JCTJournal of Cancer Therapy2151-1934Scientific Research Publishing10.4236/jct.2022.139050JCT-119757ArticlesMedicine&Healthcare The Administration of Ocoxin Increases the Quality of Life of Patients with Advanced Epithelial or Metastatic Ovarian Cancer Undergoing Neoadjuvant Chemotherapy KarenLópez Miguel1*DanielRicardo Martínez Ávila1LlisetÁlvarez Pérez1GisselleMartínez Rabasa1AlejandroLinchenat Lambert2RobertoEsperón Noa2LisandraHeredia Manzano3MargaritaDe Quesada Amigó3RafaelI. Reyes Velázquez4DanayCorrales Otero4RamonRopero Toirac5IdelmisCurbelo Heredia5MirceaBetancourt Cabeza5TaniaA. Agrelo Ramos5RosaMaría Muñoz Reyes5JuanJesús Lence Anta5RosalíaFuentes Sosa6KareliaSilvera Candó7KireniaSilva Rodríguez7ZaidaLastre Sosa8MayteRobaina García9EduardoSanz10DavidMarquez10Scientific Department, CATALYSIS, Madrid, SpainClinical Research Section, INOR, La Habana, CubaDepartment of Onco-Psychology, INOR, La Habana, CubaDepartment of Biostatistics, CENCEC, La Habana, CubaDepartment of Anatomical Pathology, INOR, La Habana, CubaDepartment of Medical Oncology, INOR, La Habana, CubaDepartment of Gynaeco-Oncology, INOR, La Habana, CubaClinical Laboratory Department, INOR, La Habana, CubaDepartment of Imaging, INOR, La Habana, CubaClinical Trials Pharmacy Department, INOR, La Habana, Cuba290820221309561584 8, August 2022 2022 10, 2022 13, © Copyright 2014 by authors and Scientific Research Publishing Inc. 2014This work is licensed under the Creative Commons Attribution International License (CC BY). http://creativecommons.org/licenses/by/4.0/

Background: 70% of ovarian cancer cases are diagnosed at an advanced stage (III or IV) of the disease and, in turn, with a high prevalence of peritoneal carcinosis and ascites, which leads to progressive malnutrition in patients, with the consequent deterioration of their general condition. There is a very important relationship between nutritional status, quality of life, survival, and the ability to tolerate multidisciplinary treatment of peritoneal carcinosis. Methods: A phase II, open-label, single-center, non-randomised clinical trial was conducted that included 36 patients with advanced disease who were administered the nutritional supplement Ocoxin, 30 ml twice a day, beginning one week before chemotherapy (CT) based on carboplatin/paclitaxel, of which they receive three cycles with neoadjuvant intent. Ocoxin treatment was continued during chemotherapy and for three weeks after completion of the last cycle, as well as during any periods for which this treatment was discontinued due to toxicity. The effect of Ocoxin on the quality of life was assessed through the QLQ C30 and QLQ OV28 questionnaires from the start of treatment until the end of the follow-up period. In addition, the Karnofsky Index and nutritional parameters were assessed. Results: There were no significant differences between adverse events versus baseline values, except in leukocytes, lymphocytes, neutrophils, ALT, and AST. There was no deterioration of the QoL scales, except for those related to the effects of chemotherapy and alopecia. Conclusions: Ocoxin as an adjuvant to chemotherapy appears to improve better tolerance to chemotherapy, showed a good safety profile, and improved quality of life. For further information on Ocoxin neoadjuvant therapy benefits, a phase III clinical trial will be needed.

Chemotherapy Radiotherapy Ovarian Cancer Oncology Quality of Life Ad-juvant Therapy Supportive Care1. Introduction

Epithelial ovarian cancer (EOC) is diagnosed at locally advanced or metastatic stages in more than 75% of women, as symptoms are often vague and short-lasting and no effective screening programs are currently available [1].

In advanced stages, the disease frequently presents with ascites and peritoneal carcinosis, leading to progressive malnutrition in patients, with the consequent deterioration of their general condition. There is a very important relationship between nutritional status, quality of life, survival, and the ability to tolerate multidisciplinary treatment for peritoneal carcinosis. In these cases, cytoreductive surgery is one of the most viable options, although only 33% of patients survive for more than five years as a result. The treatment of choice for epithelial ovarian cancer is surgical debulking followed by chemotherapy with platinum-derived agents (carboplatin or cisplatin) in combination with taxanes (paclitaxel or docetaxel), and it is suggested to start neoadjuvant chemotherapy in advanced stages. Most ovarian carcinomas are sensitive to this therapeutic regimen, but 20% - 30% are resistant [2] [3] [4] [5].

Oxidative stress has been associated with several diseases and particularly cancer, causing an imbalance in the levels of pro- and antioxidant agents. The most active pro-oxidant agents are free radicals, which constitute a threat to cellular balance. Several studies have been conducted to evaluate the efficacy of cancer-specific treatments with nutritional and antioxidant supplements to reduce adverse events and treatment interruptions and increase overall survival [6] [7].

Ocoxin (OOS), a nutritional supplement developed by Catalysis S.A., has been evaluated in preclinical and clinical studies on different cancer sites, with and without associated malnutrition. It has demonstrated antitumor effects, as it limits angiogenic processes, inhibits cell proliferation, blocks metastasis, inhibits urokinase, an enzyme found in some malignant tumours, and induces apoptosis. It works in synergy with CT, increasing the antitumor effect, as well as acting as a radiosensitizer and tissue protector, reducing toxicities from cancer treatments [8] [9] [10] [11] [12]. It is a well-tolerated product with low toxicity, and it has been used in Cuba before with no adverse effects reported [13].

Based on the evidence from the previous studies, the present clinical trial was conducted to evaluate the effect of the Ocoxin nutritional supplement on the quality of life of patients with advanced or metastatic epithelial ovarian cancer undergoing neoadjuvant chemotherapy.

2. Material and Methods

A phase II, open-label, single-center, non-randomised clinical trial was conducted. The study included thirty-six patients diagnosed with advanced, unresectable, or metastatic epithelial ovarian cancer seen at the Institute of Oncology and Radiobiology (INOR) in Cuba between November 2018 and September 2021, with organ function determined by clinical laboratory ranges, general health status ≥70 according to the Karnofsky Index and ventricular ejection fraction ≥ 55% measured by echocardiography, who were not receiving another investigational product and required neoadjuvant chemotherapy based on platinum salts and taxanes. All participants gave their informed consent.

Patients took the nutritional supplement Ocoxin (Table 1) at a dose of 30 ml twice a day, after breakfast and lunch. Treatment was initiated one week before starting a chemotherapy (CT) regimen consisting of carboplatin and paclitaxel every three weeks, of which they received three cycles with neoadjuvant intent. Treatment with Ocoxin was continued during CT and for three weeks after completion of the last cycle, as well as during any periods when CT was suspended due to toxicity. The final evaluation took place 3 weeks after the last CT cycle. The study lasted for approximately 10 weeks.

This research was approved by the Research Ethics Committee of the INOR and the regulatory agency CECMED and was included in the Cuban public registry of clinical trials and ClinicalTrials.gov Identifier NCT03562897.

2.1. Assessments of Clinical Laboratory Parameters and Quality of Life

Control variables such as age, clinical stage, histological type, comorbidities, oligometastatic disease, and presence of ascites were assessed.

