Adjuvant platinum-based chemotherapy for borderline serous ovarian tumors with invasive implants

doi:10.1016/j.ygyno.2013.11.006

Gynecologic Oncology

Volume 132, Issue 1, January 2014, Pages 23-27

https://doi.org/10.1016/j.ygyno.2013.11.006 Get rights and content

Highlights

•
Largest series of borderline ovarian tumors + invasive implants treated with adjuvant chemotherapy.
•
Adjuvant platinum-based chemotherapy (PBC) was well tolerated.
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Adjuvant PBC resulted in objective responses.
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5 year PFS and OS were encouraging at 67% and 96%, respectively.

Abstract

Background

Most borderline ovarian tumors (BOTs) are cured with surgery. However BOTs with invasive implants have a poor prognosis with a mortality of 20–40%. The benefit of adjuvant chemotherapy (CT) in this setting remains poorly defined.

Methods

Retrospective study of serous BOT + invasive implants treated with adjuvant CT.

Results

36 patients were referred with serous BOTs + invasive implants and treated with surgery and platinum-based CT between 06/1982 and 02/2011. 83% were stage III/IV. Tumors demonstrated microinvasion, micropapillary pattern or desmoplastic implants in 53%, 47% and 67% of cases, respectively. 8% had fertility-sparing surgery. Taking into account initial and completion surgeries, R0 was achieved in 84% (27/32) (NA, N = 4). The majority (72%) received a combination of platinum + taxane. 11% of patients experienced a G3/G4 toxicity. 13 of 36 (36%) patients relapsed at a median of 27.3 months after diagnosis of invasive implants. Among 12 patients with histologically confirmed relapse, 8 patients progressed with invasive disease in the form of carcinoma or invasive implants. 5 year PFS/OS were 67%/96%. Neither microinvasion, micropapillary pattern, nor desmoplastic implants predicted relapse. In cases with evaluable disease, an objective response to chemotherapy was observed in 4 of 6 patients.

Conclusion

This is the largest study of BOT with invasive implants treated with surgery and adjuvant platinum-based CT. Treatment was well tolerated and the invasive relapse rate was 22% (8/36). Although numbers are small, the objective responses suggest a possible role for adjuvant CT in BOTs with invasive implants.

Introduction

Serous borderline, or low malignant potential, ovarian tumors represent roughly 10 to 20% of serous epithelial ovarian tumors. Histologically, these tumors display greater epithelial proliferation than adenomas but lack the destructive stromal invasion that characterizes epithelial ovarian carcinomas [1]. The clinical presentation, treatment and prognosis of borderline ovarian tumors (BOTs) differ drastically from their invasive counterparts. They are typically diagnosed at an early stage (85% stage I), in younger women and are associated with an excellent clinical outcome after surgical treatment alone with 5 year overall survival rates of 95% [2], [3], [4]. Interestingly, despite the absence of stromal invasion, BOTs have the capacity to spread to the peritoneum or to pelvic and/or paraaortic lymph nodes. A proportion of serous BOTs are associated with extraovarian disease sites, but these are defined as ‘implants’ not metastases by the WHO because of their indolent nature [1]. While the vast majority of implants are non-invasive, a small subset of patients with extraovarian disease (10–15%) has invasive implants [5]. This feature has been shown by some to have a drastic impact on prognosis with a disease-associated mortality rate as high as 40% in early studies suggesting that a subset of BOTs could potentially benefit from adjuvant therapies [5]. It has now been quite clearly established that the vast majority of BOTs should be managed with surgery alone, the one exception being the subset of BOTs with invasive implants for which the NCCN 2012 updated guidelines recommend consideration of adjuvant chemotherapy (level 2B recommendation) [6]. However this remains a controversial area as no randomized studies have ever been conducted to investigate the benefit of adjuvant chemotherapy in this rare subset (< 1% of epithelial ovarian tumors). We therefore conducted a retrospective study of BOTs with invasive implants treated with surgery and adjuvant chemotherapy in order to describe their clinical outcome and potentially identify prognostic factors.

Section snippets

Methods

A list of cases of serous BOT with invasive implants referred to the Institut Gustave Roussy since 1982 was obtained through a search of our institution's pathology database and computerized medical records. Cases were reviewed centrally by the same expert pathologist and only cases with invasive implants treated with surgery and platinum-based chemotherapy were included. Given that the classification of invasive implants was not clearly established until the 1990s [5], [7], all cases diagnosed

Patient baseline clinical characteristics (Table 1)

36 patients with serous BOT and invasive implants treated with surgery and adjuvant chemotherapy between June 1982 and February 2011 were identified. Fourteen percent (5/36) had a prior history of BOT with non-invasive implants. With regard to these 5 patients, two were treated with conservative surgery (cystectomy or unilateral salpingo-oophorectomy) and relapsed with invasive implants at 5 years and 14 months, respectively. The other 3 were treated non-conservatively and relapsed with invasive

Discussion

The outcome for the vast majority of patients with serous BOT is excellent with an overall survival of 95% at 5 years [4]. Most (85%) present with early stage disease and even in the case of advanced BOT, implants are usually non-invasive. A number of randomized and retrospective studies have now clearly established that there is no indication for adjuvant chemotherapy regardless of stage, lymph node involvement or ruptured primary [11], [12], [13]. However for the minority of patients who

Conflicts of interest statement

None declared.

