Epidemiological data show that in 2022, the global incidence and mortality of ovarian cancer (OC) ranked eighth among female cancers; in China, both ranked ninth (1). The mortality rate of OC ranks first among all gynecological cancers. Epithelial ovarian cancer (EOC) accounts for approximately 90% of all cases of OC. The standard treatment is based on comprehensive staging surgery or cytoreductive surgery, followed by platinum-based chemotherapy. Approximately 70% of patients with EOC relapse within 3 years and often have a poor prognosis owing to platinum resistance or refractoriness (2). The Warburg effect (3), amino acid metabolism (4) and lipid metabolism (5) have been proved to be closely related to tumor growth, metastasis and the regulation of anti-tumor immunity. In patients with cancer, the balance of nutrient metabolism between tumor cells and immune cells in the tumor microenvironment affects the occurrence, development, treatment efficacy, and prognosis of tumors.

Malnutrition is associated with an increased risk of complications and reduced efficacy and tolerance to antitumor therapies (6). Overnutrition, such as a high-fat diet and obesity, can promote metastasis and weaken antitumor immunity in certain types of cancers (7). Many studies have shown that nutritional status is closely related to the prognosis of digestive system cancers (8), breast cancer (9), and lung cancer (10); however, studies related to EOC are few and remain controversial (11–15).

In this ambispective cohort study, we aimed to explore the clinical significance of nutritional status and identify independent nutrition-related risk factors for the prognosis of patients with newly diagnosed EOC to provide a theoretical basis for a better prognosis by improving the nutritional status.

Cancer is a metabolism-related chronic wasting disease. There is growing evidence that the prognosis of patients with cancer is not only related to tumor factors, systemic inflammation, and immune status, but also to nutritional status (22). Malnutrition is found in 32% of patients with cancer, caused by tumor-related anorexia, inflammation, or metabolic changes (6). Several clinical studies have shown that both malnutrition and overnutrition in patients with cancer can affect disease progression and efficacy of anticancer therapy (7, 23). Therefore, evaluation and intervention of the nutritional status of patients with cancer may improve their efficacy and prognosis. There are few studies on the nutritional status and prognosis of patients with EOC; the factors studied are often single indicators or scores, and the results remain controversial. In this study, we used five common pre-treatment nutrition-related indicators, BMI, DM, hyperlipidemia, and ALB and Hb levels, to explore their effects on the prognosis of 1,020 patients with newly diagnosed EOC and identified hyperlipidemia as an independent nutrition-related risk factor for shorter survival.

Globally, there has been a gradual increase in the incidence of being overweight and obese. The Ovarian Cancer Association Consortium (OCAC) combined the data of 12,390 patients with OC from 21 studies and found that a higher BMI was associated with shorter OS and PFS (15). However, a Scottish study involving 1,067 patients with OC found no statistically significant correlation between BMI and survival (11); another study involving patients with EOC reached similar conclusions (24). One study reported that pre-diagnosis BMI ≥ 35 kg/m² was associated with a lower survival rate in patients with stage I-II EOC, but in stage IV patients with BMI ≥ 35 kg/m², the survival rate was higher; this correlation weakened when factors such as ascites and intestinal obstruction were adjusted for (25). However, the relationship between BMI and prognosis in patients with EOC remains controversial. In our study, 319 patients were overweight and 73 patients were obese; however, there was no statistically significant effect of BMI on the prognosis of patients with EOC, which is consistent with most existing studies (11, 24). Obesity is associated with a higher likelihood of comorbid DM, hypertension, and coronary heart disease, while underlying diseases increase the risk of perioperative and chemotherapy complications in patients with EOC, which is not conducive to a good prognosis (26). However, the fat metabolic reserve in obese patients with advanced cancer can help them resist the physiological challenges of surgery and chemotherapy, so those with a high BMI may even have a better prognosis, the “obesity paradox,” this has not been demonstrated in patients with EOC. In addition, although BMI is a commonly used indicator for evaluating the overall nutritional status, body weight is often affected by ascites and cachexia, making BMI unreliable as an appropriate indicator in some patients with EOC. The effect of BMI on the prognosis of patients with EOC, therefore, is uncertain, which may be due to differences in the time of weight measurement, definition of the BMI cutoff, body fat proportion, volume of ascites, and obesity-related underlying diseases. Prospective clinical studies related to overall nutritional status in the future should incorporate BMI, body fat proportion, abdominal circumference, and skinfold thickness simultaneously and choose fasting weight, excluding the effect of ascites, to reduce the error of evaluation and obtain more accurate correlation analysis data.