Treatment safety was assessed through the reporting of adverse events, which were identified by laboratory tests (complete blood count and blood chemistry), physical examination, and patient questioning from the start of treatment until the final evaluation.

The chemical composition of Ocoxin nutritional supplement oral solution (30 ml bottles) is shown in the following table
IngredientValue (mg/30ml)
Glucosamine sulfate potassium chloride600 mg
L-Glycine600 mg
Malic acid360 mg
L-Arginine192 mg
L-Cysteine61.2 mg
Monoammonium glycyrrhizinate60 mg
Ascorbic acid36 mg
Sodium benzoate30 mg
Zinc sulfate30 mg
Green tea extract7.5 mg
Calcium pantothenate3.6 mg
Manganese sulfate1.2 mg
Pyridoxine hydrochloride1.2 mg
Cinnamon extract0.9 mg
Folic acid120 μg
Cyanocobalamin0.6 μg
Water q.s.p.30 ml

Health-related Quality of Life was assessed through the QLQ C30 [14] and QLQ OV28 [15] questionnaires. In addition, the Karnofsky Index and nutritional parameters were assessed.

2.2. Statistical Analysis

Planned number of subjects: To obtain the sample size for the phase II design and given that this is a dietary supplement with extensive information on its safety, A Hern’s single-stage design [16] is used, with no early termination rules. The investigational product would be declared ineffective if the success rate (P)—where P is the proportion of subjects in the trial suffering a deterioration of their quality of life (at least for some of the scales or dimensions), measured at the end of treatment in comparison with the baseline measurement—is less than or equal to 25% (p0). That is, this number is the maximum level of success below which the product shows no signs of efficacy (the study does not warrant further investigation). If there is a p1 value of 45%—where p1 is the minimum level of efficacy required above which the product would be declared as effective, then the results warrant continuation to a phase III study. Assuming a 5% α error rate (probability of rejecting the null hypothesis when it is true) and a 20% β error rate (probability of rejecting the alternative hypothesis when it is true) (power of the test: 1 – β = 80%), we decided to recruit a maximum of 36 subjects. Allowing for a 10% loss to follow-up, a total of 40 patients would be required. The trial tested the null hypothesis H0: P ≤ p0 against the alternative hypothesis: H1: P ≥ p1.

The number of responses (a) is set at 13 (cut-off point), so the product will be declared ineffective if the responses do not exceed this number (H0 is acceptable). And r = a + 1 = 14; that is, the number of responses where the generated efficacy level warrants continuation to a phase III study.

Quality of life was the main response variable, as determined by the Karnofsky index and by the general EORTC QLQ-C30 and specific EORTC QLQ-OV28 quality of life questionnaires. Nutritional status, adherence to the planned chemotherapy regimen, and the occurrence and type of any AEs were assessed as secondary variables. The non-parametric Wilcoxon signed-rank test was used to statistically compare the change in the primary response variables. For secondary variables, the response rate (improvement if value Dfinal > value D0) was estimated and the exact 95% CI was calculated.

3. Results3.1. Patient Characteristics

Data were analysed for all included patients with data recorded in the Case Report Form (CRF), for N = 36. This sample corresponded to the expected sample size (without losses). All patients remained in the study for at least 7 days and received at least 14 doses of investigational product and also the first cycle of CT (Table 2).

The mean age was 55.2 years, ranging from 31 to 73. Papillary serous adenocarcinoma was the most frequent histological type (N = 23; 63.9%). Most patients were diagnosed at stage IIIC (N = 28; 77.8%), with a Karnofsky index indicating a good general condition (N = 25; 69.4%). Ascites was present in all patients (N = 36; 100.0%) and only three had the oligometastatic disease (8%). Twenty-eight patients reported concurrent diseases (77.8%), the most frequent of which was HTN (N = 15; 41.7%).

Four treatment discontinuations occurred, three due to death caused by cancer progression and one case due to a serious adverse event (cerebral infarction), none of which were related to the product under evaluation. The rest of the patients remained until the end of the study. Patients were considered to have been assessed on schedule if they were evaluated within seven days of the study schedule. In cycles 2 (day 28) and 3 (day 49), three patients were evaluated outside the planned schedule (patients deferred due to adverse events); in the final evaluation, five patients were evaluated more than seven days behind schedule (Table 3).

Cycle deferral was due to G2 anaemia (N = 3), G1 neutropenia (N = 2). None of these adverse events interrupted the experimental treatment and they had resolved by the final evaluation.

3.2. Results of Clinical Laboratory Parameters

There was a decrease in haemoglobin (p = 0.017), leukocytes (p = 0.000), absolute neutrophil count (p = 0.000), eosinophils (p = 0.000) and platelets (p = 0.000), while monocyte (p = 0.002), lymphocyte (p = 0.000) and basophil (p = 0.034) values increased (Table 4).

Patient characteristics
VariablesN% of N
AgeMean (SD)55.2 (10.4)
Median (IQR)56 (49 - 62)
Min, Max(31; 73)
Histological type (recoded)Papillary serous adenocarcinoma2363.9
Adenocarcinoma of unknown primary616.7
Poorly differentiated carcinoma513.9
Peritoneal papillary serous carcinoma25.6
Clinical stage classification (recoded)IIIC2877.8%
IVA12.8%
IVB719.4%
Karnofsky index100822.2%
902569.4%
8038.3%
Metastatic siteNone2877.8%
Mediastinal lymphadenopathy25.6%
Liver411.1%
Pleura12.8%
Lung12.8%
AscitesYes36100%
Oligometastatic diseaseYes38%
No3392%
Concurrent diseaseYes2877.8%
No822.2%
HypertensionYes1541.7%
No2158.3%
Diabetes MellitusYes616.7%
No3083.3%
 Discontinuation and adherence to planned treatment and evaluation
N (%)
DiscontinuationDefinitive4 (11.1%)
Ocoxin treatment4 (11.1%)
CT treatment4 (11.1%)
Reasons for discontinuationDeath3 (%)
Serious adverse event1 (%)
Compliance with scheduled treatmentChemotherapy32 (88.9%)
Ocoxin32 (88.9%)
OV vials consumedMean (95% CI)130 (118; 143)
Median (IQR)143 (137; 145)
Min, Max(14; 211)
CT administrationReceived all CT cycles32 (88.9%)
Delayed administration of CT cycles (≥7 days)4 (11.1%)
CT cycles on time1st cycle36 (100%)
2nd cycle32 (88.9%)
3rd cycle32 (88.9%)
Regimen usedCarboplatin/paclitaxel36 (100%)
Cisplatin/paclitaxel0
Compliance with the evaluation timeCycleMedian (IQR); (Min, Max)
Initial0 (0); (0;3)
Cycle 1 (day 7)7 (2); (7; 12)
Cycle 2 (day 28)28 (3); (28; 53)
Cycle 3 (day 49)49 (3); (49; 77)
Final (day 63)72.5 (6); (69; 105)

In blood biochemistry parameters, there were only an increase in total bilirubin (p = 0.009), cholesterol (p = 0.000), and triglycerides (p = 0.004). Interestingly, creatinine did not show a statistically significant increase (p = 0.389) (Table 5).

3.3. Adverse Events

At least one adverse event was reported in all subjects, with a total of 290 adverse events reported (Table 6).