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Cited by (28)

Fertility-sparing treatment for serous borderline ovarian tumors with extra-ovarian invasive implants: Analysis from the MITO14 study database
2022, Gynecologic Oncology
Only 10–15% of serous borderline ovarian tumors (BOTs) with extra-ovarian disease have invasive implants, and conservative treatments have been rarely reported. The MITO14 is a multi-institutional retrospective study conducted with the aim of systematically collecting data from consecutive BOT patients. The present analysis reports the oncological and reproductive outcomes of women with serous BOT and invasive implants registered into the MITO14 database and conservatively treated between August 2002 and May 2019.
Thirteen patients (FIGO2014 stage II–III serous BOT with invasive implants) were recruited. Primary and secondary endpoints were, respectively, recurrence and death rates, and pregnancy and live birth rates. Only patients undergoing fertility-sparing surgery (FSS) were included, while patients were excluded in case of: age > 45 years; second tumor(s) requiring therapy interfering with the treatment of BOT.
Median follow-up time from primary cytoreduction was 146 months (range 27–213 months). Eleven patients (84.6%) experienced at least one recurrence (median time to first relapse 17 months, range 4–190 months), all of these undergoing secondary surgery (FSS in 7). Five patients attempted to conceive: 3 achieved at least one pregnancy and 2 gave birth at least to a healthy child. At the end of the observation period, all patients were alive with no evidence of disease.
Fertility-sparing treatment should be considered in a context of serous BOT with invasive implants. Despite the high rate of recurrence, FSS provides good chances of reproductive success without a negative impact on overall survival.
Long term follow-up of a large series of stage-II/III atypical proliferative serous ovarian tumors
2020, Gynecologic Oncology
The aim of this study was to assess prognostic factors and implications on further management in a large series of stage-II or III Atypical Proliferative Serous Tumors (APST) with a long-term follow-up.
Patients with APSTs and peritoneal implants treated in, or referred to, our institution were retrospectively reviewed. Prognostic factors on invasive recurrence, disease-free (DFS) and overall survival (OS) were analyzed.
Between 1971 and 2017, 212 patients were identified and followed (33 having invasive implants). After a median follow-up of 115 months, 70 recurrences were observed, 28 of them under the form of invasive disease. DFS at 5 years and 10 years was 73% and 62% respectively. The use of a conservative treatment (HR = 5.5[3.33–9.08], p < .0001), the presence of ≥3 peritoneal sites with implants (HR = 1.65[1.01–2.72], p = .045) were unfavorable prognostic factors for DFS. The presence of ≥3 peritoneal sites with implants (HR = 3.02[0.96–9.53], p = .049) and the presence of stromal microinvasion (HR = 3.19[1.12–9.1], p = .022) were unfavorable prognostic factors for OS. Non-conservative surgery (HR = 7[2.35–20.87], p = .0002), invasive implants (HR = 5.37[1.29–22.26], p = .013), and ≥ 3 peritoneal sites with implants (HR = 3.56 [1.11–11.39], p = .024) were identified as predictors of recurrence in the form of an invasive disease. Invasive implants were not associated with DFS (HR = 1.39[0.77–2.51], p = .27), nor OS (HR = 1.76[0.57–5.47], p = .32).
After a long-term follow-up, type of peritoneal implants is no longer a prognostic factor for OS. Implants ≥3 peritoneal sites seem to impact significantly OS and then require a specific follow-up in this subgroup of patients.
Borderline Ovarian Tumours: CNGOF Guidelines for Clinical Practice – Surgical Management of Advanced Stages of Borderline Ovarian Tumours
2020, Gynecologie Obstetrique Fertilite et Senologie
Évaluer la prise en charge chirurgicale des tumeurs frontières de l’ovaire (TFO) de stades avancés dans le cadre des recommandations pour la pratique clinique réalisées par le Collège national des gynécologues et obstétriciens français (CNGOF)
Il s’agit d’une revue exhaustive de la littérature portant sur les stades avancés de TFO. La sélection bibliographique a été effectuée dans PubMed de 2007 à 2019 inclus, en incluant les publications en langue anglaise et française. Les articles ont été sélectionnés sur la base du titre, puis du résumé et enfin de l’article intégral. Les niveaux de preuve des études ont été définis selon l’échelle proposée par la Haute Autorité de santé (HAS).
