Background
Epithelial ovarian cancer (EOC) is the most lethal gynecologic malignancy in the United States [
1]. Although primary therapy results in a complete clinical response (CCR) in more than 50% of EOC patients, achieving complete cure is rare. In fact, 3 out of 4 EOC patients develop recurrent disease within 2 years and ultimately die from the disease within 5 years [
2]. The early detection and treatment of recurrent EOC improves the survival outcome of patients; however, the absence of effective follow-up enabling early detection and treatment remains a clinical challenge. Moreover, there is no agreement regarding the characteristics that indicate recurrence, the surveillance interval, and the necessary means of follow-up [
3‐
6]. Unlike many other recurrent solid tumors, which have macroscopic masses, a significant proportion of recurrent EOC presents as immeasurable micro-nodular lesions and ascites that are widespread and diffused; therefore, quantifying recurrence in time is as difficult as seeking effective therapy in EOC patients.
The CA-125 antigen is a serum marker first identified by Bast et al. and developed through the immunization of mice by a monoclonal antibody (OC125), using an ovarian cancer cell line in 1981. Since then, CA-125 has been validated as an effective marker for monitoring EOC [
7]. Rustin et al. posited that the criterion for tumor progression in the detection of recurrent EOC is a CA-125 level of 2 × the upper limit of normal (ULN), which has a sensitivity and specificity of 88% and 98%, respectively. This CA-125 threshold is accepted by the Gynecologic Cancer InterGroup [
8‐
12]. Only one randomized trial has been conducted to investigate the value of routinely measuring follow-up CA-125 levels in EOC patients. In the MRC OV05/EORTC 55955 trial, Rustin et al. suggested that reintroducing chemotherapy in patients who have shown signs of biochemical recurrence of the disease does not improve survival duration, and that patients should not undergo regular CA-125 measurements if they have no symptoms suggesting relapse [
13]. The value of routine CA-125 follow-up was thus denied. However, this trial did not rule out the possibility of using CA-125 levels to guide the early detection of clinically recurrent EOC, which can benefit from the earlier administration of secondary cytoreductive surgery (CRS) [
14].
Secondary CRS is another major treatment for recurrent EOC. The DESKTOP I and II trials identified three independent factors for indicating complete resection, namely, good performance status, complete resection at primary surgery, and the absence of ascites. Complete resection when all three factors are present reached 79% in the DESKTOP I trail and 76% in the DESKTOP II trail [
15,
16]. The prospective DESKTOP III study on this issue is ongoing. Identifying the appropriate patients for the potentially morbidity-inducing procedure remains a clinical challenge. Hence, the possibility of utilizing rising CA-125 levels to optimize the secondary CRS in asymptomatic EOC patients with recurrent disease remains uncertain.
Prior to the appearance of a measurable disease on imaging studies, CA-125 levels rise a median of 4 months in approximately 70% of EOC patients who develop a recurrent disease [
11,
17]. The criterion used to define EOC recurrence has remained relatively stable over the past 20 years; in comparison, the density resolution technology in medical imaging has improved significantly [
18‐
20]. The widespread use of higher-resolution Computed Tomography (CT), Magnetic Resonance Imaging (MRI), and Positron Emission Tomography-Computed Tomography (PET-CT) has resulted in the more timely and accurate detection of smaller lesions. The use of sensitivity, specificity, and lead-times attained using a CA-125 level of 2 × ULN as part of the criterion in defining recurrent disease in EOC patients was formulated using radiological technology nearly two decades ago. However, the relevance of such criterion remains uncertain.
In the present study, we retrospectively evaluated EOC patients who achieved CCR through primary therapy without undergoing consolidation and maintenance therapies. The CA-125 levels recorded after completing primary therapy were used as indicators of clinical relapse. The overall survival (OS) and progression free survival (PFS) of patients receiving secondary CRS, as indicated by the CA-125 levels or the relapse-related symptoms, were analyzed. Our data revealed the value of CA-125 follow-up in patients with the opportunity for further surgery.
Discussion
The mean 5-year survival rate following the diagnosis of recurrent EOC is less than 10%. The management of recurrent diseases is a key aspect in the overall therapeutic management of patients with EOC. In addition to determining the most appropriate treatment for the primary disease, defining the triggers that signify the need for initiating or changing therapy at relapse is important in ensuring effective management [
27,
28]. The findings of the present study were focused on the use of CA-125 levels to guide the treatment of asymptomatic recurrent EOC patients who had shown CCR to primary therapy. We found that CA-125 follow-up can facilitate optimal secondary CRS and extend the OS durations of patients.
Many previous studies on this topic ignored secondary CRS, which is one of the major treatment choices apart from chemotherapy in selected cases. A previous study revealed that tumor burden was an independent factor associated with therapy response and survival [
29]. Regular follow-up once a patient who has undergone standard primary treatment has achieved CCR is warranted, because a patient who develops recurrent EOC can benefit from being treated without delay when their tumors are comparatively small.
The MRC OV05/EORTC 55955 trial showed contrasting results with those that reported that the earlier initiation of second-line chemotherapy for recurrent EOC patients can improve their outcomes as testified by some other studies [
30,
31]. Secondary CRS has also been considered to be appropriate for patients with a low-volume disease or isolated lesions. Some retrospective studies have suggested that select patients who undergo optimal secondary CRS have better PFS and OS duration than those who do not undergo therapy [
14,
32,
33].
