Survival analysis

4 Discussion

Abbreviations

Declarations

References

Additional Declarations

Supplementary Files

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