Is Prophylactic Radiotherapy to the Lymphatic Drainage Area Necessary for Patients With Stage III Ovarian Cancer After Chemotherapy Following Surgery?

Abstract

Background

For patients with stage III epithelial ovarian cancer, there are limited studies on the effects of postoperative adjuvant radiotherapy (RT). Here we assessed the therapeutic efficacy and toxicity of postoperative radiotherapy to the abdominal and pelvic lymphatic drainage area for stage III epithelial ovarian cancer patients, who had all received surgery and chemotherapy (CT).

Methods

We retrospectively collected patients with stage III epithelial ovarian cancer after cytoreductive surgery (CRS) and full-course adjuvant CT. The chemoradiotherapy (CRT) group patients were treated with intensity modulated radiotherapy (IMRT) to the abdominal and pelvic lymphatic drainage area in our hospital between 2010 and 2020. A propensity score matching analysis was conducted to compare the results between the CRT and CT groups. Kaplan-Meier analysis estimated overall survival (OS), disease-free survival (DFS), and local control (LC) rates. The log-rank test determined the significance of prognostic factors.

Results

A total of 132 patients with median follow-up of 73.9 months (9.1-137.7 months) were included (44 and 88 for the CRT and RT groups, retrospectively). The baseline characteristics of age, histology, level of CA12-5, surgical staging, residual tumour, courses of adjuvant CT, and courses to reduce CA12-5 to normal were all balanced. The median DFS time, 5-year OS, and local recurrence free survival (LRFS) were 100.0 months vs 25.9 months (P = .020), 69.2% vs 49.9% (P = .002), and 85.9% vs 50.5% (P = .020), respectively. The CRT group mainly presented with acute haematological toxicities, with no statistically significant difference compared with grade III intestinal adverse effects (3/44 vs 6/88, P = .480).

Conclusion

This report demonstrates that long-term DFS could be achieved in stage III epithelial ovarian cancer patients treated with IMRT preventive radiation to the abdominal and pelvic lymphatic area. Compared with the CT group, DFS and OS were significantly prolonged and adverse effects were acceptable.

Keywords

ovarian cancer epithelial carcinoma intensity modulated radiotherapy disease-free survival time

Introduction

Epithelial ovarian cancer (EOC) is the third common malignancies of female reproductive system,¹ and the mortality rate was over 50% after 5 years.^2,3 Due to the characteristics of hidden symptoms and lack of effective screening methods, around 75% patients are already in the locally advanced stage (stage III) at initial diagnosis. Even after standard cytoreductive surgery (CRS) and adjuvant chemotherapy (CT), over 70%-80% of these patients still had disease progression.⁴

Radiotherapy (RT) is recommended in postoperative adjuvant treatment for ovarian cancer patients with high risk factors (including higher histological grade, insufficient chemotherapy dosage and duration, poorer pathological type, age ≥65, etc). RT could control tumour recurrence, reduce peritoneal transplantation, and kill subclinical lesions. However, patients may suffer from higher risk of haematological problems and gastrointestinal toxicities.^5,6 In our centre, patients received irradiation to abdominal and pelvic lymphatic drainage area (i.e., the lymph nodes near periaortic area, mesenteric vessels, iliac vessels, obturator vessels, presacral space and paravaginal stump area), instead of whole abdominal irradiation as a method of preventive radiotherapy for postoperative locally advanced ovarian cancer patients. This irradiation pattern could increase doses to target region while minimizing doses to normal tissues, making it a reality to give higher doses in the radiotherapy of EOC patients.^7-10 Our previous studies have demonstrated its dosimetric advantage.¹¹

In the current study, we selected stage III EOC patients, who all underwent standard surgery. We compared the clinical efficacy, toxicity, and failure pattern of postoperative RT in chemoradiotherapy (CRT) group and CT group. To our knowledge, there were few studies to apply intensity modulated radiotherapy (IMRT) technique to abdominal and pelvic lymphatic drainage area in locally advanced ovarian cancer patients. The study will have a guiding significance in clinic work.

