Integrative Oncology for Biochemical Recurrence of Epithelial Ovarian Cancer

Abstract

Purpose of Review

Biochemical recurrence of epithelial ovarian cancer (EOC), defined as rising CA-125 levels without clinical or radiologic evidence of disease, is a frequent and challenging scenario. Cytotoxic therapy initiated at this stage does not improve survival and may diminish quality of life. This review evaluates integrative oncology (IO) interventions that may support women during this vulnerable period.

Recent Findings

Mind–body therapies, including mindfulness, yoga, and cognitive behavioral therapy, have demonstrated benefits in reducing anxiety, distress, and fear of recurrence. Exercise and acupuncture improve vitality, mood, and sleep. Nutritional strategies—particularly anti-inflammatory diets, vitamin D sufficiency, and omega-3 fatty acid intake—promote resilience and overall health. Natural compounds such as green tea, medicinal mushrooms, modified citrus pectin, melatonin, and AHCC show immune-modulating or anti-tumor effects in preclinical or early clinical studies. Among repurposed non-oncologic drugs, metformin provides the strongest rationale, especially for women with type 2 diabetes.

Summary

Although ovarian cancer–specific trials are limited, IO approaches are safe, feasible, and evidence-informed. They address psychosocial distress, improve quality of life, and may influence disease biology, offering meaningful options for women under surveillance during biochemical recurrence.

Introduction

Biochemical relapse of epithelial ovarian cancer (EOC)—defined as rising levels of cancer antigen-125 (CA-125) or other tumor markers in the absence of clinical or radiological evidence of disease—presents a unique clinical challenge. Women in this stage often face significant anxiety, uncertainty, and reduced quality of life (QoL), even before systemic therapy is initiated. Integrative oncology (IO) offers a holistic, patient-centered approach that may help address these unmet needs.

The standard initial treatment for EOC consists of cytoreductive surgery followed by platinum-based chemotherapy. While about 70% of patients with advanced disease respond to first-line therapy and achieve complete remission, most will experience recurrence within 18 to 28 months [1]. Recurrence is also observed in approximately 25% of women with early-stage disease (Stage I–II) and in as many as 80% of those with advanced-stage disease (Stage III–IV) [2]. A large proportion of these relapses are first detected by tumor marker elevation alone: in follow-up studies, more than half of women in remission after advanced EOC showed asymptomatic CA-125 elevation as the earliest sign of recurrence [3]. For example, one study reported that 46% of relapses initially presented as “biochemical-only” recurrence [4].

Defining Biochemical Relapse

Biochemical relapse in EOC refers to recurrence detected by rising tumor markers, most commonly CA-125, in the absence of radiological or clinical disease. This stage often precedes overt relapse and may eventually require further therapy [4]. Active surveillance with CA-125 can detect recurrence earlier than clinical findings. Tumor marker monitoring is highly sensitive, with reported sensitivity of 62–94% and specificity of 91–100% for recurrent disease [5]. Typically, CA-125 begins to rise several months before lesions become visible on imaging or before symptoms develop [5, 6]. In practice, many patients experience an interval of “biochemical recurrence,” in which CA-125 levels are persistently elevated and rising, while imaging remains negative. Although CA-125 monitoring does not identify all cases, it provides an early warning signal of relapse in most women with EOC [6].

Traditionally, a CA-125 level exceeding 35 U/mL has been used as the threshold for recurrence. However, recent studies suggest that relative increases from a patient’s post-treatment nadir may be a more sensitive and earlier indicator. For example, a retrospective analysis demonstrated that defining relapse as a CA-125 level twice the nadir value was superior to the conventional 35 U/mL threshold, offering a longer median lead time to image-confirmed recurrence (2.7 months vs. 0 months; P < .001) [7]. Furthermore, even small absolute increases within the normal range can be prognostically significant. In a study by Santillan et al., an increase of 5 U/mL from the nadir was associated with a markedly higher risk of recurrence (OR, 8.4; 95% CI, 2.2–32.6; P = .002), while a 10 U/mL increase conferred an even greater risk (OR, 71.2; 95% CI, 4.8 to > 999.9; P = .002) [8]. The time at which CA-125 levels double has also been investigated as a prognostic factor. In one large analysis, pretreatment CA-125 levels were found to predict risk of relapse and overall outcome [9].