Glycolytic reprogramming of tumor cells not only provides a large amount of energy but also produces a large number of intermediate metabolites, such as lactic acid, which promote tumor proliferation, invasion, and metastasis (27–29). The Warburg effect also strengthens tumor immune escape and suppresses anti-tumor immunity through local hypoxia, inhibiting the monitoring and lethality of tumor-infiltrating lymphocytes. Inhibiting aerobic glycolysis-related pathways can eliminate tumor growth advantage and immune escape, thereby suppressing the occurrence and development of tumors and promoting anti-tumor immunity (30). A retrospective study has shown that DM is an independent risk factor for the prognosis of patients with EOC (30). However, data from 15 studies conducted by the OCAC showed no correlation between DM and PFS in patients with OC (31). Metformin reduces the production of insulin, insulin-like growth factor, inflammatory cytokines, and vascular endothelial growth factor and has antimitotic, anti-inflammatory, and anti-angiogenic effects (32). In a clinical study, metformin reduced the risk of EOC and prolonged the survival of patients with EOC and DM (33). These findings support the hypothesis that DM influences morbidity and survival in patients with EOC. Of the 1,020 patients included in this study, 75 had DM. No statistically significant correlation was found between DM and the prognosis of patients with EOC. Since metformin use is associated with prolonged survival in EOC patients with DM (33), glycemic control status may affect the prognosis. A history of DM, and levels of blood glucose, HbA1C, and glycated albumin are commonly used to evaluate the nutritional status in relation to carbohydrates. HbA1C reflects glycemic control over the preceding the 3 months, is more stable than other indicators, and is not affected by the external environment, emotion, or current diet; therefore, it is the best indicator for evaluating the status of recent glycemic control. HbA1C has been found to be associated with a risk of recurrence and death in early-stage breast (34) and colon cancer (8). Therefore, the results of this study suggest that, when HbA1C data cannot be used as a reference, the presence of DM does not affect the prognosis of patients with EOC.

In tumor cells, amino acids not only directly participate in the growth and proliferation of tumor cells as raw materials for the synthesis of various proteins or as intermediates for energy metabolism but are also necessary to activate the mammalian target of rapamycin (mTOR) pathway involved in tumor cell proliferation and migration. Additionally, amino acids are indirectly involved in antitumor immunity by regulating immune cell function (35). Amino acid metabolic reprogramming has been shown to be closely related to the development of various cancers (4), so it is particularly important to study the effect of protein nutritional status on patients with cancer. ALB has the highest concentration in human plasma, accounting for more than 60% of the total protein in healthy adults, and not only effectively reflects the nutritional status of patients with EOC but also plays an important role in regulating inflammation, oxidative stress, and innate immunity, and thus affecting the growth of tumor cells (36). Several studies have shown that ALB levels are related to the prognosis of patients with EOC (37–39), however, several questions remain unanswered. First, it is unclear whether hypoalbuminemia is an independent risk factor for the prognosis of patients with EOC. Anorexia in patients with advanced cancer can lead to inadequate amino acid intake and decreased ALB synthesis. High catabolism in patients with cancer leads to increased ALB consumption, and with the progression of the disease, increased capillary permeability leads to the infiltration of ALB into the interstitial space, resulting in the formation of exudates in the serosal cavities. All of the above can cause hypoalbuminemia in patients with cancer; therefore, pre-treatment ALB levels are usually associated with several clinical features. Our study found that compared to the normal ALB group, patients with hypoalbuminemia had a worse prognosis, but this was not an independent predictor of prognosis, which may be because ALB levels were also affected by ascites, body weight, and other nutrition-related indicators. In the Chinese clinical guidelines, the indication for human serum albumin supplementation in patients with cancer is ALB≤30 g/L, while hypoalbuminemia is defined as ALB≤35 g/L (18). Whether ALB in the range 30–35 g/L g/L affects the efficacy and prognosis of patients is clear. Our study revealed that patients with ALB≤30 g/L had shorter OS than those with ALB in the range 30–35 g/L, but the first-line chemotherapy response and PFS were not statistically different between the two groups, which demonstrated that hypoalbuminemia, especially when the ALB level dropped below 30 g/L, might severely affect the long-term survival of patients with EOC. Future clinical trials are needed to evaluate the effect of human serum ALB supplementation on the efficacy and prognosis of patients with EOC, especially those with ALB<30 g/L.