Materials and Methods

Patients Data Collection

The report of this study conforms to the STROBE guidelines.¹² This study was approved by the Ethics Committee of Peking Union Medical College Hospital (approval number: I-22PJ637). The requirement for obtaining patient consent was waved by the IRB. We retrospectively reviewed the clinical data of stage III EOC patients treated from January 2010 to December 2020 at radiation therapy department of our hospital from the electronic medical record analytical database. The preventive IMRT technique was delivered to abdominal and pelvic lymphatic drainage area (Halcyon accelerator, based on 4 full-arc arrangements, using 6MV-FFF irradiation energy). The inclusion criteria were patients who were pathologically diagnosed as EOC and received standard surgery and first-line CT. A total of 132 patients were included, and grouped into CRT group and CT group, matched at a ratio of 1:2.

Radiotherapy Plan

All 44 locally advanced EOC patients received postoperative RT in our centre. The IMRT technique was applied, and irradiation was delivered to abdominal and pelvic lymphatic drainage area. The patients were treated in 25-28 fractions for a total dose of 45-50 Gy. The accuracy of treatment was guaranteed by cone-beam computed tomography (CBCT) once a week.

The clinical target volume (CTV) included lymph nodes near periaortic area, paravaginal stump area, and pelvic area (common iliac, external iliac, internal iliac, obturator, presacral space). The details were depicted as follows: expansion of a 2 cm margin from aortic vessels, 1 cm margin from inferior vena cava, and 5 cm margin in ventral direction. Lymphatic drainage region in common iliac area were generated by an expansion of 7 mm from common iliac vessels, and the inner border of psoas majors were included in bilateral sides. Internal and external iliac lymphatic region was generated by an expansion of 7 mm from internal and external iliac vessels, and 17 mm from external iliac group in anterolateral direction. Presacral space was determined by an expansion of 15 mm from spinal cord, and obturator space was the 18 mm space connecting external and internal iliac regions. The planning target volume (PTV) was expanded 10 mm in the head-to-foot direction and 7 mm in all other directions based on the delineation of the CTV target area. The contouring details were illustrated in Figure 1.

Figure 1.

The clinical efficacy of CRT group and CT group in stage III epithelial ovarian cancer patients.

Additionally, it is worth emphasizing that the preventive radiotherapy referred to in this article pertains to administering corresponding radiotherapy when there is no clinical signs of local recurrence or metastasis after surgery and adjuvant chemotherapy.

Other Treatment

Other treatment included cytoreductive surgery (CRS) and full-course adjuvant chemotherapy. During CRS, tumour tissue is removed as much as possible from the abdominal cavity, including tumors on the ovaries, fallopian tubes, uterus, and surrounding organs. Any metastatic lesions on the peritoneum or other abdominal surfaces are also meticulously resected.

After surgical treatment, patients will undergo a full course of chemotherapy. Depending on the patient’s tolerance, chemotherapy will typically last for 6 cycles, or at least 2 cycles after normalization of serum tumor markers. The chemotherapy regimen consists of a 3-week cycle of paclitaxel plus carboplatin.

Follow-up and Clinical Evaluation Parameters

The clinical data of all 132 patients were retrieved retrospectively through the reference of clinical records and telephone call. Patients were regularly followed up once every 3 months in 2 years, and once every 6 months in 2-5 years after treatment. The follow-up contents included: sex, age, blood tumour markers, surgical staging, whether initial treatment or not, times of recurrence, level of blood tumour markers when recurrence, and treatment pattern after recurrence. Toxicity was evaluated using Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0.

Follow-up period ranged from the first day of diagnosis to the last day of follow-up or death, and the deadline date was September 30, 2022. Overall survival (OS) was defined as time in months from the day of diagnosis until the last contact day or death. Disease free survival (DFS) was defined as time in months from surgery until the occurrence of disease progression. Local recurrence free survival (LRFS) was defined as time in months from surgery until local in-field recurrence. Distant metastasis free survival (DMFS) was defined as time in months from surgery until the occurrence of distant metastasis.

Statistical Analysis

Statistical analyses were run on SPSS version 25.0 for windows (SPSS, Inc., Chicago, IL). The distribution of categorical variables was studied using Chi-square analysis. The normality of continuous data was analyzed using the Kolmogorov-Smirnov test. The student-T test and Whitney U test were used to assess mean differences for normal and non-normal distribution variables, respectively. The Kaplan-Meier analysis was used to estimate the incidence of OS, DFS, and local control (LC), and the log-rank test was used to evaluate the significance of prognostic factors. A P < .05 was considered statistically significant.