Biochemical Relapse: to Treat or Not to Treat?

The key clinical dilemma during biochemical relapse is whether to initiate treatment early or to delay therapy until clinical or radiologic progression. Rising CA-125 often precedes symptomatic relapse by several months, but the benefit of early intervention has been questioned.

In a landmark randomized trial, Rustin et al. compared early treatment (within 28 days of CA-125 doubling) with delayed treatment (initiated at clinical or radiologic relapse) in 529 women with advanced EOC who had achieved remission after first-line platinum-based chemotherapy [3]. No difference in overall survival was observed between groups (median OS: 25.7 months in the early-treatment arm vs. 27.1 months in the delayed-treatment arm; HR, 0.98; 95% CI, 0.80–1.20; P = .85). Importantly, quality of life deteriorated earlier in the early-treatment group. This trial established that initiating chemotherapy based solely on rising CA-125 provides no survival benefit and negatively affects QoL.

Subsequent reviews and expert consensus statements have confirmed these findings, concluding that early intervention based solely on tumor marker elevation offers no survival advantage and may expose patients to unnecessary toxicity [2]. Accordingly, the European Society for Medical Oncology (ESMO) and European Society of Gynaecological Oncology (ESGO) guidelines recommend that CA-125 monitoring during follow-up should be discussed with patients, emphasizing the lack of evidence that earlier detection translates into improved survival [2].

Current National Comprehensive Cancer Network (NCCN) Guidelines recommend several options for women with biochemical relapse:

• Defer treatment until clinical relapse;

• Enroll in a clinical trial;

• Consider low-toxicity second-line therapies, such as hormonal or biologic agents (e.g., tamoxifen), rather than initiating cytotoxic chemotherapy.

Table 1 lists possible treatment options for this situation with description of benefits and limitations of each selected option.

Table 1.

Treatment options for biochemical relapse in ovarian cancer: benefits and limitations

Treatment Option	Benefits	Limitations
Observation	Avoids treatment-related toxicity; maintains quality of life	Psychological distress from uncertainty; risk of progression without intervention
Chemotherapy	Effective in platinum-sensitive disease; can improve progression-free survival	Limited efficacy in platinum-resistant disease; significant toxicity (neuropathy, myelosuppression); no overall survival benefit
PARP Inhibitors	Effective maintenance in BRCA-mutated or HRD-positive patients; oral administration	High cost; not effective in all patients; adverse effects (anemia, fatigue); no consistent OS benefit
Anti-angiogenic Therapy	Can prolong progression-free survival; usable in combination with chemotherapy	Risk of hypertension, thromboembolism, cardiovascular side effects; no OS benefit
Hormonal Therapy	Well-tolerated; useful for hormone receptor–positive tumors (e.g., low-grade serous ovarian cancer)	Limited to select subtypes; not effective in aggressive histologies; no OS benefit
Integrative Therapies	Safe, feasible, and evidence-informed for reducing anxiety, fatigue, and stress; improve quality of life	Limited evidence for direct impact on survival or disease progression
Clinical Trials	Access to novel or targeted therapies; contributes to advancing treatment options	Limited availability; interventions may not yet be proven effective

Clinical Unmet Needs and the Role of Integrative Oncology

Biochemical relapse of epithelial ovarian cancer (EOC) represents a subclinical recurrence that poses major challenges for patients and physicians alike. Although women may still be considered in remission by clinical criteria, rising CA-125 levels strongly suggest that relapse is underway, typically preceding symptomatic or radiologic disease by 2–6 months. Despite this early signal, clinical trials have demonstrated that initiating systemic therapy based solely on CA-125 elevation does not improve survival [3]. As a result, there is no proven therapeutic strategy to meaningfully delay or prevent progression at this stage.