Alopecia was reported in all 36 subjects included and was associated with chemotherapy. The other most frequent adverse events were anaemia, abdominal

pain, headache, diarrhoea, and nausea (Table 7).

According to the intensity classification, the majority of adverse events were

Description of haematological parameters by time and evaluation of final change vs initial value
Laboratory parameterInitial evaluationCycle 2Cycle 3EndPaired Initial-Final variances (Var 95% CI) p
Haemoglobin (g/l)363332326.9 (1.4 - 12.5) 0.017
115 (106 - 125.5)112 (106 - 119)111.5 (96 - 119)110.5 (100.5 - 117.5)
Leukocytes (×109/l)363432323.6 (2.8 - 4.3) 0.000
8.61 (7.72 - 0.42)6.12 (4.74 - 8)5.37 (4.71 - 6.6)5.28 (4.41 - 6.6)
Neutrophils (%)3634323220 (16 - 24.1) 0.000
72.6 (66.4 - 76.9)58.5 (50.1 - 65.5)54.8 (45.1 - 58.8)51 (45.6 - 60.9)
Monocytes (%)36323032−2.3 (−3.7 - 0.9) 0.002
8.35 (7 - 10.1)10.2 (7.5 - 12.4)9.9 (8.6 - 11.6)10.0 (8.4 - 13)
Lymphocytes (%)36343132−18.9 (−22.4 - 15.4) 0.000
16.5 (12.6 - 22.9)28.8 (20.7 - 35.8)34.6 (28.2 - 42.2)37.05 (32.6 - 43.4)
Eosinophils (%)362726281.2 (0.5 - 1.8) 0.000
1.4 (0.7 - 2.1)0.8 (0.4 - 1.5)0.65 (0.3 - 1.3)0.45 (0.25 - 0.95)
Basophils (%)33262627−0.2 (−0.4 - 0) 0.034
0.3 (0.2 - 0.5)0.45 (0.2 - 0.6)0.4 (0.3 - 0.6)0.5 (0.3 - 0.7)
Platelets (×109/l)36343232232.5 (169.5 - 295.5) 0.000
453 (407.5 - 541.5)320 (250 - 386)267 (218.5 - 348)243 (191 - 324.5)
ANC (×109/l)363431323.7 (3.1 - 4.3) 0.000
6.41 (5.28 - 7.77)3.135 (2.54 - 4.92)2.82 (2.06 - 3.84)2.44 (2.01 - 3.325)
 Description of blood chemistry parameters by the time of evaluation and differences between the final value and initial value
Laboratory parameterInitial evaluationCycle 2Cycle 3EndPaired Initial-Final variances (Var 95% CI) p
ALT/GPT (U/l)36343030−12.2 (−22.9 - 1.5) 0.072
17 (11.825 - 28.5)24.5 (15.7 - 41)19.5 (13 - 32)23.5 (18 - 43.2)
AST/GOT (U/l)131111172 (−5.5 - 9.5) 0.500
19 (16 - 30.6)40 (19 - 44)25 (18.9 - 48)21 (18 - 30)
Direct bilirubin (mmol/l)35302730−1.3 (−2.7 - 0.2) 0.096
3.2 (2.6 - 4.3)3.55 (2.9 - 4.7)3.8 (2.7 - 4.9)3.8 (2.5 - 4.7)
Total bilirubin (mmol/l)35302530−5.3 (−11.6 - 1) 0.009
9.7 (5.6 - 11)12 (9.6 - 15.2)11.6 (7.9 - 13.9)12.1 (8.3 - 13.7)
Glycaemia (mmol/l)36343032−0.2 (−0.5 - 0.2) 0.492
5.15 (4.6 - 5.5)4.9 (4.5 - 5.4)5.2 (4.6 - 5.9)5.1 (4.55 - 5.7)
Creatinine (mmol/l)36343132−0.4 (−5.3 - 4.5) 0.389
57 (49.5 - 66.5)55.5 (48 - 72)59 (48 - 71)60.5 (51 - 70.5)
Uric acid (mmol/l)35323130−22 (−75.9 - 31.9) 0.262
282 (224 - 365)276 (222 - 331)288 (245 - 349)304 (268 - 366)
Total proteins (g/l)36343031−0.8 (−4.5 - 2.8) 0.643
71.5 (65.3 - 77.5)74.1 (69.2 - 79)75.2 (70.8 - 79)73.1 (69.3 - 78.5)
Albumin (g/l)36343031−0.3 (−3 - 2.4) 0.825
37.0 (33.75 - 40.55)37.7 (33.2 - 42.07)38.05 (34.4 - 40.7)38.1 (35.4 - 41.7)
Cholesterol (mmol/l)35342830−0.7 (−1.1 - −0.4) P < 0.0001
4.03 (3.45 - 4.42)4.22 (3.86 - 4.9)4.8 (4.0 - 5.24)4.6 (4.2 - 5.32)
Triglycerides (mmol/l)35342829−0.4 (−0.7 - −0.1) 0.004
1.12 (0.9 - 1.4)1.4 (1.1 - 1.7)1.5 (1.09 - 1.7)1.3 (1.2 - 1.8)
Alkaline phosphatase (U/l)34342929−11.7 (−61.6 - 38.2) 0.554
122 (103 - 161)133.5 (104.5 - 173.7)110 (98 - 140)115 (88 - 124)
 Frequency of adverse events in the study
Adverse eventsN = 36
Patients presenting at least one AE, n % 95% CI (exact)36 (100%) (90.3%; 100.0%)
The total number of AEs reported in the study290
Days between the start of the trial and adverse events
Mean (SD)30 (20.8)
Median (IQR)28 (11.7-46.3)
Min, Max0; 103
 Description of the type of adverse event
types of adverse eventsn = 290
n%
Alopecia3612.4
Anaemia258.6
Abdominal pain248.3
Headache165.5
Diarrhoea165.5
Nausea165.5
Arthralgia113.8
Asthenia113.8
Hypoalbuminemia93.1
Vomiting82.8
Colic62.1
Myalgia62.1
Itching62.1
Epigastric pain51.7
Thrombocytopenia51.7
Infections (cellulitis, dehiscence, pneumoperitoneum, dental abscess)41.4
Heartburn41.4
Constipation41.4
Dehydration41.4
Elevated direct bilirubin41.4
Neutropenia41.4
Other6321.7

mild (N = 192; 66.2%) and moderate (N = 74; 25.5%) (Table 8).

Fifteen adverse events (5.2%) were classified as Serious, including three deaths and an equal number of serious adverse events with life-threatening or incapacitating effects. None of the AEs classified as serious were related to the investigational product (Table 9).

There were 250 non-serious adverse events (86.2%) that were not related to the investigational product. One, eight, and four of these adverse events were classified in terms of causality as very likely, possible, and likely, respectively (TableA1).

Regarding the investigational product, there were 12 (4.1%) definitive discontinuations and 7 temporary discontinuations (2.4%). In a total of 162 cases, the patient recovered from the adverse events (resolved); one patient experienced sequelae and 96 patients had adverse events that persisted until the final evaluation date.

3.4. Adverse Events Affecting Clinical Laboratory Results

The haematological parameters that appeared to be linked to the time of evaluation were leukocytes, which increased in grade 1 adverse events (p = 0.0001), and lymphocytes, which decreased in grade 1 adverse events (p = 0.040) (TableA2).

