Clinical efficacy analysis of chemotherapy of isolated neck lymphatic metastasis in advanced epithelial ovarian cancer

Abstract

Objective

The aim of this study was to retrospectively investigate the efficacy of chemotherapy for neck lymph node metastasis (NLNM) by determining the characteristics and survival of patients with isolated NLNMs metastases from epithelial ovarian carcinoma (EOC) at stage IV of the Federation of Gynecology and Obstetrics (FIGO).

Methods

The clinicopathological characteristics and survival outcome of 24 cases with stage IV FIGO EOC with isolated NLNM were retrospectively analyzed between December 1, 2014, and November 30, 2021.

Results

Among the 24 patients, 2 (8.3%) underwent primary debulking surgery (PDS), 21 (87.5%) received neoadjuvant chemotherapy(NACT) followed by interval debulking surgery (IDS), and 1 (4.2%) received chemotherapy alone. Additionally, 13 (54.2%) cases achieved abdominal R0 debulking, while 11(45.8%) cases achieved R1/R2 debulking. The chemotherapy response of NLNMs included complete response (8/24, 33.3%), partial response (15/24,62.5%), or stable disease (1/24,41.7%). None of the patients received resection or radiotherapy of NLNMs. Recurrence was observed in 15 (62.5%) patients, with only 2 experiencing recurrence of NLNMs. The median progression-free survival (PFS) and overall survival (OS) were 35 months and 48 months, respectively. R0 debulking led to a significantly longer PFS (not reached) and OS (57 months) compared to non-R0 debulking (PFS: 10 months, P = 0.001; OS: 22 months, P = 0.001). Interestingly, patients with EOC with lymphatic recurrence had better OS ( 57 months) than did those with abdominal or distant recurrence (OS: 29 months; P = 0.012).

Conclusions

Chemotherapy is an effective treatment for neck lymph nodes metastasis, and a favorable response to chemotherapy could eliminate the necessity for NLNM resection or radiotherapy. Effective control of abdominal disease with surgery may be a critical factor in managing FIGO stage IV EOC patients with isolated NLMNs.

Introduction

Ovarian cancer remains the leading cause of death among gynecological cancer worldwide [1]. The primary treatment for EOC to achieve no residual tumor involves a combination of surgery and platinum-based chemotherapy [2, 3]. In recent years, maintenance therapy has significantly enhanced the survival rates of patients with advanced EOC [4–6].

Distant lymph node metastasis is uncommon in EOC, particularly when appear as the sole site of distant involvement [7, 8]. According to the 2014 Federation of Gynecology and Obstetrics (FIGO) classification [9], patients with extra-abdominal lymph node metastases, including neck lymph node metastasis (NLNM), should be upstaged to stage IVB. Timmermans et al. found that the prognosis of patients with stage IVB EOC, characterized solely by extra-abdominal lymph node metastases was notably better than that of patients with other sites of metastases [10]. Similarly, Suh et al. reported that EOC cases with metastases to the supraclavicular lymph nodes had better overall survival (OS) than did other stage IV cases and were less likely to have multiple distant metastases [11].

To date, the appropriate treatment approach for patients with NLNMs remains to be established. Recent evidence suggests that these metastases can be removed surgically or treated with radiotherapy [12, 13]; however, long-term follow-up is necessary to assess the impact of these approaches on survival. In a case report by Hong et al., a patient with EOC who initially presenting with supraclavicular lymph node metastasis achieved a complete response (CR) following two cycles of platinum-based chemotherapy confirmed by positron emission tomography–computed tomography (PET/CT) [14]. This case indicates that patients who initially present with distant metastatic lymph nodes might expect a favorable prognosis and thus avoid overtreatment. Nevertheless, the efficacy of NLNM resection or radiotherapy in improving prognosis as well as the effectiveness of chemotherapy, remain unclear. Additionally, the prognostic significance of primary cytoreduction when complete resection of NLNMs cannot be achieved is not well understood. The impact of NLNM on the prognosis of patients with EOC remains ambiguous, preventing the proposal of evidence-based recommendations. Therefore, we attempted to investigate the objective response of NLNM to chemotherapy and identify the prognostic factors in this specific group of stage IVB ovarian cancer patients.