This uncertainty creates a management dilemma: whether to initiate treatment early or continue observation until clinical relapse. While some physicians consider repeat imaging or clinical trial enrollment, most default to active surveillance—a strategy often driven more by necessity than conviction. For patients, this “watch-and-wait” period is fraught with uncertainty, distress, and impaired quality of life. Many women describe feeling as if they are “living with a ticking clock,” knowing relapse is likely but being told to simply wait. This state of limbo can undermine trust in medical care, reduce adherence to follow-up, and place strain on family and social relationships. Fear of progression may manifest as sleep disturbance, difficulty concentrating, or avoidance of future planning. The psychological burden can equal or even exceed the physical challenges of active disease, highlighting the urgent need for supportive care strategies that address emotional as well as clinical dimensions of recurrence.

In this context, integrative oncology (IO) offers a supportive, evidence-informed framework to address unmet needs during biochemical relapse. IO interventions—such as mind–body therapies, exercise, acupuncture, nutritional strategies, and selected nutraceuticals—can help patients manage psychosocial distress, sustain physical resilience, and optimize health while awaiting further treatment. Stress management is particularly critical: not only does it improve mental health, but preclinical studies also suggest that chronic behavioral stress can accelerate tumor progression. In an orthotopic mouse model of ovarian carcinoma, stress exposure led to greater tumor burden and more invasive growth [9]. These findings underscore the importance of incorporating psychosocial care and resilience-building interventions into comprehensive management for women with biochemical relapse, where conventional treatment options remain limited.

Mind–Body Interventions

Mindfulness and Meditation

Women with ovarian cancer often report anxiety, fear of recurrence, and loss of control during follow-up. Mindfulness-based interventions can alleviate these concerns. A pilot study of mindfulness-based cognitive therapy for ovarian cancer survivors demonstrated significant reductions in fear of cancer recurrence and improvements in psychological well-being [10]. Broader oncology evidence confirms that mindfulness programs reduce anxiety, depression, and stress while enhancing resilience [11].

Yoga and Gentle Movement

Yoga combines physical postures, breath control, and relaxation. A pilot trial of restorative yoga in ovarian and breast cancer survivors reported improvements in sleep quality, fatigue, and overall well-being [12]. More recently, a randomized controlled trial comparing vigorous vs. restorative yoga found cognitive improvements in sedentary ovarian and breast cancer survivors, suggesting yoga may mitigate “chemo brain” and enhance daily functioning [13].

Cognitive Behavioral Therapy (CBT) and Supportive Approaches

Short-term CBT or psycho-oncology interventions effectively reduce anxiety and depression in gynecologic cancer survivors [14]. Participation in support groups or expressive therapies provides connection and validation, countering isolation that is common during disease surveillance. These interventions strengthen coping and improve quality of life, complementing other IO strategies.

Exercise and Physical Activity

Regular exercise is one of the most robustly supported integrative interventions in oncology. A systematic review of exercise in women with ovarian cancer concluded that physical activity is safe and improves fitness, fatigue, and quality of life [15]. Even low-intensity activities such as walking, stretching, or tai chi can help maintain functional independence. Observational studies suggest physical activity may also reduce risk of disease progression and improve survival across gynecologic cancers [16].

For women under surveillance, exercise provides both physical and psychological benefits: enhancing mood, reducing fatigue, and fostering a sense of agency. Tailored home-based exercise programs, supervised group classes, or yoga-based strengthening can all be integrated according to preference and capacity.

Acupuncture and Acupressure

Although many acupuncture studies focus on chemotherapy side effects, its utility extends to broader supportive care. Acupuncture has been shown to reduce anxiety, sleep disturbance, and autonomic imbalance in cancer patients [16–19]. Auricular (ear) acupressure has been tested in gynecologic oncology, with pilot trials reporting improvements in sleep quality and reductions in distress.²¹ Reflexology—a related acupressure technique—has been associated with decreased anxiety and improved mood in women with gynecologic cancers [20].

For patients in biochemical recurrence, acupuncture and acupressure may be used not for acute symptom relief but to promote relaxation, improve sleep, and support emotional balance.