Par analogie avec le cancer épithélial de l’ovaire, en cas de suspicion préopératoire ou après un diagnostic postopératoire de TFO de stade avancé, la patiente doit être référée à un centre ayant une expertise dans la prise en charge des cancers de l’ovaire (grade C). Aucune donnée de la littérature ne permet de conclure quant à la réalisation systématique d’une hystérectomie, cependant l’objectif dans les stades avancés de TFO est le résidu tumoral nul (grade C). Dans les TFO de stades avancés, il n’est pas recommandé de réaliser une lymphadénectomie à titre systématique, mais l’exérèse des adénopathies suspectes d’envahissement en pré ou peropératoire à but curatif peut être discuté afin de ne pas laisser de résidu tumoral en fin d’intervention (grade C). Il est recommandé de décrire la carcinose péritonéale avant toute exérèse ainsi que les résidus tumoraux en fin de chirurgie (grade B). L’utilisation d’un score de carcinose péritonéale permettant d’évaluer de façon objective la charge tumorale comme le « Peritoneal Carcinosis Index » (PCI) est recommandée (grade C). Un traitement conservateur comportant au minimum la conservation de l’utérus et d’un fragment d’ovaire chez une patiente désireuse de grossesse, peut être proposé après avis en réunion de concertation pluridisciplinaire dans les stades avancés de TFO (grade C). La réalisation d’une biopsie de l’ovaire controlatérale n’est pas recommandée dans les TFO de stades avancés (grade C), mais une chirurgie de restadification associée à l’exérèse de toutes les lésions tumorales est recommandée si elle n’a pas été réalisée initialement (grade C). Il n’est pas possible d’émettre de recommandation concernant une indication de chimiothérapie dans stades avancés même en cas d’implants invasifs.
La littérature peu importante et le caractère rétrospectif des études sur les stades avancés de TFO limitent le grade des recommandations.
To evaluate the surgical management of borderline ovarian tumors (BOT) in the framework of recommendations for clinical practice made by the National College of Obstetricians and Gynecologists (CNGOF)
This is a comprehensive review of the literature on the advanced stages of BOT. Bibliographic selection was conducted in PubMed from 2007 to 2019 inclusive, selecting publications in English and French. Articles were selected on the basis of the title, then the abstract and finally the full article. The levels of evidence of the studies were defined according to the scale proposed by the High Authority of Health (HAS).
By analogy with epithelial ovarian cancer, in case of preoperative suspicion or after a postoperative diagnosis of advanced BOT, the patient must be referred to an expert centre in ovarian cancer (grade C). There is no data from the literature to conclude that a hysterectomy should be performed routinely, however, the goal in the advanced stages of BOT is no tumor residue (grade C). In advanced stages of BOT, systematic lymphadenectomy is not recommended, but excision of suspected lymph node on preoperative and intraoperative evaluation, for curative purposes, may be discussed to obtain no residual disease (grade C). It is recommended to describe peritoneal carcinomatosis before any excision as well as tumor residues at the end of surgery (grade B). The use of a peritoneal carcinomatosis score to evaluate tumor burden such as the “Peritoneal Carcinosis Index” (PCI) is recommended (grade C). For advanced stages of BOT, a conservative treatment with at least the preservation of the uterus and an ovarian fragment in a patient wishing a pregnancy may be proposed after Multidisciplinary Concertation Meeting (Grade C). Contralateral ovary biopsy is not recommended in advanced stage BOT (Grade C) but restaging surgery associated with removal of all tumor lesions is recommended when not performed initially (Grade C). It is not possible to make a recommendation on chemotherapy indication in advanced stages even with invasive implants.
The weakness of the literature and the retrospective nature of BOT advanced stage studies limit the grade of the recommendations.
ESMO-ESGO consensus conference recommendations on ovarian cancer: Pathology and molecular biology, early and advanced stages, borderline tumours and recurrent disease
2019, Annals of Oncology
Citation Excerpt :
The role of adjuvant chemotherapy in advanced-stage sBOTs is highly debated [152, 153]. Recent retrospective data, collecting the largest number to date of patients with invasive implants treated with surgery and adjuvant chemotherapy, suggested a potential advantage in selected groups of patients [152]. According to the available evidence, there is no benefit in adding adjuvant treatment to upfront surgery in patients with sBOTs with invasive implants [111, 151–171].
The development of guidelines recommendations is one of the core activities of the European Society for Medical Oncology (ESMO) and European Society of Gynaecologial Oncology (ESGO), as part of the mission of both societies to improve the quality of care for patients with cancer across Europe. ESMO and ESGO jointly developed clinically relevant and evidence-based recommendations in several selected areas in order to improve the quality of care for women with ovarian cancer. The ESMO–ESGO consensus conference on ovarian cancer was held on 12–14 April 2018 in Milan, Italy, and comprised a multidisciplinary panel of 40 leading experts in the management of ovarian cancer. Before the conference, the expert panel worked on five clinically relevant questions regarding ovarian cancer relating to each of the following four areas: pathology and molecular biology, early-stage and borderline tumours, advanced stage disease and recurrent disease. Relevant scientific literature, as identified using a systematic search, was reviewed in advance. During the consensus conference, the panel developed recommendations for each specific question and a consensus was reached. The recommendations presented here are thus based on the best available evidence and expert agreement. This article presents the recommendations of this ESMO–ESGO consensus conference, together with a summary of evidence supporting each recommendation.