Material and methods

Patients

We conducted a retrospective study utilizing the databases of Sichuan Cancer Hospital. We reviewed all patients with high-grade serous ovarian cancer (HGSOC) who were pathologically confirmed to have isolated NLNM through ultrasound-guided fine-needle aspiration cytology (FNAC) between December 2014 and November 2021. Patients with physical neck lymph node enlargement lacking pathological confirmation were excluded. In total, 24 cases were included in this study. This study was approved by the institutional review board of Sichuan Cancer Hospital. Informed consent was waived due to the secondary analysis of de-identified data.

Treatment

All patients underwent cytoreductive surgery combined with platinum-based chemotherapy, with some also receiving maintenance therapy with PARP inhibitors. All patients were evaluated with the “Suidan” criteria (age, American Society of Anesthesiologists [ASA] score, cancer antigen 125 [CA125], CT results) for primary debulking surgery (PDS). Those with a predictive score ≥ 3 before surgery and uncertain R0 tumor resection for PDS received neoadjuvant chemotherapy (NACT), Patients who responded to NACT received IDS (NACT-IDS),while those with an inoperable tumor and progression during NACT received chemotherapy only. The primary objective of surgery was to achieve complete cytoreduction with no intra-abdominal macroscopically visible residual disease (RD). Cytoreductive surgery procedures included hysterectomy, bilateral salpingo-oophorectomy, omentectomy, and additional procedures based on organ involvement, such as small bowel or colonic resection, resection of the diaphragmatic peritoneum, and resection of suspicious pelvic and para-aortic lymph nodes. Postoperative intra-abdominal RD after PDS or IDS was categorized as follows: (1) R0 = no RD, (2) R1 = residual tumor > 0 and ≤ 1 cm, and (3) R2 = residual tumor > 1 cm.

Outcome measures

The clinicopathological characteristics of the 24 EOC patients with isolated NLMNs included age, maximum diameter of the NLNMs, treatment, postoperative residual size of abdominal disease, ascites condition, preoperative CA125 value, first site of recurrence, and survival time, among others. Treatment response of NLNMs was evaluated using the Response Evaluation Criteria In Solid Tumors 1.1 (RECIST 1.1). OS was calculated with Kaplan–Meier curves from.

the date of primary treatment to the date of death or last follow-up. Progression-free survival (PFS) was measured with Kaplan–Meier curves from the date of treatment to the first documented date of progression or last follow-up.The follow-up period ended on February 21, 2024.

Statistical methods

Statistical analysis included the Student t test for continuous variables and the χ2 test or Fisher exact test for categorical variables. Survival rates were calculated using Kaplan–Meier curves, and survival comparison was performed using the log rank test. All analyses were performed using SPSS statistical software version 27 (IBM Corp.). A P value of less than 0.05 was considered statistically significant.

Results

Patient characteristics

From December 2014 to November 2021, a total of 2380 patients with ovarian malignancies underwent surgery in our hospital. Among these 24 patients were identified with isolated NLNMs via FNAC. The clinicopathological features of these patients are detailed in Table 1.

Table 1.

