Retrospective Analyses of Complete Resection Combined with Systemic Chemotherapy and Targeted Therapy for Patients with Ovarian Metastases from Colorectal Cancer

Abstract

Background:

The aim of the study is to evaluate clinical outcomes of patients with ovarian metastases from colorectal cancer (OM-CRC) treated with complete resection combined with chemotherapy and targeted therapy.

Materials and Methods:

Fifty female patients with OM-CRC who were treated in two different hospitals were categorized into three groups: 14 patients with OM-CRC received resection and chemotherapy combined with targeted therapy, 16 patients with OM-CRC only received chemotherapy combined with targeted therapy, and 20 patients with non-OM-CRC (NOM-CRC) received chemotherapy combined with targeted therapy. The primary outcomes, including overall survival (OS), the objective response rate (ORR), disease control rate (DCR), safety, and progression-free survival (PFS), were observed.

Results:

The ORR of OM-CRC was significantly lower compared with NOM-CRC (36.7% vs. 70.0%, p = 0.021), and the DCR of OM-CRC was also lower compared with NOM-CRC (76.7% vs. 90.0%, p = 0.229). The following chemotherapy and targeted therapy in the additional surgical resection of OM-CRC were positively associated with longer PFS and OS compared to no surgical resection (9.0 vs. 6.0 months and 21.0 vs. 15.0 months, respectively, p < 0.001), but the PFS and OS were best in patients with NOM-CRC (9.0 and 35.0 months). Improved OS was associated with R0 resection (23.0 vs. 17.0 months, p < 0.001). Multivariate analysis indicated that patients with well-differentiated pathology and unilateral ovarian metastasis had a better prognosis.

Conclusion:

Multidisciplinary treatment strategy, including systemic chemotherapy, targeted therapy, and complete surgery, may contribute to the prolongation of OS and be safe for treatment of OM-CRC.

Introduction

Colorectal cancer (CRC) is the third most common malignancy cancer, and about 20% of patients are diagnosed with advanced stage at the time of diagnosis, among which liver is a common metastatic organ.¹ Studies have reported that ovarian metastases from CRC (OM-CRC) are relatively rare, and the incidence of synchronous ovarian metastasis is about 9.0%, and the incidence of heterochronous ovarian metastasis is about 7.0%, mostly in colon cancer. Moreover, ovarian metastasis of rectal cancer is even less than 1.0%, which may be related to the use of radiotherapy for rectal cancer, reducing the local recurrence rate.² Recently, clinical application of chemical drugs, targeted drugs, and immune drugs significantly improves the prognosis of patients with metastatic CRC (MCRC). In particular, the 5-year survival rate of patients with liver metastasis of operable CRC is 53.6% ,³ and the median overall survival (OS) of patients with lung metastasis of operable colon cancer is up to 45 months.⁴ However, the therapeutic response and prognosis of OM-CRC were significantly worse than those of nonovarian metastases from CRC (NOM-CRC), with a survival time of about 10–20 months.⁵ The poor prognosis of OM-CRC may be due to the ovary as a barrier to prevent standard chemotherapy drugs. Low efficiency of traditional treatment regimen for OM–CRC prompted us to seek new treatments, especially those capable of rapid relief of clinical symptoms, which improves their quality of life.

In recent years, it has been reported that ovariectomy can improve the prognosis of OM-CRC patients and may be beneficial in selected patients with OM-CRC.⁶ Chung et al. analyzed pathological and follow-up data on 34 patients who underwent surgical resection of OM-CRC. It was found that the 3-year OS rate is 25.1%, and the median OS time in patients who underwent complete cytoreduction is higher than that in all patients (36 vs. 19 months).⁷ Laparoscopy using the three-trocar technique proved to be a safe procedure for treating OM-CRC, including in elderly patients.⁸ However, these retrospective studies have relatively small sample size, which limits their clinical implication. In addition, clinical studies such as FIRE-3/AIO KRK0306, CALGB/SWOG 80405, and PEAK have confirmed that targeted drugs combined with standard chemotherapy can improve the prognosis of MCRC patients,⁹ but clinical evidence regarding whether adding ovariectomy to this combination can improve the prognosis of OM-CRC is lacking. Therefore, to improve their understanding of the role of targeted therapy and chemotherapy combined with ovariectomy in OM-CRC, the authors conducted a retrospective analysis of the response to treatment and prognosis of OM-CRC and NOM-CRC patients in two hospitals.