Adverse events related to increased liver enzymes ALT and AST were associated with a decrease at the end of the evaluation, with statistically significant differences (p = 0.034 and p = 0.048, respectively). Adverse events for the remaining blood chemistry parameters assessed were not associated with the time of assessment (TableA3).

The global health status/QoL scale (based on Q29 and Q30 in QLQ-C30 [V3]), which can be considered as an overall summary measure, shows an increase in mean values. At 2.5 months after the start of treatment the difference was −11.5 points, 95% CI (−21.0; −1.9). Both confidence interval limits show a statistically significant increase (p = 0.027).

The scales that evaluate the symptoms (fatigue, loss of appetite and insomnia) show values that demonstrate a significant improvement after 2 months of treatment. It is also evident that for the fatigue and loss of appetite scales, the confidence interval limits have values outside the clinically relevant threshold of 5 points, which is a criterion for a clinically meaningful response. Overall, more than half of the patients improved in the different dimensions of the quality-of-life questionnaire two weeks after the end of treatment (Table 10).

Frequency of adverse events by intensity
IntensityN%
Serious, life-threatening or incapacitating31.0
Death31.0
Severe186.2
Moderate7425.5
Mild19266.3
Total290100.0
 Frequency of intensity of serious adverse events
Adverse events classified as SeriousIntensityN%
Serious, life-threatening, or incapacitating320.0
Death320.0
Severe746.7
Moderate213.3
Total15100

Evaluations of the QLQ-OV28 questionnaire indicate that the Gastrointestinal Symptom Rating Scale (GSRS) shows significantly reduced values at the end of the study compared to baseline (mean 27.1, 95% CI 16: 38.1). The confidence interval limits have values outside the clinically relevant threshold of 5 points, which is a criterion for a clinically meaningful response.

Except for the items regarding attitude to treatment (N = 7, 47.2%, 95%CI 30.4, 64.5), peripheral neuropathy (N = 6, 44.4%, 95% CI 27.9, 61.9) and other chemotherapy-related effects, all other items were favourable in more than half of the patients (Table 11).

The Karnofsky index improved at the end of the study in 31 of the 36 patients included (86.1%); 95%CI (70.5, 95.3) (Table 12).

The evaluation of the secondary variables measuring nutritional status during the study shows that there was a statistically significant decrease in BMI (p = 0.0001) and body weight (p = 0.0001). There were no statistically significant changes in serum albumin and protein values (Table 13).

4. Discussion

The vast majority of patients with epithelial ovarian cancer are diagnosed at locally advanced and metastatic stages (stages III-IV) [17] [18], associated with malignant ascites and peritoneal carcinosis, which leads to protein-energy

Comparison of the QLQ-C30 quality of life (QoL) scales (initial/final)
ScalesNo. of signs −/0/+ (=Total)Var (initial-final) 95% CIResponse% 95% CIP
Health/Overall QoL10/4/18 = (32)−11.5 (−21.0; −1.9)2261.1 (43.5; 76.9)0.027
Functioning
Physical Functioning10/6/16 = (32)−5.6 (−14.4; 3.2)2261.1 (43.5; 76.9)0.232
Personal Functioning10/7/15 = (32)−8.9 −24.6; 6.92261.1 (43.5; 76.9)0.293
Emotional Functioning11/5/16 = (32)−2.3 (−13.5; 8.8)2158.3 (40.8; 74.5)0.621
Cognitive Functioning9/16/7 = (32)0.0 (−10.0; 10.0)2363.9 (46.2; 79.2)0.979
Social Functioning8/12/12 = (32)−7.3 (−17.6; 3.1)2466.7 (49.0; 81.4)0.148
Symptoms
Fatigue17/10/5 = (32)15.3 (5.1; 25.4)2775.0 (57.8; 87.9)0.006
Nauseas-Vomiting16/12/4 = (32)9.9 (−1.0; 20.8)2877.8 (60.8; 89.9)0.083
Pain12/12/5 = (32)10.9 (−4.1; 25.9)2466.7 (49.0; 81.4)0.052
Dyspnoea7/23/2 = (32)8.3 (−1.8; 18.5)3083.3 (67.2; 93.6)0.102
Insomnia11/17/4 = (32)19.8 (4.0; 35.6)2877.8 (60.8; 89.9)0.014
Loss of Appetite14/14/4 = (32)26.0 (9.4; 42.7)2877.8 (60.8; 89.9)0.004
Constipation8/17/7 = (32)4.2 (−12.8; 21.1)2569.4 (51.9; 83.7)0.604
Diarrhoea7/18/7 = (32)3.1 (−11.3; 17.6)2569.4 (51.9; 83.7)0.657
Financial Difficulties5/18/9 = (32)−7.3 (−20.12; 5.6)2363.9 (46.2; 79.2)0.267
 Comparison of the QLQ-OV28 quality of life (QoL) scales (initial/final)
ScalesNo. of signs −/0/+ (=Total)Var (initial-final) 95% CIResponse% 95% CIP
Functional scales
Body image14/12/6 (=32)9.9 (−3.6; 23.4)2672.2 (54.8; 85.8)0.148
Sexuality6/20/6 (=32)0.9 (−12.5; 10.7)2672.2 (54.8; 85.8)0.937
Attitude to illness/treatment14/3/15 (=32)−0.3 (−13.6; 12.9)1747.2 (30.4; 64.5)0.811
Symptom scales
Gastrointestinal/abdominal symptoms23/5/4 (=32)27.1 (16; 38.1)2877.8 (60.8; 89.9)0.0001
Peripheral neuropathy7/16/9 (=32)−9.4 (−22.3; 3.5)1644.4 (27.9; 61.9)0.084
Menopausal/hormonal symptoms10/12/10 (=32)−3.1 (−18.8; 12.5)2261.1 (43.5; 76.9)0.895
Other CT-related effects8/7/17 (=32)−2.7 (−12.1; 6.7)1541.7 (25.5; 59.2)0.268
Hair loss5/17/10 (=32)−7.8 (−19.9; 4.3)2261.1 (43.5; 76.9)0.240
 Karnofsky index at the beginning and end of the study
T_ini N = 32T_final N = 32Difference (fin-ini) N = 32Improvement or Stability* (95CI)**
Karnofsky index31/36* (70.5; 95.3)**
Median (IQR)90 (90; 97.5)100 (90; 100)10 (0; 10)
Min, Max(80; 100)(80; 100)(−20; 20)
 Secondary variables for measuring nutritional status
VariablesT_ini N = 31T_Cycle2 N = 31T_final N = 31Difference (fin-ini) N = 31General (95%CI)
BMI6/36 16.7 (6.4; 32.8)
Median (IQR)25 (21.8; 30.4)23.7 (20.2; 29.4)23.3 (19.6; 27.7)−1.3 (−2.2; −0.4)
Wilcoxon signed-rank test (Two-sided, asymptotic significance) p = 0.0001
Weight5/36 13.9 (4.7; 29.5)
Median (IQR)61 (55; 76.5)61 (51; 72)60 (50.5; 73)−3.5 (−5.5; −1)
Wilcoxon signed-rank test (Two-sided, asymptotic significance) p = 0.0001
Total proteins16/36 44.4 (27.9; 61.9)
Median (IQR)72.2 (68.1; 77.5)74.2 (69.2; 79)73.1 (69.3; 78.5)1.1 (−6.6; 8)
Wilcoxon signed-rank test (Two-sided, asymptotic significance) p = 0.597
Albumin15/36 41.7 (25.5; 59.2)
Median (IQR)37.2 (35.3; 41.9)38 (33.3; 42.1)38.1 (35.4; 41.7)−0.2 (−5.8; 4.6)
Wilcoxon signed-rank test (Two-sided, asymptotic significance) p = 0.914.

malnutrition in patients. This profoundly alters their physical functions, psychological well-being, and social life, as it significantly impairs their health, increases complications, decreases tolerance to cancer treatment, and reduces the patient’s quality of life. These patients need treatments based on chemotherapy and cytoreductive surgery as much as possible, which requires an adequate nutritional status.