Nutrition and Dietary Patterns

Mediterranean Diet and Anti-Inflammatory Nutrition

A Mediterranean-style diet, emphasizing fruits, vegetables, whole grains, legumes, fish, and olive oil, has been linked to reduced inflammation and improved metabolic health. Epidemiological studies show that pro-inflammatory diets (high in processed meats, refined grains, and sugars) increase ovarian cancer risk [21]. Adopting an anti-inflammatory diet may therefore be protective during surveillance and could reduce risk of progression.

Dietary Counseling

A study of ovarian cancer patients during chemotherapy found that those who adopted healthier dietary patterns reported improved quality of life [22]. While this study focused on active treatment, it underscores the role of nutrition counseling in survivorship and surveillance. Encouraging patients to minimize ultra-processed foods and maintain stable body weight can improve energy and mood, while also supporting long-term health.

Nutritional Supplements and Natural Compounds

Vitamin D

Vitamin D deficiency is common in ovarian cancer patients and has been associated with worse survival outcomes. In the Australian Ovarian Cancer Study Group, higher circulating 25-hydroxyvitamin D levels at diagnosis were significantly associated with improved survival [23]. Ensuring adequate vitamin D through supplementation or safe sun exposure is a low-cost, evidence-based intervention that may improve bone health, immunity, and possibly disease outcomes.

Omega-3 Fatty Acids

Omega-3 fatty acids from fish oil have anti-inflammatory and immunomodulatory effects. Clinical studies across cancer populations suggest omega-3 supplementation can reduce fatigue, preserve muscle mass, and improve quality of life [11]. Though ovarian-specific evidence is limited, omega-3s may be particularly useful in reducing systemic inflammation during surveillance.

Green Tea

Green tea contains bioactive compounds, such as catechins and polyphenols, with potential chemo preventive activity. Epidemiological data support a protective association between tea consumption and ovarian cancer risk. In a Chinese case–control study, ovarian cancer risk declined significantly with increasing frequency and duration of green tea intake [24, 25]. A review further highlighted green tea’s possible role in ovarian cancer prevention and survivorship [24]. While clinical trials are lacking, encouraging moderate daily consumption of green tea may be a safe and practical integrative recommendation.

Medicinal Mushrooms

Mushroom extracts such as Trametes versicolor (Turkey tail), Ganoderma lucidum (Reishi), and Agaricus blazei contain beta-glucans with immune-modulating activity. In a randomized trial, ovarian and endometrial cancer patients taking Agaricus extract demonstrated improved natural killer (NK) cell activity and better quality of life [26]. Meta-analyses in gastrointestinal cancers confirm survival benefits when mushroom polysaccharides are combined with standard care [27].

Modified Citrus Pectin (MCP)

MCP, a soluble fiber derived from citrus peels, inhibits galectin-3, a molecule involved in tumor adhesion and metastasis. Laboratory studies in ovarian cancer spheroids showed that MCP suppressed STAT3 signaling, reduced integrin expression, and sensitized tumor cells to paclitaxel [28]. While clinical trials in ovarian cancer are lacking, a pilot study in advanced solid tumors demonstrated that oral MCP was safe and led to disease stabilization in some patients [29].

Melatonin

Melatonin, best known as a sleep-regulating hormone, also exhibits antioxidant and oncostatic properties. Molecular studies suggest melatonin may inhibit ovarian cancer growth and progression by modulating survival pathways, apoptosis, and angiogenesis [30]. Clinically, melatonin supplementation has been associated with reduced fatigue, improved sleep, and better quality of life in cancer patients [30]. In the surveillance setting, melatonin may alleviate insomnia, reduce anxiety, and potentially exert anti-tumor effects.

AHCC (Active Hexose Correlated Compound)

AHCC is a standardized extract from the mycelia of Lentinula edodes (shiitake mushroom). It has demonstrated immune-enhancing properties, particularly in increasing dendritic cell activity and NK cell function. Clinical studies show that AHCC supplementation enhances immune response and promotes clearance of persistent HPV infections in women [31]. While not yet studied in ovarian cancer specifically for prevention, its immune-modulating effects may support resilience and host defense during biochemical recurrence [32].