Results

Patients

A total of 132 patients were enrolled in the study. The patients’ baseline characteristics were listed in Table 1. The median follow-up times for CRT group and CT group are 1171 [907,1,942] and 1208 [662,2,471] days, respectively. All patients had a high Karnofsky performance score (KPS) score over 80. The patient cohort, averaging 54 years old, comprised 117 without residual disease post-surgery and 19 with residual disease. Pathological findings included serous (29), endometrioid (5), clear cell (5), mucinous (3), and other carcinoma types (2). Postoperative staging revealed IIIa (8), IIIb (9), and IIIc (115) cases. Chemotherapy ranged from 4-9 cycles, with 24 receiving 4-6 cycles and 20 receiving over 6 cycles. Pre-treatment CA-125 levels varied: <100 (21), 100-500 (7), 500-1000 (11), and >1000 (5). Additionally, 29 out of 44 patients achieved CA-125 normalization within 3 cycles.

Table 1.

The Baseline Clinical Characteristics of 132 Patients.

Characteristics	Total (n = 132)		CRT Group (n = 44)		CT Group (n = 88)		P
Characteristics	n	%	n	%	n	%	P
Age
<60	92	71.2	34	77.3	58	65.9	.229
≥60	40	28.8	10	22.7	30	34.1
Residue after operation
No	117	88.6	32	72.7	75	85.2	.008
Yes	19	14.4	12	27.3	13	14.8
Pathology
Serous	93	70.5	29	65.9	64	72.7	.431
Endometrioid	20	15.2	5	11.4	15	17.1
Clear cell	8	6.0	5	11.4	3	3.4
Mucous	6	4.5	3	6.8	3	3.4
Other type	5	3.8	2	4.5	3	3.4
Postoperative staging
IIIa	8	6.1	5	11.4	3	3.4	.136
IIIb	9	6.8	4	9.1	5	5.7
IIIc	115	87.1	35	79.5	80	90.9
Postoperative CT cycles
<6	49	37.1	24	54.5	25	28.5	.216
≥6	83	62.9	20	45.5	63	71.6
Level of CA12-5 before treatment
<100	47	35.6	21	47.7	26	29.5	.117
≥100 and <500	28	21.2	7	15.9	21	23.9
≥500 and <1000	30	22.7	11	25.0	19	21.6
≥1000	27	20.5	5	11.4	22	25.0
CT cycles reducing CA12-5 to normal
<3 cycles	74	56.1	29	65.9	45	51.1	.332
≥3 cycles	58	43.9	15	34.1	43	48.9

Patients in postoperative CRT group (n = 44) and CT group (n = 88) were compared in age, postoperative residual, postoperative staging, pathology, postoperative CT cycles, level of CA 12-5 before treatment, and cycles of CT reducing CA 12-5 to normal. The details were listed in Table 1.

Clinical Efficacy

The median follow-up time for all patients was 73.9 months (9.1-137.7 months). The median survival time (MST) was 78.5 months. The 1-year, 3-year, and 5-year OS was 91.7%, 80.3%, and 66.2%, respectively. The 1-year, 3-year, and 5-year DFS was 84.8%, 45.4% and 35.0%, respectively. The 1-year, 3-year, and 5-year LRFS was 97.7%, 69.0%, and 62.7%, respectively. The 1-year, 3-year, and 5-year DMFS was 97.7%, 73.9%, and 62.6%, respectively.

As in Figure 2A, compared to CT group, median OS in CRT group was significantly higher (108.1 vs 60.2 months, P = .002). Figure 2B showed the DFS curves in 2 groups. The median DFS in CRT and CT group was 100.0 months and 25.9 months, respectively (P = .020). There was also significant difference in LRFS, and the median LRFS was 110.0 months in CRT group and 62.8 months in CT group (P = .020), as shown in Figure 2C. The median DMFS in CRT and CT group found no significant difference (103.1 vs 111.1 months, P = .366), as shown in Figure 2D.

Figure 2.

These curves represent the (A) OS, (B) DFS, (C) LRFS, (D) DMFS in CT + RT and CT group. CRT group is outlined in red colour, and CT group in blue.

Failure Pattern

Treatment had failed in a total of 78 (68.9%) patients. Among these, 33 cases had local recurrence, 32 cases had distant metastasis, and 13 cases had both local recurrence and distant metastasis.