Patients with epithelial ovarian cancer have an altered metabolism, marked by increased proteolysis and lipolysis, while muscle protein synthesis is decreased, ultimately leading to a loss of muscle mass and fat [19] [20]. In addition, carbohydrate metabolism is modified by tumour growth, with decreased hepatic glucose production and increased Cori cycle activity, while insulin sensitivity in peripheral tissues is reduced. All this leads to weight loss and reduced immune response to the tumour and the treatment received [21] [22].

The main variable that influences the development of malnutrition regardless of tumour histology is the cancer stage. In other words, it is more frequent in patients with disseminated disease, which characterises our study since there is a predominance of locally advanced and metastatic stages, where there is a deterioration in nutritional status caused by the tumour itself and ascites, in addition to the digestive symptoms typical of intra-abdominal dissemination, which lead to anorexia [23].

There are several factors regarding the origins of malnutrition in cancer patients, as the mechanisms involved depend on both the tumour and the treatment received. It is a clinical condition that includes an energy and nutrient imbalance affecting tissues and body composition [24].

The production of hormones and pro-inflammatory cytokines released during the pathological process of cancer, such as IL-6, IL-1, CRP, and PIF, reduce appetite, leading to anorexia. In turn, these mediators alter macronutrient metabolism, decreasing the body’s muscle mass and increasing basal energy expenditure. Protein demands compromise protein reserves, meaning that if requirements are not met, visceral protein is depleted, leading to gastrointestinal malabsorption and reduced plasma protein production in the liver [25].

The prevalence of signs of malnutrition in ovarian cancer patients ranges from 28% to 67%, making this the type of cancer that is most associated with malnutrition [26]. There is also a very important relationship between nutritional status, quality of life, survival, and the ability to tolerate multidisciplinary treatment for peritoneal carcinosis [27] [28].

In the present study, the results obtained in terms of demographic data and clinical and pathological characteristics of epithelial ovarian cancer are in line with internationally reported epidemiological patterns, and stage IIIC was the most represented.

The adverse effects of CT treatment will depend on the type of regimen. In this series, the regimen administered was carboplatin/paclitaxel, which has an intermediate emetogenic potential and it is important to prescribe antiemetic protocols for adequate prophylaxis, which were complied with in the study subjects. However, nausea and vomiting are among the most frequently encountered symptoms in ovarian cancer patients, caused by the tumour itself, ascites and peritoneal carcinosis. Once CT treatment is initiated, control of tumour-mediated symptoms and ascites begins, especially in high-grade papillary serous carcinomas, which are the most common and most chemo sensitive.

Neijt et al. [29] showed in their research (N = 71) a higher number of grade 3 toxicities related to the carboplatin-paclitaxel regimen, namely grade 3 nausea/vomiting (16%), whereas in this trial, grade 1-2 nausea (5.5%) and grade 1 vomiting (2.8%) were reported. The ICON 4 study reported grade 2 - 4 nausea/ vomiting (35%). These differences in the decrease in the intensity and frequency of these adverse events could be mediated by the investigational product. These results in turn show significantly reduced values at the end of the study compared to baseline (mean 27.1, 95% CI 16; 38.1), when applying the ovarian-specific quality of life questionnaires (QLQ-OV28), where the confidence interval limits show values outside the clinically relevant threshold of 5 points, which is a criterion for clinically significant response.

Traditionally used anti-cancer drugs induce apoptosis or cell death mechanisms by inhibiting cell growth or by damaging cellular deoxyribonucleic acid. However, this action does not specifically target tumour cells and may have a toxic effect on healthy tissues, limiting the dose to be administered. CT treatments have a severe impact on haemoglobin levels, causing varying degrees of anaemia [30]. Several antioxidants have shown a positive effect on haemoglobin levels during cancer treatment [31]. In groups receiving Ocoxin supplementation, anaemia decreased in 80% of patients compared to those receiving CT without the supplement. However, only 58% of patients receiving adjuvant CT without OV supplementation showed no toxicity [18].

Neutropenia is one of the adverse reactions of chemotherapy that most often makes it necessary to postpone administration or reduce the dose, which adversely affects patients’ progress [32].

Similar results were reported by Ruiz-Lorente et al. [18] in cervical and endometrial cancer in patients receiving Ocoxin plus CT. They showed better haemoglobin levels compared to the group receiving CT/RT plus brachytherapy without OV supplementation. It was concluded that Ocoxin supplementation in the group receiving CT is more effective in mitigating the decrease in platelets and leukocytes compared to the group receiving CT without supplementation.

In this series, neutropenia accounted for 1.4% and was grade 1 - 2 and there was thrombocytopenia grade 1 - 2 in 1.7%, in contrast to Neijt et al., who showed neutropenia grade 3 (31%) and grade 4 (45%), as well as thrombocytopenia grade 3 (4%). As for neurotoxicity, which is also dose-limiting, neurotoxicity (grade 3) occurred in 1% of the patients [13]. However, our series of 36 patients differs from those results, showing grade 1 - 2 peripheral neuropathy (N = 6, 44.4%), perhaps related to the protective effect on peripheral nerves of B-complex vitamins such as pyridoxine and cyanocobalamin, which are components of Ocoxin.

One of the organs that most suffers during CT treatments is the liver, as most cytostatic agents are metabolised in the liver, hence the need to monitor liver enzymes [33]. Liver damage is reflected in decreased albumin levels and increased ALT, AST, alkaline phosphatase and GGT. Previous clinical studies using Ocoxin coupled with CT in patients with gastric cancer revealed a significant increase in liver toxicity. The administration of Ocoxin together with CT led to an increase in serum albumin levels compared to the group receiving CT without the supplement [34]. In addition, Ocoxin counteracted hepatotoxicity related to increased ALT and AST in 92% of patients on the adjuvant CT treatment regimen after 3 weeks of treatment, while only 50% of patients in the non-supplemented CT group had unchanged AST and ALT levels. This reduction in hepatotoxicity was confirmed by Shumsky et al. (2019) in patients who received Ocoxin to decrease oral mucositis related to CT and RT [35]. They reported 4- and 7-fold lower ALT and AST levels in patients in the group receiving Ocoxin as a supplement compared to those receiving only CT and RT. The present investigation showed similar results, as adverse events related to increased levels of liver enzymes ALT and AST were associated with a decrease at the end of the evaluation period, with statistically significant differences (p = 0.034 and p = 0.048, respectively). Therefore, the antioxidant effect of Ocoxin may prevent liver tissue damage, as is the case with other antioxidants such as glucuronic acid, which is one of the components of OV [36] [37].