Materials and Methods

This study was approved by the Ethics Committee of the Peking University Shenzhen hospital.

Patients

From January 2014 to January 2019, patients with MCRC registered in the database of Peking University Shenzhen Hospital and The Second People's Hospital of Shenzhen were diagnosed by pathology. The authors retrieved the cancer registry of two hospitals and looked for women CRC patients with the international classification of diseases code. Then the authors narrowed the search scope, searched with ovaries transfer or not, and found all potential patients. Finally, a total of 30 patients with OM-CRC were found, and 20 patients with NOM-CRC were randomly selected. General data of patients are shown in Table 1.

Table 1.

General Data of 50 Patients with Metastatic Colorectal Cancer

Group	OM-CRC operation (n = 14)(n, %)	OM-CRC nonoperation (n = 16)(n, %)	NOM-CRC (n = 20)(n, %)	p-value
Variable
Age (Mean, years)	38.4 (23–54)	40.4 ( 24–55)	50.6 (31–61)
ECOG core				0.252
0	5 (35.7)	7 (43.8)	13 (65.0)
1	9 (64.3)	9 (56.2)	7 (35.0)
Tumor site				0.866
Left colon	9 (64.3)	9 (56.3)	9 (45.0)
Right colon	4 (28.6)	6 (37.5)	9 (45.0)
Rectum	1 (7.10)	1 (6.20)	2 (10.0)
Pathological differentiated				0.267
High	0 (0)	0 (0)	4 (20.0)
Moderately	4 (28.6)	4 (25.0)	4 (20.0)
Low	10 (71.4)	12 (75.0)	12 (60.0)
Ovarian metastasis time				0.817
Simultaneous	8 (57.1)	9 (56.2)	0
Heterochronous	6 (42.9)	7 (43.8)	0
Ovary parts				0.502
Unilateral ovarian	10 (71.4)	8 (50.0)	0
Bilateral ovaries	4 (28.6)	8 (50.0)	0
RAS condition				0.674
Wild type	5 (45.7)	7 (43.8)	10 (50.0)
Mutant	9 (54.3)	9 (56.2)	10 (50.0)
BRAF condition				0.684
Wild type	3 (21.4)	5 (31.3)	9 (45.0)
Mutant type	6 (42.9)	6 (37.5)	5 (25.0)
Unknown	5 (35.7)	5 (31.2)	6 (30.0)
MSI				0.965
dMMR	0 (0)	1 (6.20)	1 (5.0)
pMMR	13 (92.9)	13 (81.3)	16 (80.0)
Unknown	1 (7.10)	2 (12.5)	3 (15.0)
First-line treatment				0.465
Bevacizumab	5 (35.7)	7 (43.8)	9 (45.0)
+mFOLOFOX6
Bevacizumab	4 (28.6)	2 (12.4)	7 (35.0)
+FOLFIRI
Cetuximab	5 (35.7)	7 (43.8)	4 (20.0)
+FOLFIRI

ECOG, Eastern Cooperative Oncology Group; OM-CRC, ovarian metastases from colorectal cancer; NOM-CRC, nonovarian metastases from colorectal cancer; BRAF, b-type Raf proto-oncogene; MSI, microsatellite instability; dMMR, deficient of mismatch repair; pMMR, proficiency of repair deficient.

The inclusion criteria were: (1) age from 18 to 70; (2) primary CRC was confirmed by pathology, and NOM-CRC was confirmed by pathology through puncture specimens and surgical specimens; (3) OM-CRC was confirmed by biopsy or surgical specimen pathology, and the immunohistochemical indicators included CK7, CA125, CK20, CDX2, and PAX8, excluding primary malignant ovarian tumor or other malignant tumor metastasis to the ovary; (4) computed tomography (CT) and/or magnetic resonance (MR) to identify distant metastatic sites and evaluate the efficacy; (5) Eastern Cooperative Oncology Group (ECOG) 0–2, with survival of more than 3 months; (6) the patients were treated for the first time, with no obvious abnormalities in blood routine, liver function, and renal function, no serious complications, and normal functions of other important organs; and (7) all patients had complete clinical data and gave the informed consent.