Clinical characteristics of patients

Variables
Age, year
median	51
range	38–73
CA125, U/ml
median	1070
range	72.5–6546
Ascites, N (%)
No	8(33.33)
< 500 ml	14(58.33)
≥ 500 ml	2(8.33)
RD, N (%)
R0	14(58.33)
R1	5(20.83)
R2	5(20.83)
Treatment, N (%)
IDS	21(87.50)
PDS	2(8.33)
-	1(4.17)
NLNM size, N (%)
≤ 2 cm	17(70.83)
> 2 cm	7(29.17)
NLN evaluation after neoadjuvant chemotherapy, N (%)
SD	1(4.17)
CR	8(33.33)
PR	15(62.50)
BRAC gene testing, N (%)
BRCA mutant	59(20.83)
BRCA wild-type/BRCA status unknown	19(79.17)
Sites of first recurrence, N (%)
lymph nodes	4(26.67)
Abdomen or other distant sites(lung,brain,bone,…)	11(73.33)
Maintenance therapy, N (%)
Not obtain PARPi maintenance therapy	18(75)
Obtain PARPi maintenance therapy	6(25)

RD residual disease, R0 complete intra-abdominal tumor resection, R1 residual tumor > 0 and ≤ 1 cm, R2 residual tumor > 1 cm, IDS interval debulking surgery, PDS primary debulking surgery, CR complete response, PR partial response, SD stable disease

Among the 24 cases, 2 patients(8.3%) underwent PDS, 21 patients(87.5%) received NACT-IDS, and 1 patient(4.2%) received chemotherapy alone. Notably, no patients underwent resection or primary radiotherapy for NLNMs Following initial treatment, the response of NLNM was evaluated, revealing that 8 cases (33.3%) with complete response (CR), 15 cases (62.5%) with partial response (PR), and 1 case with stable disease (SD). The overall effective rate (CR + PR) was 95.8% (23 cases).

Additionally, 13 cases (54.2%) achieved complete intra-abdominal gross resection (R0). Recurrence was observed in 15 cases (62.5%, 15/24) post-treatment with 2 cases (2/15, 13.3%) experiencing initial relapse in NLNM and 13 cases (13/15, 86.7%) showing relapse in other locations, including other lymph nodes, the abdomen, pleura, brain, bone, etc., indicating that initial relapse in NLNMs is relatively uncommon.

Survival analysis

The median PFS for the cohort was 35 months (95%: CI 28.8–41.2), and the median OS was 48 months (95%: CI 38.9–57.1). The 1-year and 2-year PFS rates were 83.3% and 66.7%, respectively, while the 1-year and 2-year OS rates were 95.8% and 83.3%, respectively. PFS for patients with R0 resection was not reached, and the OS was 57 months (95% CI: not reached); In contrast, patients with RD had a PFS of 10 months (95%: CI 7.7–12.3) and OS of 22 months (95% CI: 7.7–36.3), respectively, indicating a significant difference (both P values)(Fig. 1A and B). For those receiving PARP inhibitor maintenance therapy, the PFS was 37 months (95% CI: 9.6–64.4), compared to 17 months (95%: CI 5.9–28.1) for those without maintenance therapy (P = 0.233). Patients with lymph node recurrence exhibited a PFS of 16 months (95% CI: 3.3–28.7) and an OS of 57 months (95% CI: not reached), whereas, patients with abdominal or other distant site recurrences experienced a PFS of 10 months (95% CI: 6.8–13.2; P = 0.066) and an OS of 29 months (95% CI: 16.8–41.1; P = 0.012) (Fig. 2A and B). Kaplan–Meier analysis revealed postoperative intra-abdominal RD as the sole factor significantly associated with both PFS and OS (Tables 2 and 3).

Fig. 1.

A Kaplan–Meier OS Survival Curve for postoperative intra-abdominal residual disease; B Kaplan–Meier PFS Survival Curve for postoperative intra-abdominal residual disease

Fig. 2.

A Kaplan–Meier OS Survival Curve for sites of first recurrence; B Kaplan–Meier PFS Survival Curve for sites of first recurrence

Table 2.