Other studies evaluated the effect of supplementation with essential amino acids such as arginine, glutamine, and the ketone body hydroxybutyrate [38]. The study by May [39], conducted in the United States with 33 patients, concluded that the administration of essential amino acids such as hydroxymethylbutyrate (3 g/day), L-arginine (14 g/day), L-glutamine (14 g/day) in cancer patients increased body weight secondary to fat synthesis and decreased proteolysis (average gain of 0.95 kg compared to the loss of 0.26 kg). In this study, the investigational product is composed of essential and non-essential amino acids, as well as B vitamins, among other chemicals, which could favour the increase in patients’ body weight. To establish the mechanism of action of this supplement, it is necessary to design experimental studies with such objectives in mind.

The Karnofsky index is a scale that measures the functional capacity of cancer patients and is a predictor of patient prognosis. If the patient achieves a high Karnofsky score, his/her prognosis will be better. From previous studies, it is known that the administration of Ocoxin together with CT increases the Karnofsky index by 59.26%, compared to 30.38% in those receiving CT alone, which is the case in different epithelial tumours such as head and neck, cervical [40] and non-small cell lung carcinoma [41]. This effect may be mediated by the overall increase in health status observed in patients receiving daily doses of OV in conjunction with CT. Among the study subjects, this effect of the investigational product was positive as it shows that the Karnofsky index improved at the end of the study in 31 of the 36 patients included (86.1%), 95% CI (70.5, 95.3), bearing in mind that there were 4 definitive discontinuations due to disease progression.

According to statistical hypothesis assessment: From the results of the quality-of-life assessment based on the QLQ 30 scale and the Karnofsky index in this study, it can be observed that in all cases the number of patients responding exceeds the cut-off value (14) pre-specified by design in the study protocol. A minimal effect is evident, justifying further development of the product Ocoxin.

Based on the possibilities offered by the cancer treatment, patients receive treatment with curative or palliative intent. In both cases, treatment may be accompanied by appropriate specific nutritional interventions that primarily aim to improve the patient’s general condition and quality of life (QoL) [42]. Nutritional supplementation accompanying curative treatment has additional and specific objectives, such as increasing the response to treatment, decreasing the rate of complications, and possibly reducing morbidity by maintaining the balance between energy expenditure and intake or minimising the imbalance between them [43] [44]. Nutritional treatment in palliative care aims to improve the QoL of patients, helping to manage the clinical symptoms associated with the natural course of neoplastic disease (nausea, vomiting, etc.) [45] [46].

Considering the safety profile of Ocoxin and its effect on improving the quality of life and health status of the patients included in this trial, we suggest that a phase III clinical trial should be conducted.

5. Conclusion

Cancer disrupts the balance of patients’ physical functions, psychological well-being, and social life. During the acute phase of cancer treatment with curative intent, adequate support with the Ocoxin nutritional supplement has been shown to improve short-term outcomes in patients with advanced epithelial ovarian cancer by reducing the number of complications and reducing adverse events. This clinical improvement has had a positive impact on patients’ quality of life.

Author Contributions

Study Concept: All authors. Study Design: Karen López Miguel, Juan Jesús Lence Anta, Eduardo Sanz. Statistical analysis: Mayté Robaina García, Ramón Ropero Toirac. Manuscript preparation: Karen López Miguel. Manuscript editing: Karen López Miguel, Ramón Ropero Toirac, Eduardo Sanz, and David Marquez. Manuscript review: All authors. All the authors have read and agreed to the published version of the manuscript.

Funding

This research was partly funded by Catalysis, S.L. (Madrid, Spain), which provided the investigation product (Ocoxin) used for the trial.

Conflicts of Interest

The authors declare no conflicts of interest regarding the publication of this paper.

Cite this paper

Miguel, K.L., Ávila, D.R.M., Pérez, L.Á., Rabasa, G.M., Lambert, A.L., Noa, R.E., Manzano, L.H., De Quesada Amigó, M., Velázquez, R.I.R., Otero, D.C., Toirac, R.R., Heredia, I.C., Cabeza, M.B., Ramos, T.A.A., Reyes, R.M.M., Anta, J.J.L., Sosa, R.F., Candó, K.S., Rodríguez, K.S., Sosa, Z.L., García, M.R., Sanz, E. and Marquez, D. (2022) The Administration of Ocoxin Increases the Quality of Life of Patients with Advanced Epithelial or Metastatic Ovarian Cancer Undergoing Neoadjuvant Chemotherapy. Journal of Cancer Therapy, 13, 561-584. https://doi.org/10.4236/jct.2022.139050