Exposures

Fifty female patients with MCRC were categorized into three groups: (1) operation group of 14 OM-CRC patients. OM-CRC resection was performed in patients with simultaneous ovarian metastasis. Ovariectomy was performed in patients with heterochronous metastatic ovarian cancer. One patient with liver metastasis underwent surgery to remove primary and metastatic foci; (2) nonoperation group of 16 OM-CRC patients; and (3) control group of 20 NOM-CRC patients.

First-line treatment consisted of: (1) bevacizumab + mFOLFOX6: bevacizumab (Roche): 5 mg/kg, intravenous drops of 30–90 min, 1 d, oxaliplatin (Sanofi): 85 mg/m² intravenous drops of 2 h, 1 d, leucovorin (Hengrui, China): 400 mg/m², intravenous drops of 2 h, 1 d, 5-FU (Hengrui, China): 400 mg/m², intravenous injection, 1 d, 2400 mg/m² on continuous pumping for 48 h, repeated for 2 weeks; (2) bevacizumab +FOLFIRI: bevacizumab (Roche): 5 mg/kg, intravenous drips for 30–90 min, 1 d, irinotecan (Hendri): 180 mg/m², intravenous drips for 90 min, 1 d; (3) + FOLFIRI: cetuximab (Merck): 400 mg/m², intravenous drips for 120 min, 1 week, then 250 mg/m² weekly, intravenous drips for 60 min, 1 d, the same as above. CT or MR was used to evaluate the efficacy every 2 cycles. In the operation group, patients with OM-CRC were given first-line treatment to maximize the efficacy or chose surgical treatment after PD. Bevacizumab treatment should be given at least 6 weeks after surgery. Patients with SD or above should continue with the original treatment after surgery, and patients with PD could choose effective treatment after surgery (perioperative treatment time was 6 months). The dose of chemotherapy drugs or targeted drugs was adjusted according to the patient's tolerance, and the evaluation criteria for side-effects were referred to the World Health Organization (WHO) standards.

Outcomes

The primary end point was OS, defined as the time from diagnosis of MCRC to time of death for any cause. The secondary end points were objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), and surgical safety. PFS was defined as the time between the diagnosis of MCRC and the observation of disease progression or the occurrence of death from any cause. During the treatment, CT or MR examinations were performed regularly to evaluate the efficacy, which was divided into complete response (CR), partial response (PR), stable response (SD), and progressive disease (PD) according to the Response Evaluation Criteria in Solid Tumors (RECIST) standard. ORR was calculated as CR+PR, and DCR was calculated as CR+PR+SD. Simultaneous ovarian metastasis was defined as ovarian metastasis within 6 months after the initial diagnosis of CRC, and heterochronous ovarian metastasis was defined as ovarian metastasis at more than 6 months after the initial diagnosis of CRC.

Statistical analysis

SPSS version 22.0 (SPSS, Inc., Chicago, IL) was used for statistical analysis. Fisher's exact test and Wilcoxon rank sum test were used for rate comparison. Survival was estimated by Kaplan–Meier method, and log-rank test was used for comparison between the two groups. Cox proportional hazard model was used to assess the relationship between mortality risk and clinical pathology and treatment characteristics. Missing values were excluded pairwise from analysis, and all tests were two sided. p < 0.05 was considered statistically significant.