Tumors of low malignant potential a single institution experience
2019, International Journal of Surgery Case Reports
The tumors of low malignant potential are an independent group of the ovarian epithelial tumors. They represents 10–20% of all ovarian epithelial tumors.
Our aim through this study to determine how to treat this disease in the most suitable way.
A retrospective study involving 73 patients diagnosed with TLMP and treated at our Institute between September 1975 and June 2010.
The median age was 49 years. In 33% of the cases, the patients were younger than 40 years. Our study included 38 mucinous tumors, 30 serous and 5 mixed. The tumors were stage I in 69% of the cases, stage II in 11% and stage III in 20%.
All patients had surgery as a primary treatment. The surgery was radical in 77% of the cases. Five patients had an adjuvant chemotherapy. After a mean follow up of 10 years, we reported 7 cases of local relapses. The prognostic factors for a disease free survival were: the stage of the tumor and the presence of invasive implants. The overall survival at 5 and 10 years was respectively of 96.9% and 92.8%. The prognostic factors for overall survival were: the age, the stage, the existence of a residual tumor, the presence of pseudomyxoma or peritoneal implants. After having a conservative surgery two patients achieved full term pregnancies.
Randomized studies are required to back-up our findings and give a higher grade of recommendation to the actual standard of care.
Fertility preservation in women with borderline ovarian tumours
2016, Cancer Treatment Reviews
Citation Excerpt :
Indications of adjuvant platinum-based chemotherapy remain rare in this disease and are limited to patients with invasive peritoneal implants or with nodal spread located near the nodal sinus. Of note, no randomized studies have demonstrated any survival advantage of adjuvant chemotherapy [5,22]. The overall risk of recurrence after fertility-sparing surgery is higher (0–25%) than after bilateral salpingo-oophorectomy (0–5%) [23].
Borderline ovarian tumours (BOT) may occur in young women and have an excellent survival rate. Therefore, there is the obligation to put emphasis on fertility preservation in affected women. On the other hand, it has also been underlined that the disease should be managed with caution because these tumours can relapse and, albeit rare, malignant transformation can also occur. Unfortunately, evidence on fertility preservation in women with BOT is scanty. In this opinion paper, we tried to draw some clinical indications based on the few available studies on the clinical management of BOT and their possible relation with controlled ovarian hyper-stimulation (COH). We ultimately came to the following conclusions: (1) Fertility counselling should become an integral part of the clinical management of women with BOT. Conservative management without pre-surgical counselling may expose women without reasonable chances of future conceptions to undue risks. (2) Despite some epidemiological concerns on the possible relation between COH and BOT, the conservative surgical treatment should be associated to oocyte cryopreservation considering the high risk of recurrence of the disease. (3) Letrozole during COH should be considered to temper the theoretical risk of increased recurrences. (4) Pregnancy should not be delayed in women at low-moderate risk of recurrences. Fertility preservation may be avoided in these women provided that they start active pregnancy seeking early. (5) Albeit experimental, oocytes retrieval from affected ovaries removed at the time of surgery can be considered. Conversely, ovarian cortex cryopreservation is not justified given the possible risks of malignant reseeding.

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Adjuvant platinum-based chemotherapy for borderline serous ovarian tumors with invasive implants

Highlights

Abstract

Background

Methods

Results

Conclusion

Introduction

Section snippets

Methods

Patient baseline clinical characteristics (Table 1)

Discussion

Conflicts of interest statement

Hum Pathol

Gynecol Oncol

Hum Pathol

Lancet Oncol

Gynecol Oncol

Obstet Gynecol

Lancet Oncol

DPWHO: tumours of the breast and female genital organs in press I (ed): pathology and genetics

Current concepts in management of epithelial ovarian tumors of low malignant potential

Obstet Gynecol Surv

The management of borderline epithelial tumors of the ovary

Int J Gynecol Cancer

Outcome of patients with borderline ovarian tumors: results of the multicenter AGO ROBOT study

J Clin Oncol

Peritoneal implants of ovarian serous borderline tumors. Histologic features and prognosis

Cancer

Phase I, dose-escalation study of BKM120, an oral pan-Class I PI3K inhibitor, in patients with advanced solid tumors

J Clin Oncol