Several factors influence whether recurrent lesions can be optimally resected, including the number and size of the tumors, the presence of ascites and/or carcinomatosis, and progression-free interval. CA-125 levels can help to recruit populations for secondary debulking. Fleming et al. showed that a shorter interval between the CA-125 elevation and the secondary CRS correlates with a greater incidence of optimal resection, thus leading to a longer median OS duration (47 months) than that of longer interval cases (23 months) [
32]. They also found that the secondary CRS was delayed every week in the 16.4 weeks following the first elevation in CA-125 level; furthermore, the likelihood that the resection would be complete decreased by 3%. Frederick et al. proposed that a preoperative CA-125 level of < 250 U/ml can predict surgical success leading to prolonged survival [
34]. In the present study, we found that the CA-125 level-guided asymptomatic recurrent EOCs have higher secondary CRS rates and longer OS and PFS durations than those in symptoms that determined relapse.
Recurrent EOC, unlike other solid tumors, tends to present without accompanying symptoms and forms multiple small implantations, particularly in the small intestine and mesentery, which cannot be readily detected using conventional imaging examinations [
35,
36]. The RECIST and WHO criteria for recurrent EOC focus on detectable changes in tumor size rather than the metastatic characteristics of the disease. However, imaging study results may not accurately reflect disease progression, because the microlesions are difficult to detect using such studies. The CA-125 level is an alternative indicator of tumor relapse, and is a surrogate of imaging study-defined relapse. The GCIG criterion is initially effective in identifying asymptomatic patients with recurrent EOC with sufficient sensitivity and an extremely low false positive rate (specificity > 97%) while avoiding the unnecessary treatment of patients who do not have recurrent disease. However, the sensitivity of these biochemical relapse criteria has since decreased to 36.9%. The resolutions attainable through imaging systems have improved dramatically over the past two decades. Imaging-based relapse criteria are confounded by the use of low- or high-density resolution imaging studies to detect smaller lesions [
37]. Other imaging technologies, such as PET-CT, dynamic contrast-enhanced MRI, diffusion-weighted MRI and perfusion CT, have further elevated the resolution efficiency, accurately detecting the presence of microlesions. The combination of image-guided biopsy and a lower CA-125 level can be used to detect microlesions. In the present study, the sensitivity attained using a CA-125 level of 1.68 × nadir was relatively high (85.6%).
Ovarian cancer patients who have CCR to primary therapy are not a homogenous group. The nadir CA-125 level is a factor in determining patient prognosis. A slight increase in the CA-125 levels within the normal range at the end of primary treatment is inversely associated with that of PFS and OS. In the present study, the time during which the CA-125 levels increased from different individual nadir value to 2 × ULN was significantly different. The comparison between the threshold CA-125 level defined by the GCIG and the absolute CA-125 values without taking individual nadir CA-125 levels is considered in our criterion.
The continuous increase of CA-125 levels implies a continuous dominant course of tumor progression. Determining a CA-125 level at which the recurrent disease would be distinguishable using imaging studies is important. In the present study, this CA-125 value was determined on the basis of its use in diagnosing recurrent EOC. In contrast to the data presented by previous studies, the potential cut-off CA-125 values have been tested using their diagnostic performance and areas under the ROC curve.
An increase in CA-125 levels in an asymptomatic patient presents a dilemma. Some gynecologic oncologists recommend a wait-and-see approach, but the duration of the waiting period and how the patients should be monitored are unclear. Asymptomatic patients waiting for symptoms can experience significant anxiety and report unspecific symptoms to their physicians, thereby resulting in unnecessary imaging examinations. Regular CA-125 testing might also give rise to the psychosocial impairments of the patients based on the possible rise of CA-125 levels during their daily lives. A clear clinical interventional point of the CA-125 level can thus help patients overcome CA-125 addiction to a certain extent only if they prefer to not know the specifics. Other gynecologic oncologists argued that time and treatment choices are lost from asymptomatic to symptomatic. A CA-125 level of 1.68 × nadir in asymptomatic patients undergoing a wait-and-see approach can be used as a threshold at which specific imaging examinations become warranted to avoid missing the opportunity to perform secondary CRS. However, our findings did not reveal a relationship between the CA-125 levels at disease relapse and the imaging study-determined longest diameters of tumors or tumor areas.
Given the selection bias inherent to non-blinded studies, attempts to translate these favorable outcomes to all EOC patients with recurrent disease should be approached with caution. We recommend using a CA-125 level of 1.68 × nadir to indicate the need to initiate imaging studies in detecting recurrent disease in EOC patients who had CCR to primary therapy. Using this criterion would result in fewer instances of specious relapse and unnecessary imaging examinations. The ongoing DESKTOP III trial can prospectively assess the role of secondary CRS in patients with platinum-sensitive ovarian cancer. This important trial should answer several key questions regarding the management of recurrent EOC, including whether secondary CRS results in better outcomes than second-line chemotherapy.
Competing interests
The authors declare that they have no competing interests.
Authors’ contributions
XXC and FW participated in drafting the full manuscript and writing of this manuscript. FW and YFY partly participated in clinical study design, coordination and data analysis. XX and XHZ participated in creating figures. XX and YFY contributed by writing specific sections of this manuscript. XHZ and JHW provided advice and participated in revising the manuscript. XXC participated in substantial contribution to conception and revising it critically for important intellectual content. All the authors in this manuscript have read and approved the final version.