Results

Patient characteristics

According to the inclusion criteria, 50 patients with MCRC were collected as shown in Table 1. It was suggested that mean age for OM-CRC operation group, OM-CRC nonoperation group, and NOM-CRC group was 38.4, 40.4, and 50.6 years old, respectively. In OM-CRC operation group, 9 primary tumors (64.3%) were identified in the left colon in comparison with 4 (28.6%) in the right colon and 1 (7.10%) in the rectum. In OM-CRC nonoperation group, 9 primary tumors (56.3%) were identified in the left colon in comparison with 6 (37.5%) in the right colon and 1 (6.20%) in the rectum. In NOM-CRC group, 9 primary tumors (45.0%) were identified in the left colon in comparison with 9 (45.0%) in the right colon and 2 (10.0%) in the rectum. Simultaneous ovarian metastasis was identified in 8 cases (57.1%) of OM-CRC operation group and 9 cases (56.2%) of OM-CRC nonoperation group, and heterochronous ovarian metastasis was identified in 6 cases (42.9%) of OM-CRC operation group and 7 cases (43.8%) of OM-CRC nonoperation group. Ten cases (71.4%) of OM-CRC operation group and 8 cases (50.0%) of OM-CRC nonoperation group showed metastasis in unilateral ovaries, and 4 cases (28.6%) of OM-CRC operation group and 8 cases (50.0%) of OM-CRC nonoperation group had metastasis in bilateral ovaries. There was no difference in tumor locations between OM-CRC operation and nonoperation groups (p > 0.05).

In OM-CRC operation group, 1 of the 8 patients with simultaneous ovarian metastasis also had liver metastasis, while all 6 patients with heterochronous ovarian metastasis were simple ovarian metastasis. In OM-CRC nonoperation group, 1 of the 9 patients with simultaneous ovarian metastasis also had lung metastasis, while all 7 patients with heterochronous ovarian metastasis were simple ovarian metastasis.

First-line treatments

All patients completed first-line treatments, and the response to treatments is shown in Table 2. The ORR and DCR of the NOM-CRC group were higher than those of the OM-CRC group, with ORR of 70.0% (14/20) and 36.7% (11/30), respectively (χ ² = 5.333, p = 0.021) and DCR of 90.0% (18/20) and 76.7% (23/30), respectively (χ ² = 1.445, p = 0.229). However, there was no difference between OM-CRC operation and nonoperation groups, with ORR of 35.7% (5/14) and 37.5% (6/16) (χ ² = 0.010, p = 0.919) and DCR of 78.6% (11/14) and 75% (12/16) (χ ² = 0.053, p = 0.818) for operation and nonoperation groups, respectively.

Table 2.

The Efficacy of the First-Line Treatment

Group	OM-CRC operation (n = 14)(n, %)	OM-CRC nonoperation (n = 16)(n, %)	NOM-CRC (n = 20)(n, %)	p-values
Efficacy
CR	0 (0)	0 (0)	2 (10.0)	0.300
PR	5 (35.7)	6 (37.5)	12 (60.0)
SD	6 (42.9)	6 (37.5)	4 (20.0)
PD	3 (21.4)	4 (25.0)	2 (10.0)
ORR	5/14 (35.7)	6/16 (37.5)	14/20 (70.0)
DCR	11/14 (78.6)	12/16 (75.0)	18/20 (90.0)

OM-CRC, ovarian metastases from colorectal cancer; NOM-CRC, nonovarian metastases from colorectal cancer; CR, complete response; PR, partial response; SD, stable response; PD, progressive disease; ORR, objective response rate; DCR, disease control rate.

Survival analysis

By the end of the follow-up on September 1, 2019, 42 patients among the entire cohort have died, with median PFS of 8.0 months [95% confidence interval (CI), 6.95–9.05] and median OS of 24.0 months (95% CI, 15.8–32.2). PFS was 9.0 months (95% CI, 8.1–10.0) in NOM-CRC group, 9.0 months (95% CI: 7.9–10.0) in OM-CRC operation group, and 6.0 months (95% CI: 5.4–6.6) in OM-CRC nonoperation group (p < 0.001). NOM-CRC group (median [95% CI], 35.0 [33.7–36.3]) had longer OS than both OM-CRC groups, and OM-CRC operation group (median [95% CI], 21.0 [16.1–26.0]) had longer OS than the nonoperation group (median [95% CI], 15.0 [14.3–15.7]) (p < 0.001) (Fig. 1). In OM-CRC operation group, R0 resection patients had longer OS than R1 resection patients (median [95% CI], 23.0 [20.6–25.4] vs. 17.0 [16.0–19.0], p < 0.001). Multivariable analysis of pathological differentiation, ECOG, ovarian metastasis time, ovarian metastasis site, RAS status, and first-line treatment efficacy showed that OS was associated with ovarian metastasis site (HR[95% CI], 0.27 [0.09–0.85], p = 0.025) and pathological differentiation (HR [95% CI], 7.73 [1.09–54.9], p = 0.041), suggesting that higher differentiation and unilateral ovarian metastasis were associated with better OM-CRC prognosis.

