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 . 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) . 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 . 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 . 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.