Annexe The causal relationship of non-serious and serious adverse events
Non-Serious Adverse EventsCausal Relationship
UnlikelyVery LikelyNot AssessableUnrelatedPossibleLikely
IntensityMild91117164
Moderate1007010
Severe100910
Subtotal111125084
Serious adverse eventsUnlikelyVery LikelyNot AssessableUnrelatedPossibleLikely
IntensityModerate000200
Severe000700
Serious, life-threatening000300
Death000300
Subtotal0001500
 Distribution of the intensity of haematological adverse events according to the time of evaluation
IntensityInitialCycle 2Cycle 3Endp
Haemoglobin
0232319190.759
17446
26796
30001
36343232
Leukocytes
0362220160.0001
10121216
36343232
Lymphocytes
0293232300.040
16100
21101
30001
36343232
Platelets
0363431290.083
10013
36343232
Absolute neutrophil count (ANC)
0362929260.179
10434
20102
 Distribution of adverse blood chemistry events by time of assessment
IntensityInitialCycle 2Cycle 3Endp
36343232
ALT
0363027300.034
10440
36343130
AST
01389290.048
10321
13111130
Direct bilirubin
0191311110.290
110131113
26363
30103
35302830
Total bilirubin
0352726290.154
10200
20001
35292630
Creatinine
0343332320.592
11000
21100
36343232
Uric acid
0262726210.512
19569
35323230
Glucose
0282624270.340
13364
G1 hypoglycaemia5511
36343132
Total proteins
0332728291.00
33272829
Albumin
0151616170.724
121181514
36343131
Cholesterol
0323330290.363
10001
32333030
Triglycerides
0302421210.489
15988
35332929
Alkaline phosphatase
0333030280.522
11210
20001
40100
34333129
ReferencesClarke-Pearson, D.L. (2009) Screening for Ovarian Cancer. The New England Journal of Medicine, 361, 170-177. https://doi.org/10.1056/NEJMcp0901926Cortez, A.J., Tudrej, P., Kujawa, K.A. and Lisowska, K.M. (2018) Advances in Ovarian Cancer Therapy. Cancer Chemotherapy and Pharmacology, 81, 17-38. https://doi.org/10.1007/s00280-017-3501-8Cortés, A., Ibá&ntilde;ez, M., Hernández, A. and García, M.A. (2020) Cáncer de Ovario: Tamizaje y diagnóstico imagenológico. Medicina Legal de Costa Rica, 37, 54-61. https://doi.org/10.15359/abra.37-54.2Yoneoka, Y., Ishikawa, M., Uehara, T., Shimizu, H., Uno, M., Murakami, T., et al. (2019) Treatment Strategies for Patients with Advanced Ovarian Cancer Undergoing Neoadjuvant Chemotherapy: Interval Debulking Surgery or Additional Chemotherapy? Journal of Gynecologic Oncology, 30, e81. https://doi.org/10.3802/jgo.2019.30.e81Coleridge, S.L., Bryant, A., Kehoe, S. and Morrison, J. (2021) Chemotherapy versus Surgery for Initial Treatment in Advanced Ovarian Epithelial Cancer. Cochrane Database of Systematic Reviews, No. 2. CD005343. https://doi.org/10.1002/14651858.CD005343.pub5Singh, K., Bhori, M., Kasu, Y.A., Bhat, G. and Marar, T. (2018) Antioxidants as Precision Weapons in War against Cancer Chemotherapy Induced Toxicity—Exploring the Armoury of Obscurity. Saudi Pharmaceutical Journal, 26, 177-190. https://doi.org/10.1016/j.jsps.2017.12.013Thyagarajan, A. and Sahu, R.P. (2018) Potential Contributions of Antioxidants to Cancer Therapy: Immunomodulation and Radiosensitization. Integrative Cancer Therapies, 17, 210-216. https://doi.org/10.1177/1534735416681639Márquez, J., Mena, J., Hernandez-Unzueta, I., Benedicto, A., San, E., et al. (2016) Ocoxin Oral Solution Slows down Tumor Growth in an Experimental Model of Colorectal Cancer Metastasis to the Liver in Balb/cmice. Oncology Reports, 35, 1265-1272. https://doi.org/10.3892/or.2015.4486Al-Mahtab, M., Akbar, S.M., Khan, M.S. and Rahman, S. (2015) Increased Survival of Patients with End-Stage Hepatocellular Carcinoma Due to Intake of Ocoxin, a Dietary Supplement. Indian Journal of Cancer, 52, 443-446. https://doi.org/10.4103/0019-509X.176699Roomi, M.W., Ivanov, V., Kalinovsky, T., Niedzwiecki, A. and Rath, M. (2005) In Vivo Antitumor Effect of Ascorbic Acid, Lysine, Proline and Green Tea Extract on Human Colon Cancer Cell HCT 116 Xenografts in Nude Mice: Evaluation of Tumor Growth and Immunohistochemistry. Oncology Reports, 13, 421-425. https://doi.org/10.3892/or.13.3.421Hernández-García, S., González, V., Sanz, E. and Pandiella, A. (2015) Effect of Oncoxin Oral Solution in HER2-Overexpressing Breast Cancer. Nutrition and Cancer, 67, 1159-1169. https://doi.org/10.4236/jct.2020.115023Díaz-Rodríguez, E., El-Mallah, A.M., Sanz, E. and Pandiella, A. (2017) Antitumoral Effect of Oncoxin in Hepatocellular Carcinoma. Oncology Letters, 14, 1950-1958. https://doi.org/10.3892/ol.2017.6440Rivas, I.C., Silva, J.A., Alfonso, G., Candanedo, H., Cuervo, Y., Mestre, B., et al. (2018) Oncoxin-Viusid with Radiotherapy and Chemotherapy in Patients with Head and Neck Cancer: Results from a Phase II, Randomised, Double-Blind Study. Journal of Cancer Science and Therapy, 10, 317-327. https://doi.org/10.4172/1948-5956.1000562Aaronson, N.K., Ahmedzai, S., Bergman, B., Bullinger, M., Cull, A., Duez, N.J., Filiberti, A., Flechtner, H., Fleishman, S.B., de Haes, J.C.J.M., Kaasa, S., Klee, M.C., Osoba, D., Razavi, D., Rofe, P.B., Schraub, S., Sneeuw, K.C.A., Sullivan, M. and Takeda, F. (1993) The European Organisation for Research and Treatment of Cancer QLQ-C30: A Quality-of-Life Instrument for Use in International Clinical Trials in Oncology. Journal of the National Cancer Institute, 85, 365-376. https://doi.org/10.1093/jnci/85.5.365Cull, A., Howat, S., Greimel, E., Waldenstrom, A.C., Arraras, J., Kudelka, A., Chauvenet, L., Gould, A., EORTC Quality of Life Group [European Organization for Research and Treatment of Cancer] and Scottish Gynaecological Cancer Trials Group (2001) Development of a European Organization for Research and Treatment of Cancer Questionnaire Module to Assess the Quality of Life of Ovarian Cancer Patients in Clinical Trials: A Progress Report. European Journal of Cancer, 37, 47-53. https://doi.org/10.1016/S0959-8049(00)00369-5A’Hern, R.P. (2001) Sample Size Tables Exact Single-Stage Phase II Designs. Statistics in Medicine, 20, 859-866. https://doi.org/10.1002/sim.721Schorge, J.O., Modesitt, S.C., Coleman, R.L., Cohn, D.E., Kauff, N.D., Duska, L.R., et al. (2010) SGO White Paper on Ovarian Cancer: Etiology, Screening, and Surveillance. Gynecologic Oncology, 119, 7-17. https://doi.org/10.1016/j.ygyno.2010.06.003Edmundo Mora, E. and Gutiérrez, E. (2016) Características de las pacientes con cáncer de ovario en el Hospital de San José, Bogotá D.C., 2009-2013. Repertorio de Medicina y Cirugía, 25, 15-21. https://doi.org/10.31260/RepertMedCir.v21.n1.2012.788Delano, M.J. and Moldawer, L.L. (2006) The Origins of Cachexia in Acute and Chronic Inflammatory Diseases. Nutrition in Clinical Practice, 21, 68-81. https://doi.org/10.1177/011542650602100168Fearon, K.C., Moses, A.G. (2002) Cancer Cachexia. International Journal of Cardiology, 85, 73-81. https://doi.org/10.1016/S0167-5273(02)00235-8Kathiresan, A.S., Brookfield, K.F., Schuman, S.I. and Lucci, J.A. (2011) Malnutrition as a Predictor