Univariate analysis for PFS in EOC patients with FIGO stage IV with isolated NLNMs metastasis

Variables		Recurrence	No Recurrence	Log rank p-value
Age	≤ 60	14	6	0.132
	> 60	1	3
CA125	< 600U/ml	6	4	0.711
	≥ 600U/ml	9	5
Ascites	No	6	2	0.112
	< 500 ml	7	7
	≥ 500 ml	2	0
RD	R0	5	8	0.001
	R1/R2	9	1
Surgery	IDS	12	9	0.427
	PDS	2	0
NLNM size	≤ 2 cm	11	6	0.908
	> 2 cm	4	3
BRAC gene testing	BRCA mutant	3	2	0.693
	BRCA wild-type/BRCA status unknown	12	7
Sites of first recurrence	lymph nodes	4	-	0.066
	Abdomen or other distant sites(lung,brain,bone,…)	11	-
Maintenance therapy	Not obtain PARPi maintenance therapy	12	6	0.233
	Obtain PARPi maintenance therapy	3	3

Table 3.

Univariate analysis for OS in EOC patients with FIGO stage IV with isolated NLNMs metastasis

Variables		Death	Survival	Log rank p-value
Age	≤ 60	10	10	0.061
	> 60	0	4
CA125	< 600U/ml	3	7	0.491
	≥ 600U/ml	7	7
Ascites	No	4	4	0.369
	< 500 ml	4	10
	≥ 500 ml	2	0
RD	R0	2	11	0.001
	R1/R2	7	3
Surgery	IDS	8	13	0.395
	PDS	1	1
NLNM size	≤ 2 cm	8	9	0.563
	> 2 cm	2	5
BRAC gene testing	BRCA mutant	2	3	0.654
	BRCA wild-type/BRCA status unknown	8	11
Sites of first recurrence	lymph nodes	1	3	0.012
	Abdomen or other distant sites(lung,brain,bone,…)	9	2
Maintenance therapy	Not obtain PARPi maintenance therapy	9	9	0.135
	Obtain PARPi maintenance therapy	1	5

Discussion

Although cases of EOC with NLNM in are infrequent, the management of NLNM and its prognostic role in EOC require thorough understanding. In our study, all the patients received either surgery combined with chemotherapy or chemotherapy alone, however, none underwent resection or radiotherapy of NLNMs. Our findings indicated that post-initial treatment, NLMNs exhibited an overall response rate (ORR) of 95.8% with a CR rate of 33.3% and a PR rate of 62.5%. Eight patients achieved complete remission of neck lymph nodes after chemotherapy, while, one patient with SD exhibited resistance to chemotherapy, missed the chance for surgery, and consequently failed to achieve a favorable outcome despite undergoing over eight cycles of chemotherapy. These findings suggest that the NLNMs in EOC patients respond well to chemotherapy, leading to a high rate of complete remission, which is consistent with previous studies [14–17]. The regression of metastatic NLNMs following chemotherapy may serve as a predictive indicator of chemotherapy sensitivity in EOC. Tanaka et al. reported that radiotherapy for supraclavicular lymph nodes in patients with recurrent gynecologic cancer is effective as palliative irradiation [13], though it is worth noting that radiotherapy can induce toxic side effects. Our research demonstrates that chemotherapy is an effective treatment for neck lymph nodes metastasis, and when chemotherapy is successful, NLNM resection or radiotherapy can be avoided.

The spreading routes of lymphatic metastases in EOC appear to progress in a stepwise manner from the pelvic lymph nodes to the para-aortic lymph nodes (PANs) and eventually to the supraclavicular lymph nodes. In our study, 24 cases progressed with NLNMs as the sole distant involvement, however, a majority of these had concurrent extensive metastasis within the abdominal cavity, involving sites such as the diaphragm, omentum, intestinal surface, mesenteric surface, para-aortic lymph nodes, hepatorenal recess, and liver capsule, etc. NLNM reflects a substantial abdominal tumor burden and advanced lymphatic metastasis in EOC. Achieving optimal debulking with no residual tumor throughout the body often requires extremely aggressive and multi-incision surgeries, potentially including neck lymph node dissections. Lymphadenectomy is associated with increased surgery-related morbidity, including extended operative time, significant blood loss, higher transfusions rate, and the need for intensive unit care. Therefore, careful consideration must be given to balancing the potential survival benefits against the risks posed by complex surgical procedures. It is imperative not to excessively pursue surgical resection at the expense of increasing perioperative risks for the patient. Consideration must be given to the high-risk factors associated with ovarian cancer patients, tumor biology, hospital resources and conditions, as well as the expertise of the surgical team, and multidisciplinary team physicians. Careful evaluation of patients and multidisciplinary approach in referral centers is mandatory [18].