Repurposed Non-Oncologic Drugs

In parallel with integrative oncology interventions that address quality of life and resilience, increasing attention has also been directed toward the repurposing of well-established non-oncologic drugs as potential adjuncts to reduce recurrence risk in ovarian cancer. Several classes of medications have demonstrated anticancer activity in preclinical and early clinical studies, including statins, metformin, itraconazole, bisphosphonates, ivermectin, and ritonavir [33].

Metformin, a widely used antidiabetic agent, has shown promise in ovarian cancer by reversing chemoresistance, blocking epithelial–mesenchymal transition, reducing migration and metastasis, inhibiting angiogenesis, and potentiating chemotherapy activity [34]. A randomized phase II clinical trial is ongoing to evaluate metformin as maintenance therapy in patients with advanced-stage ovarian, fallopian tube, or primary peritoneal cancer (NCT02122185).

Ivermectin, a broad-spectrum antiparasitic drug, demonstrates antitumoral activity in vitro and in vivo by modulating signaling pathways and targeting cancer stem cell populations [35]. In ovarian cancer models, ivermectin inactivates PAK1, thereby blocking tumor cell growth [33], and inhibits YAP1, a prognostic indicator of poor outcomes when expressed in ovarian cancer [34].

Finally, statins, widely used for hyperlipidemia, have demonstrated inhibitory effects on ovarian cancer proliferation and migration in vitro. In preclinical ovarian cancer models, simvastatin delayed tumor formation and suppressed metastatic potential [36].

Collectively, these findings suggest that repurposed non-oncologic drugs may complement conventional or integrative strategies, though large-scale clinical trials are still needed to establish their role in the management of ovarian cancer recurrence. At present, among repurposed drugs, only metformin can be considered, given its strong mechanistic and clinical rationale, particularly for women with type 2 diabetes or insulin resistance, and under medical supervision.

Conclusion

Integrative strategies (summarized in Table 2) may support women with biochemical recurrence of epithelial ovarian cancer. These modalities are evidence-informed, safe, and feasible in the surveillance setting, where conventional treatment is often deferred. They help address common unmet needs such as anxiety, fatigue, poor sleep, and uncertainty, while also promoting immune resilience and overall well-being. Among repurposed drugs, only metformin is included, given its strong mechanistic and clinical rationale, particularly for women with type 2 diabetes or insulin resistance.

Table 2.

Integrative options for biochemical recurrence of epithelial ovarian cancer

Category	Intervention	Key Evidence/Benefits	Practical Considerations
Mind–Body	Mindfulness, meditation, CBT	Reduces anxiety, depression, and fear of recurrence; improves resilience [12, 13, 16, 18]	Easily accessible via online or group programs; requires patient motivation and regular practice
	Yoga (restorative or gentle)	Improves sleep, fatigue, cognition, and mood in ovarian/breast cancer survivors [14, 15]	Adaptable to fitness level; can be done at home or in group sessions
Exercise	Aerobic and resistance activity	Improves fatigue, quality of life, physical fitness; may reduce progression risk [17]	Encourage individualized programs (walking, light weights, yoga-based strengthening)
Acupuncture / Acupressure	Acupuncture, auricular acupressure, reflexology	Improves sleep, anxiety, and overall well-being in cancer populations [18–22]	Generally safe; requires trained practitioner; acupressure can be taught for self-care
Nutrition	Mediterranean / anti-inflammatory diet	Associated with reduced inflammation, improved metabolic health, and lower ovarian cancer risk [23]	Emphasize fruits, vegetables, legumes, whole grains, fish, olive oil; minimize ultra-processed foods
	Nutrition counseling	Improves quality of life and supports behavior change [24]	Works best with ongoing follow-up; aligns dietary goals with patient preferences
Supplements / Natural Compounds	Vitamin D	Low levels linked to worse survival; supplementation improves bone and immune health [25]	Check serum 25(OH)D before supplementation; safe correction recommended
	Omega-3 fatty acids	Anti-inflammatory, preserve muscle mass, improve quality of life [13]	May be useful in fatigued or cachectic patients; encourage dietary fish intake as well
	Medicinal mushrooms (e.g., Agaricus, Trametes, Ganoderma)	Enhance NK cell activity, quality of life, possible survival benefits [28,29]	Use standardized extracts from reputable sources
	Modified citrus pectin (MCP)	Inhibits galectin-3, reduces adhesion/metastasis, synergizes with chemotherapy in preclinical models [30, 31]	Generally well tolerated; human data still limited
	Melatonin	Improves sleep, reduces fatigue/anxiety, has anti-proliferative effects [32]	Bedtime dosing (2–20 mg) commonly used; minimal toxicity
	AHCC (shiitake extract)	Enhances immunity, promotes viral clearance (HPV studies) [33, 34]	Limited ovarian cancer–specific data; promising immune-support
Repurposed Drug (Selected)	Metformin (in diabetics)	Blocks tumor growth, migration, angiogenesis; may enhance survival; trials ongoing [35, 36]	Best integrated in patients with type 2 diabetes or insulin resistance under medical supervision