FIG. 1.

Kaplan–Meier curve of all patients stratified by ovarian metastasis and surgical statuses.

Surgical safety

All 14 OM-CRC patients in the operation group underwent surgery, including 6 patients with heterochronous ovarian metastasis (4 of them with R0 resection) and 8 patients with simultaneous ovarian metastasis (6 of them with R0 resection). Cancer cells were found in peritoneal lavage fluid of 4 patients. The R0 resection rate was 71.4% (10/14). The median size of postoperative metastatic ovarian cancer was 4.2 cm (3–15). Radiological images showed unilateral ovarian metastasis in 5 patients, and postoperative pathological examinations showed metastatic carcinoma in bilateral ovaries. Delayed wound healing occurred in 2 patients and abdominal infection occurred in 1 patient, all of which were successfully treated. No treatment-related death occurred.

Discussion

OM-CRC is not necessarily associated with worse prognosis than metastasis to other sites. Abroad study shows that 80% OM-CRC patients come from primary colon cancer, suggesting that the transfer mechanism may give priority to implantation metastasis. Some other researches also demonstrate that OM-CRC commonly develops in premenopausal women, and blood metastasis is one of the transfer mechanisms, while lymphatic metastasis is relatively rare.¹⁰ This study confirmed that ovarian metastasis is more likely to happen in colon cancer, accounting for 93.3% (28/30), and only 2 cases are rectal cancer patients with ovary metastases. Furthermore, OM-CRC patients showed abdominal pain, abdominal distention, intestinal obstruction, etc. as the main clinical manifestations.

On the basis of traditional chemical treatment of bevacizumab, cetuximab, and immunosuppressive drugs in clinical application, the prognosis of patients with MCRC has been dramatically improved, but the efficacy of OM-CRC patients is limited. Previous studies have found that the first-line treatment on OM-CRC patients is obviously worse than the NOM-CRC patients, ORR is 23.5% and 63.6%, respectively, but DCR is similar (88.2% vs. 86.4%).¹¹ This study found that the ORR and DCR of NOM-CRC patients are similar to previous large clinical studies, both significantly better than OM-CRC patients. Although NOM-CRC patients also have an advantage with DCR, the difference is not statistically significant, confirming that the efficacy of OM-CRC patients is poor. Another study found that the curative effect of gastric cancer with ovarian metastasis is poor. The specific mechanism may be associated with metastatic carcinoma of ovary tumor microenvironment which may exist in the microenvironment of the drug resistance factors.¹² Some studies have found that these patients have more genetic mutations, leading to drug resistance, such as KRAS and SMAD4, KMT2D, or NTRK1, among them the NTRK1 mutation rate is as high as 10.5%, providing theoretical basis for the future treatment of targeted drugs.¹³