However, the increased risk of complications and the reduced quality of life associated with extensive cytoreductions should not be overlooked. On the one hand retroperitoneal staging is not correlated to survival benefits both in early and advanced ovarian cancer, on the other hand it is associated with an increased surgery-related morbidity [19]. As demonstrated in the LION trial, there was no improvement in outcomes, but rather higher complication and mortality rates linked to lymphadenectomy [20]. Although the safety of NLNM dissection has been confirmed, the correlation between this procedure and prognosis remains unclear. Chen et al. reported that patients with ovarian lesions spreading to the abdominal cavity at NLNM identification had significantly poor outcomes [17]. If feasible, surgical removal of NLNMs in patients with EOC with confined to a pelvic mass during the initial surgical intervention of primary tumors may enable complete tumor eradication. However, managing tumor dissemination arising from adverse tumor biology through surgical resection alone is challenging, as highlighted by prior studies [21, 22]. Recent trials indicate substantial survival rate improvements with PARP inhibitors [4–6]. Advancements in adjuvant therapy, like PARP inhibitor maintenance therapy provide novel treatment options for postoperative neck lymph node metastases. In our study, the PFS for patients treated with PARP inhibitor maintenance therapy was 37 months, compared to 17 months without, showing a PFS extension of 20 months, albeit the statistical significance was not reached (P = 0.233). Comprehensive treatment, rather than surgery alone.can enhance the survival of patients with advanced EOC.

A previous study reported that the short-term PFS can be improved in EOC patients with germline BRCA1/2 mutations [23]. However, in our study, only six patients underwent BRCA genetic testing, and we found no significant difference in the PFS or OS was observed between patients with BRCA mutations and those with wild-type BRCA or unknown BRCA status. Kim et al. reported that despite a similar disease burden and surgical interventions, individuals carrying BRCA mutation carriers were more inclined to achieve complete resection; nonetheless,this initial survival advantage did not forecast long-term survival [24]. Regardless of BRCA status, patients with advanced-stage EOC with R0 and displaying a favorable histopathological response to chemotherapy generally have a better prognosis [25].The absence of RD at resection remains one of strongest predictors of positive outcomes [26].In our study, only postoperative intra-abdominal RD was significantly associated with both PFS and OS. Another study indicated that within stage IVB ovarian cancer patients with supraclavicular lymph nodes metastasis, those characterized as “continuous-metastasis type” with positive PALNs experienced a improved prognosis. Optimal abdominopelvic debulking conferred prognostic advantages for this subset, even in instances where metastatic supraclavicular lymph nodes remained unresected [27].

For untreated distant metastatic tumors, chemotherapy remains the primary nonsurgical intervention with established efficacy [28, 29]. Our study noted initial recurrence at various sites: 13.3% (n = 2) in NLNMs, 13.3% (n = 2) in other lymph nodes, 53.4% (n = 8) in the abdomen, and 20% (n = 3) in distant sites like the pleura, brain, and bone. The leading cause of mortality among patients was the progression of the abdominal lesions and parenchymal metastasis, which was more prevalent than mortality due to lymph node metastasis. Notably, in patients with postoperative residual tumor, the presence of enlarged NLNMs did not correlate with reduced survival. Our analysis revealed that the patients with first relapse in lymph nodes had significantly better OS compared to those with first relapse in the abdomen or parenchymal organs (57 months vs. 29 months; P = 0.012) (Fig. 2A). The abdomen emerged as the most common site of initial recurrence [10, 29–32]. Several studies have also reported that the presence of NLNM alone does not adversely affect prognosis, assuming peritoneal disease is limited and is surgically managed optimally [16, 17].