Lipids play a key role in the occurrence and development of tumors, with increased lipid levels supporting the high energy demand of growing tumor cells. Tumor cells reprogram lipid metabolism, mainly by affecting lipid uptake, synthesis, and catabolism. Studies have shown that lipid metabolism-related genes are overexpressed in a variety of cancers to adapt to the high energy demand of tumor cells, and their overexpression has been shown to be associated with poor cancer prognosis. In addition, excessive lipids can affect the function of various immune cells in the tumor microenvironment, thereby inhibiting antitumor immunity (7, 40). The accumulation of unsaturated fatty acids supports the growth and migration of OC cells, leading to worse prognosis. In addition, increased lipogenesis and lipid uptake promote chemotherapy resistance and suppress the immune response required to eliminate tumors (41). Blood lipid levels are commonly used as clinical indicators of lipid nutrition. Although there have been a few clinical studies on the correlation between hyperlipidemia and EOC prognosis, the use of statins after OC diagnosis prolongs survival (14, 42). Our study directly evaluated the effect of pre-treatment hyperlipidemia on the treatment efficacy and prognosis of patients with newly diagnosed EOC. We found that hyperlipidemia was an independent risk factor for poor prognosis, predicting shorter PFS and OS. Patients with hyperlipidemia also had poorer first-line chemotherapy responses than those without hyperlipidemia. However, in the subgroup analysis of patients with early stage EOC, hyperlipidemia was not an independent risk factor for OS. This suggests that pre-treatment hyperlipidemia only affects the short-term survival of patients with early stage EOC but does not affect their long-term survival. A study involving 249 patients with EOC found that the HDL-cholesterol (C)/TC ratio was significantly correlated with chemoresistance and that the HDL-C/LDL-C ratio was an independent protective factor for survival (43). The results regarding hyperlipidemia in our study are consistent with those of that study. Some patients were included in our study retrospectively. Specifically, for patients who had been diagnosed with hyperlipidemia before hospitalization, only their medical history regarding hyperlipidemia was collected during data gathering. Additionally, the lipid profiles of patients without hyperlipidemia were not available. In future prospective studies of patients with EOC, the associations between HDL-C/LDL-C or HDL-C/TC ratios and prognosis should be explored, especially for those with SD/PD.

Anemia is common in patients with cancer. Hb carries oxygen, and anemia is associated with many symptoms such as fatigue, depression, and dyspnea, which seriously affect the quality of life. Hypoxia promotes the metastatic potential and growth of tumor cells, decreases the cellular response to apoptotic signals, and generates therapeutic resistance (44). In addition, anemia itself may induce a feedback mechanism that promotes angiogenesis and leads to a higher proliferation rate of tumor cells (45). Existing studies on Hb levels and prognosis in patients with EOC have small sample sizes, and the results are inconsistent (46). Our study not only analyzed the effect of Hb levels on prognosis but also analyzed the response to first-line chemotherapy. Although the Hb level had no statistically significant effect on PFS or OS, patients with anemia had poorer first-line chemotherapy responses than those with normal Hb levels. Clinical practice should focus on the effects of increased Hb levels during treatment to improve the prognosis of patients with EOC.

The retrospective inclusion of patients, along with the changes in clinical guidelines and testing technologies, has led to certain selection biases and information biases, which in turn have contributed to the limitations of the results in this study. However, our study included patients with newly diagnosed EOC, with a large sample size of 1,020 cases and a median follow-up period of 48 months. Five nutrition-related indicators and three treatment-efficacy or prognostic indicators were analyzed, allowing the effect of nutritional status on patients to be comprehensively considered. Multivariable analysis eliminated the interactions between different types of nutrition-related indicators, as well as between indicators and clinicopathological characteristics, and thus more accurately identified the independent nutrition-related indicator risk factors affecting the treatment efficacy and prognosis of patients with EOC. Our research demonstrated that pre-treatment hypoalbuminemia, hyperlipidemia, and anemia negatively affected the response to first-line chemotherapy in patients with newly diagnosed EOC. Additionally, pre-treatment hypoalbuminemia and hyperlipidemia negatively affected survival, with hyperlipidemia being an independent risk factor for shorter survival. However, BMI and DM did not affect the prognosis of patients with EOC. These five nutritional indicators are easy to assess even in less-developed and resource-limited regions. In future clinical practice, nutritional status intervention during anti-tumor treatment of patients with EOC might improve treatment efficacy and prognosis.