As in Table 2, the local recurrence rate was significantly lower in CRT group, compared with CT group (13.6% vs 45.5%, P = .016). For the 6 patients who developed local recurrence in CRT group, 2 cases developed recurrence in paraaortic lymph nodes, 1 case developed recurrence in pelvic lymph node area, and 3 cases developed recurrence in mesenteric region. There were 3 recurrences inside the radiation fields, and 3 outside the radiation fields.

Table 2.

Failure Pattern.

Failure Pattern	Total Number (n = 78)
	Total (n = 78)	CRT Group (n = 19)	CT Group (n = 59)	P
	n (%)	n (%)	n (%)	P
Local recurrence	33 (42.3)	1 (5.3)	32 (54.2)	.001
Distant metastasis	32 (41.0)	13 (68.4)	19 (32.3)	.548
Local recurrence and distant metastasis	13 (16.7)	5 (26.3)	8 (13.6)	.254

For the 51 patients who had distant metastases: there were metastases in clavicular lymph nodes in 9 cases, liver in 8 cases, lung in 5 cases, mediastinum in 4 cases, brain in 3 cases, bone in 2 cases, and other sites (mammary gland, axilla, etc) in 20 cases. No significant difference was found in CRT and CT groups. See Table 2 in detail.

Toxicity

Forty-three patients (97.7%) had completed radiotherapy in abdominal and pelvic lymphatic drainage area after postoperative chemotherapy (45-50 doses). One patient stopped treatment due to gastrointestinal effect after 40 Gy of radiation. The acute adverse effect was mainly hematological toxicity. Grade 3 hematological toxicity was presented in 29 patients (65.9%), and grade 3 gastrointestinal toxicity was presented in 13 cases (29.5%). In terms of late side effect, grade 4 lower intestinal adverse events were presented in 9 cases in 2 groups, including intestinal obstruction in 8 patients, and intestinal perforation in 1 patient. Three cases were in CRT group, and 6 in CT group. No significant difference was found in late adverse effect rate between 2 groups, as depicted in Table 3.

Table 3.

Acute and Late Toxicity in Two Groups.

Failure Pattern	Total Number (n = 78)
	Total (n = 132)	CRT Group (n = 44)	CT Group (n = 88)	P
	n (%)	n (%)	n (%)	P
Acute hematological toxicity (grade ≥3)	73 (55.3)	29 (65.9)	44 (50.0)	.083
Acute gastrointestinal toxicity (grade ≥3)	32 (24.2)	13 (29.5)	19 (21.6)	.315
Late gastrointestinal toxicity (grade = 4)	9 (6.8)	3 (6.8)	6 (6.8)	1.0

Discussion

For patients of ovarian cancer, CRS plus postoperative CT was the recommended therapeutic regimen in guideline. Adjuvant CT was recommended in middle-risk and high-risk patients with ovarian cancer. In the era of intensity modulated radiotherapy, our centre innovatively applied preventive radiation to abdominal and pelvic lymph drainage area, in replace of whole abdominal and pelvic radiation. The target dose was increased to 45 – 50 Gy, and doses to normal organs were largely decreased. The radiation protocol was proved to be well tolerable and safe. Compared to CT group, patients received CRT had significantly higher OS, DFS, and LRFS. So far as we knew, this was the first comparative study focusing on the efficacy and safety of preventive radiation to abdominal and pelvic lymph drainage area in patients with stage III EOC patients after CRS and adjuvant CT.

In recent years, a few related research have indicated that patients could benefit from RT after postoperative CT in ovarian cancer patients. Based on Pickel’s randomized study, patients with stage IC – IV ovarian cancer who received whole abdominal irradiation after surgery had significantly higher 5-year DFS and OS, compared to those who only received CT.¹³ Sorbe and his colleagues indicated in a perspective study that for group III ovarian cancer patients, consolidation RT would bring benefit and result in a longer PFS.¹⁴ In a small-scale dosimetric study and phase I clinical research, DFS reached 77 months.^15,16 In our study, IMRT was applied to abdominal and pelvic lymph node drainage area for 44 advanced ovarian cancer patients who had received standard surgery and full cycles of adjuvant CT. The median follow-up time was 64.1 months (9.1 – 113.2 months). The 5-year OS, DFS was 69.2% and 85.9%, respectively. The median DFS was 100 months. Compared to CT group, the results showed better clinical efficacy. DFS was prolonged, and patients had lower probability of receiving additional treatment. Baldwin et al studied 40 692 advanced ovarian cancer patients in Surveillance, Epidemiology, and End Results (SEER) database from 1995 to 2007, and the 5-year OS was 36.0% among FIGO stage III EOC patients.¹⁷ In the research of OVAR-IMRT-01, the median DFS was 27.6 months and 5-year OS was 33.0%. Our study showed a significant improvement.