Previous studies have found that surgery combined with chemotherapy can improve the prognosis of OM-CRC patients with OS up to 43 months, among which BRAF wild-type patients have a better prognosis.¹⁴ However, the status of combination of targeted drugs with chemotherapy and ovarian surgery in OM-CRC is not very clear at present. This study confirmed that this therapy can improve the survival of OM-CRC patients. The PFS and OS of the operation group are significantly better than those of the nonoperation group, indicating that the combined surgically based comprehensive treatment model does improve the prognosis of OM-CRC patients. A previous study also showed that improved median survival is significantly promoted (28.8 vs. 8.2 months) following use of adjuvant chemotherapy. And the OS of OM-CRC patients treated with surgery combined with chemotherapy was 23.5 months, and the OS of R0 resection patients reaches up to 30.5 months. It is indicated that improved survival in OM-CRC patients is associated with complete surgical resection in combination with systemic chemotherapy.¹⁵ Their study also proved that the OS of R0 resection patients is indeed better compared with R1 resection patients, reaching 23.0 months. In addition, a retrospective study found that cytoreductive surgery followed by hyperthermic intraperitoneal chemotherapy (CRS-HIPEC) can improve the prognosis of patients with OM-CRC. The median survival time can reach 34.1 months, which is significantly better compared with patients with simple surgical resection (17.5 months). However, this study also has limitations. For example, all patients had synchronous ovarian metastasis of colorectal cancer, but do not include patients with heterochronous ovarian metastasis. In addition, this study lacks DFS data. Although retrospective studies using small sample have confirmed that CRS-HIPEC can improve the prognosis of OM-CRC patients or OM-CRC patients with peritoneal metastasis,^16,17 CRS-HIPEC is not the standard treatment mode of OM-CRC, and more clinical studies are needed to confirm its functions. Some foreign studies even suggested that preventive ovariectomy for postmenopausal female patients with left hemicolonic cancer or rectal cancer at the age of 60–70 years can reduce the incidence of heterochronous ovarian metastasis,¹⁶ although the treatment is still controversial.

Different strategies such as chemotherapy, surgery, radiation therapy, and immunotherapy, as well as nutritional-supplement therapy, have been used for CRC treatment.¹⁸ However, these approaches are accompanied with certain pitfalls and restrictions such as bleeding, rash, nausea, diarrhea, neuropathy, hair loss, healthy cell damages, and decreased bioavailability of high molecular weight chemotherapeutic agents, as well as drug resistance.¹⁹ The limitations of cancer chemotherapy might be overcome through the use of targeted therapies, which can impede tumor growth through inhibiting cell proliferation, differentiation, and migration.²⁰ Nanosized therapeutics, including nanoconjugates of monoclonal antibodies along with drugs and organic/inorganic nanoparticles, were also used to treat CRC.²¹ Furthermore, angiogenesis inhibitors, epidermal growth factor receptor-targeted therapy, Serine/Threonine-protein kinase B-raf (BRAF) mutation-targeted therapies, and other novel strategies, including immunotherapy, have been used in the management of CRC metastases.²² In this study, the authors found that the combination of targeted drugs with chemotherapy and ovariectomy treatment model could indeed improve the prognosis of OM-CRC patients.

This study has some limitations. Due to the overall low incidence of OM-CRC, the sample size of this study was relatively small even after surveying two large hospitals. For the same reason, the time span of this study was also longer than usual to enroll as many patients as possible. During this period, with the development of second-generation gene sequencing, the follow-up treatment mode of patients became more accurate. For instance, the detection of BRAF and HER-2 guided the treatment of new targeted drugs, which might affect the prognosis of patients. Therefore, it is necessary to carry out randomized controlled trials to confirm their findings in the future.

Conclusions

In summary, their study showed that the combination of targeted drugs with chemotherapy and ovarian resection was associated with favorable clinical outcomes of OM-CRC patients. Their data also suggested that this treatment model was safe and practical.

Ethics Approval

This study was approved by the Ethics Committee of the Peking University Shenzhen hospital.

Informed Consent

All patients had complete clinical data and gave the informed consent.

Availability of Data and Materials

The datasets used during the present study are available from the corresponding author upon reasonable request.

Footnotes

Authors' Contributions

G.T. and Q.L. conceived and designed the study. X.P. and B.C. performed the experiments. G.L. and S.W. acquired and analyzed the data. G.T. wrote the article. Q.L. and X.L. reviewed and edited the article. All authors read and approved the article and agree to be accountable for all aspects of the research in ensuring that the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Author Disclosure Statement

All authors declare that they have no competing financial interests that exist.

Funding Information

This work was supported by Shenzhen Sanming Project of Medicine (No.SZSM201612041) and Shenzhen Science and Technology Innovation Commission (JCYJ20190809100005672, GJHZ20180420180754917, and ZDSYS20190902092855097).

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