Isolated lymph node recurrence (ILNR) represents a less aggressive pattern of ovarian carcinoma relapse, with a relatively high percentage of cases progressing within the lymph nodes. However,, the occurrence of peritoneal spreading following ILNR is linked to a rapidly fatal outcome [33]. Other studies have reaffirmed a better prognosis regarding treatment response and survival following ILNR [34–37]. Minimizing residual tumors remains a crucial prognostic factor in the management of advanced ovarian cancer. Studies have validated that cytoreductive surgery achieving R0 significantly improves OS and PFS in individuals with stage IV EOC [16, 38, 39]. The site of extra-abdominal disease does not alter prognosis or recurrence patterns in those with stage IV EOC, with most recurrence occurring in the abdomen, underscoring the significance of surgical control of abdominal disease in all stage IV disease.

To our knowledge, this is the first study to evaluate the efficacy of chemotherapy in treating isolated NLMNs in EOC patients and to further confirm whether NLNM resection or radiotherapy is necessary if chemotherapy is effective. Postoperative intra-abdominal RD is the most critical prognostic factors in this patient population. However, it is essential to acknowledge several limitations of our study. Firstly, the research included a homogeneous group of ovarian cancer patients who underwent surgery at a single center from 2014 to 2021 resulting in a relatively small sample size for a retrospective study, and thus constraining the generalizability of our findings. Secondly, a limited number of patients who underwent genetic testing and received maintenance therapy. Thirdly, the analysis did not encompass the assessment of treatment after recurrence. Additionally, none of patients received NLNM resection or radiotherapy, resulting in a lack of comparative data between different treatment modalities. Future studies efforts should focus on larger sample sizes and more rigorous research designs are necessary to further elucidate the prognostic implication of NLNM and to identify the appropriate management strategies for this specific patient population.

Conclusions

Our study revealed that complete intra-abdominal tumor resection (R0) remains a significant prognostic factor for patients diagnosed with stage IV EOC with NLNM. Furthermore, our findings suggest that chemotherapy could serve as a viable treatment option for NLNMs in these patients. A prospective study with a considerable sample size is warranted to provide a comprehensive evaluation of the prognosis for individuals with stage IV EOC and NLNMs.

Abbreviations

NLNM

Neck lymph node metastasis

EOC

Epithelial ovarian carcinoma

FIGO

Federation of Gynecology and Obstetrics

PDS

Primary debulking surgery

NACT

Neoadjuvant chemotherapy

IDS

Interval debulking surgery

PFS

Progression-free survival

OS

Overall survival

CR

Complete response

PET-CT

Positron emission tomography–computed tomography

HGSOC

High-grade serous ovarian cancer

FNAC

Fine-needle aspiration cytology

ASA

American Society of Anesthesiologists

RD

Residual disease

RECIST 1.1

Response Evaluation Criteria In Solid Tumors 1.1

PR

Partial response

SD

Partial response

ORR

Overall response rate

PANs

Para-aortic lymph nodes

Authors’ contributions

Study concept and design, H Liu and M Luo; investigation of clinical data and follow-up, M Luo and CR Peng; quality control of data and algorithms, H Liu and DF Wang; statistical analysis, XH Cheng and M Luo; drafting of the manuscript, H Liu and M Luo; and manuscript review, JM Huang and GN Zhang.

Funding

This work was supported by Sichuan Key Research and Development Project from Science & Technology Department of Sichuan Province (Grant No: 2019YFS0036) and Sichuan Medical Research Project (Grant No: S18063).

Data availability

No datasets were generated or analysed during the current study.

Declarations

Ethics approval and consent to participation

The study was conducted in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines as well as authorized by the institutional review board of Sichuan Cancer Hospital.The requirement for informed consent was waived because we analyzed de-identified data secondarily.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.