In aspect of failure pattern, distant metastasis was still the primary reason (57.6%), and local failure was the second (42.3%). The results were in line with the previous studies. The difference between 2 groups lied in the fact that radiation to abdominal and pelvic lymph node region could reduce local recurrence rate and improve OS, with effective CT preventing distant metastasis in both groups. Local failure pattern in locally advanced ovarian cancer patients was mainly the lymphatic drainage area near the vessels.^18,19 Therefore, our centre applied preventive RT in abdominal and pelvic drainage area instead of whole abdominal radiotherapy (WART). We followed up the failure pattern under this mode: distant metastasis was the primary failure reason, and local failure outside the irradiation field was rare, representing around 2% (2 out of 99). This demonstrated that preventive radiotherapy to abdominal and pelvic lymphatic drainage area in locally advanced ovarian cancer patients was meaningful.¹¹

The safety of postoperative radiotherapy is an important issue in clinical practice. In the past two-dimensional RT world, WART could cause high toxicity among patients. It was controversial whether consolidative RT could be used and recommended in EOC patients for a long time.^8,20-22 The past decade witnessed the development of IMRT, which could increase target dose and cause limited adverse effect at the same time.^14-16,23 We have proved that the preventive RT to abdominal and pelvic lymphatic drainage area instead of WART could be used as an alternative. Because the radiation range was narrowed, doses to normal organs were much lower, and related toxicity was thus minor. In our study, 44 patients received CRT with good tolerance and compliance, and only 1 patient withdrew from the treatment due to serious gastrointestinal side effect. In aspect of late adverse effect, the incidence of grade 4 gastrointestinal toxicity was 6.8% in CRT group, showing no difference compared with CT group.

The novel preventive RT method in our centre showed relatively good results in advanced EOC patients. The shortcomings of this study mainly include the following: There is still considerable heterogeneity among patients with stage III ovarian cancer. Due to data limitations, we did not conduct in-depth subgroup analysis, which would help physicians better understand the risk-benefit ratio of such irradiation. Also, despite the matching, the CRT group still had more postoperative residuals compared to the RT group. This did not significantly affect our conclusions, as the group with more postoperative residuals actually had better survival outcomes, which supports our findings. Secondly, there are still a certain number of patients experiencing local field recurrence after radiotherapy. For such patients, the normal tissue irradiation dose brought by recurrent radiotherapy (re-RT) will exceed the limit. Therefore, the loss of the opportunity for re-RT after local recurrence should be considered as a clinical factor. Finally, this study is still a single-center retrospective study, which has certain selection bias. In the future, multicenter prospective randomized controlled trials could be considered to increase the reliability of the conclusions.

Conclusion

For stage III EOC patients who had received standard cytoreductive surgery and first-line full cycle of CT, preventive RT to abdominal and pelvic lymphatic drainage area using IMRT (45-50 Gy in 25-28 fraction) could increase OS, DFS, LRFS, and DMFS. The toxicity was tolerable. Thus, CRT could be the first choice for adjuvant treatment, which will be further studied and verified in the future studies.

Footnotes

Acknowledgments

We would like to extend our gratitude to all our colleagues for their support.

Authors’ Contributions

SJ and TYJ contributed equally to this manuscript. SJ was responsible for the manuscript draft, data interpretation and study design; TYJ was responsible for data analysis and manuscript draft; ZJY was responsible for data collection and drafted the manuscript; GQ, ZHN, HK, HXR, and YJF participated in the design of the study; LZK, HK and ZFQ were responsible for the supervision of the study. All authors read and approved the manuscript.

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by the Ministry of Science and Technology of the People’s Republic of China (Grant No. 2022YFC2407100).

Ethical Statement

ORCID iD

Zhikai Liu

Data Availability Statement

The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.*

Abbreviations

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