Biochemical recurrence represents a vulnerable period marked by uncertainty and the absence of active treatment. Integrative oncology can provide meaningful support by reducing psychosocial distress, strengthening resilience, and optimizing physical and immune health. Mind–body therapies—including mindfulness, yoga, and CBT—alleviate anxiety and fear of recurrence. Exercise and acupuncture enhance vitality, mood, and sleep. Nutritional strategies such as anti-inflammatory diets, adequate vitamin D, and omega-3 intake contribute to long-term health. Evidence-supported supplements—including medicinal mushrooms, green tea, modified citrus pectin, melatonin, and AHCC—offer further options to improve immunity and potentially slow disease progression. Research into repurposed non-oncologic drugs adds another layer of innovation, expanding future therapeutic possibilities.

Although more ovarian-specific clinical trials are needed, the cumulative evidence across oncology supports the integration of these approaches into care for women under surveillance. Such strategies empower patients, instill hope, and align with a holistic model of care that is particularly relevant during the uncertain interval of biochemical recurrence.

Key References

• Rustin GJ, van der Burg ME, Griffin CL, et al. Early versus delayed treatment of relapsed ovarian cancer (MRC OV05/EORTC 55955): a randomised trial. Lancet. 2010;376(9747):1155–1163. doi:10.1016/S0140-6736(10)61268-8.

  • ◦ This is the landmark trial demonstrating that early initiation of systemic therapy based solely on rising CA-125 does not improve survival and worsens quality of life. It defines the clinical dilemma at the heart of biochemical recurrence and provides the evidence base for active surveillance.
• Thaker PH, Han LY, Kamat AA, et al. Chronic stress promotes tumor growth and angiogenesis in a mouse model of ovarian carcinoma. Nat Med. 2006;12(8):939–944. doi:10.1038/nm1447.

  • ◦ This pivotal preclinical study demonstrated that chronic behavioral stress directly accelerates ovarian cancer progression by increasing tumor burden and angiogenesis. It provides a strong biologic rationale for addressing psychosocial distress through integrative oncology interventions such as mindfulness, CBT, and stress reduction strategies.
• Webb PM, de Fazio A, Protani MM, et al. Circulating 25-hydroxyvitamin D and survival in women with ovarian cancer: results from the Australian Ovarian Cancer Study. Am J Clin Nutr. 2015;102(1):109–114. doi:10.3945/ajcn.114.105395.

  • ◦ This large, prospective study highlights the potential role of vitamin D in ovarian cancer outcomes, showing that higher circulating levels were associated with improved survival. It supports the inclusion of nutrition and supplement strategies as meaningful integrative options.

Author Contributions

M.F. and T.B. wrote the main manuscript text and E.M. and C. BD prepared the introduction. All authors reviewed the manuscript.

Data Availability

No datasets were generated or analysed during the current study.

Declarations

Competing Interests

The authors declare no competing interests.