of Poor Postoperative Outcomes in Gynecologic Cancer Patients. Archives of Gynecology and Obstetrics, 284, 445-451. https://doi.org/10.1007/s00404-010-1659-yMadhok, B.M., Yeluri, S., Haigh, K., Burton, A., Broadhead, T. and Jayne, D.G. (2011) Parenteral Nutrition for Patients with Advanced Ovarían Malignancy. Journal of Human Nutrition and Dietetics, 24, 187-191. https://doi.org/10.1111/j.1365-277X.2010.01127.xDewys, W.D., Begg, C., Lavin, P.T., et al. (1980) Prognostic Effect of Weight Loss Prior to Chemotherapy in Cancer Patients. The American Journal of Medicine, 69, 491-497. https://doi.org/10.1016/S0149-2918(05)80001-3Fuchs-Tarlovsky, V., Alvarez-Altamirano, K., Turquie-Sacal, D., Alvarez-Flores, C. and Hernandez-Steller, H. (2013) Nutritional Status and Body Composition Are Already Affected before Oncology Treatment in Ovarian Cáncer. Asia Pacific Journal of Clinical Nutrition, 22, 426-430.Gupta, D., Lis, C.G., Vashi, P.G. and Lammersfeld, C.A. (2010) Impact of Improved Nutritional Status on Survival in Ovarian Cancer. Supportive Care in Cancer, 18, 373-381. https://doi.org/10.1007/s00520-009-0670-yBillson, H.A., Holland, C., Curwell, J., Davey, V.L., Kinsey, L., Lawton, L.I., et al. (2013) Perioperative Nutrition Interventions for Women with Ovarian Cancer. Cochrane Database of Systematic Reviews, No. 9, CD009884. https://doi.org/10.1002/14651858.CD009884.pub2Vashi, P.G., Guptan, D., Lammerfeld, C.A., Braun, D.P., Popiel, B., Misra, S., et al. (2013) The Relationship between Baseline Nutritional Status with Subsequent Parenteral Nutrition and Clinical Outcomes in Cancer Patients Undergoing Hyperthermic Intraperitoneal Chemotherapy. Nutrition Journal, 12, 118. https://doi.org/10.1186/1475-2891-12-118García, T., Monta&ntilde;és, B., Vicedo, A., Llueca, J.A., Escrig, J., Herraiz, J.L., et al. (2016) Nutritional Assessment and Support in Patients with Peritoneal Carcinomatosis of Ovarian Cancer with Cytoreductive Surgery. Nutrición Clínica y Dietética Hospitalaria, 36, 31-40.Neijt, J.P., Thigpen, J.T. and Du Bois, A. (1999) First Line Chemotherapy with Carboplatin plus Paclitaxel in Advanced Ovarian Cancer a New Standard of Care? Annals of Oncology, 10, S35-S41. https://doi.org/10.1016/S0923-7534(20)31482-4Dicato, M., Plawny, L. and Diederich, M. (2010) Anemia in Cancer. Annals of Oncology, 21, 167-172. https://doi.org/10.1093/annonc/mdq284Fuchs-Tarlovsky, V., Rivera, M.A., Altamirano, K.A., Lopez-Alvarenga, J.C. and Ceballos-Reyes, G.M. (2013) Antioxidant Supplementation Has a Positive Effect on Oxidative Stress and Hematological Toxicity during Oncology Treatment in Cervical Cancer Patients. Supportive Care in Cancer, 21, 1359-1363. https://doi.org/10.1007/s00520-012-1674-6Pérez Ruiz, L., Fernández águila, J.D. and Ramos Cede&ntilde;o, A.M. (2009) Factor estimulante de colonias de granulocitos en el tratamiento ambulatorio de la neutropenia posterior a la quimioterapia. Revista Panamericana de Salud Pública, 26, 281-282. https://doi.org/10.1590/S1020-49892009000900013 http://www.scielosp.org/scielo.php?script=sci_arttext&pid=S1020-49892009000900013Grigorian, A. and O’Brien, C.B. (2014) Hepatotoxicity Secondary to Chemotherapy. Journal of Clinical and Translational Hepatology, 2, 95-102. https://doi.org/10.14218/JCTH.2014.00011Ruiz-Lorente, R., Hernández-Durán, D., García-Viamontes, J., Lence-Anta, J., Ortiz-Reyes, R. and Sanz-Navares, E. (2020) Efficacy of Oncoxin-Viusid on the Reduction of Adverse Reactions to Chemotherapy and Radiotherapy in Patients Diagnosed with Cervical Cancer and Endometrial Adenocarcinoma. Journal of Cancer Therapy, 11, 276-295. https://doi.org/10.4236/jct.2020.115023Shumsky, A., Evgeniy, B., Sanz, E. and Petrovskiy, F. (2019) Oncoxin Nutritional Supplement in the Management of Chemotherapy- and/or Radiotherapy-Associated Oral Mucositis. Molecular and Clinical Oncology, 10, 463-468. https://doi.org/10.3892/mco.2019.1809Palipoch, S., Punsawad, C., Koomhin, P. and Suwannalert, P. (2014) Hepatoprotective Effect of Curcumin and Alpha-Tocopherol against Cisplatin-Induced Oxidative Stress. BMC Complementary and Alternative Medicine, 14, Article No. 111. https://doi.org/10.1186/1472-6882-14-111Yan, Y., Mo, Y. and Zhang, D. (2015) Magnesium Isoglycyrrhizinate Prevention of Chemotherapy Induced Liver Damage during Initial Treatment of Patients with Gastrointestinal Tumors. Chinese Journal of Hepatology, 23, 204-208. (In Chinese)Madeddu, C., MacCiò, A., Astara, G., Massa, E., Dessì, M., Antoni, G., et al. (2010) Open Phase II Study on Efficacy and Safety of an Oral Amino Acid Functional Cluster Supplementation in Cancer Cachexia. Mediterranean Journal of Nutrition and Metabolism, 3, 165-172. https://doi.org/10.3233/s12349-010-0016-9May, P.E., Barber, A., D’Olimpio, J.T., Hourihane, A. and Abumrad, N.N. (2002) Reversal of Cancer-Related Wasting Using Oral Supplementation with a Combination of Beta-Hydroxy-Beta-Methylbutyrate, Arginine, and Glutamine. The American Journal of Surgery, 183, 471-479. https://doi.org/10.1016/S0002-9610(02)00823-1Uddin, D., Islam, M., Mahmood, I., Ghosh, A., Khatun, R. and Kundu, S. (2018) Findings of the 3-Month Supportive Treatment with Oncoxin Solution beside the Standard Modalities of Patients with Different Neoplastic Diseases. TAJ, 22, 172-175. https://doi.org/10.3329/taj.v22i2.37718Shen, S. and Jiang, S. (2019) Chinese Herbal Medicines of Supplementing Qi and Nourishing Yin Combined with Chemotherapy for Non-Small Cell Lung Cancer: A Meta-Analysis And Systematic Review. Journal of Cellular Biochemistry, 120, 8841-8848. https://doi.org/10.1002/jcb.28192Andreyer, H.J., Norman, A.R., Oates, J. and Cunningham, D. (1998) Why Do Patients with Weight Loss Have a Worse Outcome When Undergoing Chemotherapy for Gastrointestinal Malignaces? European Journal of Cancer, 34, 503-509. https://doi.org/10.1016/S0959-8049(97)10090-9Tunca, J.C. (1983) Nutritional Evaluation of Gynaecologic Cáncer Patients during Initial Diagnosis of Their Disease. American Journal of Obstetrics & Gynecology, 147, 893-896. https://doi.org/10.1016/0002-9378(83)90241-7Laky, B., Janda, M., Bauer, J., Vavra, C., CLeghorn, G. and Obermair, A. (2007) Malnutrition among Gynecological Cáncer Patients. European Journal of Clinical Nutrition, 61, 642-646. https://doi.org/10.1038/sj.ejcn.1602540Asher, V., Lee, J. and Bali, A. (2012) Preoperative Serum Albumin Is an Independent Prognostic Predictor of Survival In Ovarian Cancer. Medical Oncology, 29, 2005-2009. https://doi.org/10.1007/s12032-011-0019-5Benizri, E.I., Bereder, J.M., Rahili, A., Bernard, J.L. and Bechimal, D. (2013) Ascites, and Malnutrition Are Predictive Factors for Incomplete Cytoreductive Surgery for Peritoneal Carcinomatosis from Gastric Cáncer. The American Journal of Surgery, 205, 668-673. https://doi.org/10.1016/j.amjsurg.2012.06.009