European Journal of Cardiovascular Medicine

The ovarian cancer is among the most lethal, seventh most common gynaecological malignancy in the world. But it is the fourth most common malignancy in Indian(incidence of 4.9 cases per 100,000) of which 90% derived from coelomic epithelium germ cell tumors ( 5%)  and sex cord stromal tumors for 7%.The most common among epithelial ovarian cancers are high grade serous(70%),endometroid (10%),clear cell (10%),mucinous(3%) and low grade serous(<5%).All these have different epidemiology, molecular profiles, mode of spread ,response to chemotherapy and hence different prognosis. The majority of the patients with Fallopian tube ,ovarian and primary peritoneal cancers are diagnosed at an advanced stage. About 70% of patients with EOC present with advanced disease, as a result of the lack of any satisfactory screening test and specific symptoms.

BIOMARKERS-The pelvic ultrasonography and CA- 125 determined with  the sensitivity and specificity 70-80 % in epithelium ovarian cancer. Moore and colleagues  was developed risk of ovarian malignancy algorithm (ROMA)  using a combination of CA-125 levels, HE4 expression, and menopausal status. The Risk of Ovarian Malignancy Algorithm (ROMA) and  Predictive Index (PI) to classify patients as being at a low or high risk for malignant epithelial ovarian cancer disease was calculated by Moore.

TREATMENT PROTOCOL:-Complete resection during cytoreductive surgery is the most important independent prognostic factor in advanced EOC. Survival is inversely related to the residual disease after surgery. Bristow et al. found that each 10% increase in maximal cytoreduction rates was associated with a 5.5% increase in median survival time.(19). The median overall survival (OS) for patients with no residual disease was 70 months, compared to 53 months for patients with 1–5 mm, 40 months for patients with 1–10 mm, and 30 months for patients with >10 mm (P < 0.001).Although the aim of cytoreductive surgery should be leaving no gross residual disease, there is still a significant benefit in trying to achieve “optimal” residual disease status (i.e., <1 cm), because such patients have a 10 months longer median OS, compared to patients with suboptimal residual disease.The European Organization for Research and Treatment of Cancer (EORTC) and the Medical Research Council (MRC) Clinical Trials Unit, have shown no significant differences in progression-free & Overall Survival between the group with primary cytoreduction  vs NACT followed by interval cytoreduction.Optimal cytoreduction was  achieved residual tumor <1 cm in 41.6% of patients after primary cytoreduction and 80.6% of the patient after interval cytoreduction. Postoperative death (within 28 days of surgery) and surgical morbidity were lesser in the interval cytoreduction surgery group.

The American Society of Clinical Oncology (ASCO) and the Society of Gynecologic Oncology (SGO) recommend that for women who have a high perioperative risk profile or women who are fit for PCS but are deemed unlikely to have cytoreduction to <1 cm (ideally to no visible disease) by a gynecologic oncologist, NACT is recommended over PCS. NACT is associated with less peri- and post-operative morbidity and mortality and shorter hospitalizations.

AIMS AND OBJECTIVES: To evaluate role of Neoadjuvant chemotherapy, to assess the pros & cons and to compare the mortality & morbidity with primary debulking surgery in epithelial ovarian cancer.

Place of Research Work: IPGMER -SSKM H, Kolkata, WB, India. Broad Area: Clinical, Research, Academic. Specific Area: Gynecology-Oncology. Proposed Primary Investigator: Professor Sarbeswar Mandal, Department of OBGY. Duration of Study: March 2021-August 2022Study Design: Prospective randomized control study, Clinical Trial. The study population was divided into two groups: Group A- Neoadjuvant Chemotherapy followed by Interval debulking Surgery Group B- Primary Debulking Surgery P- Patients the 60( Sixty) having Epithelial Ovarian Cancer. I-Gr-A( 30) underwent 6 cycles of chemotherapy with Paclitaxel and Carboplatin followed by Interval Debulking Surgery. C-Gr- Gr-B(30) underwent Primary Debulking surgery. O- To evaluate role, to assess and compared its outcomes , mortality & morbidity in both the groups. T- Time(1&1/2 years) CASE SELECTION:-Women suspected or diagnosed with Ca Ovary based on history, examination and investigations. HISTORY: The symptoms of ovarian cancer can be difficult to recognize, particularly early on. They’re often the same as symptoms of less serious conditions, such as Irritable bowel syndrome (IBS) or PMS (pre-menstrual syndrome).The most common symptoms of ovarian cancer are -Nonspecific, Like abdominal distension, pelvic discomfort, loss of appetite INVESTIGATIONS: Imaging studies like USG(TAS or TVS), CT SCAN, MRI, CHEST X-RAY, FNAC, USG or CT guided biopsy, laparoscopic biopsy, Genetic mutation study(BRCA 1 &2).Serum levels of CA-125, CEA, CA19. INCLUSION CRITERIA:- Taking RMI (RISK MALIGNANCY INDEX) > 200[RMI = U (ultrasound score) × M (menopausal status) × serum CA125 (kU/L)],ROMA [Risk of Ovarian Malignancy Algorithm]->1.4% for premenopausal women and >29.9% for postmenopausal women and HPE proven ovarian malignancy. EXCLUSION CRITERIA:1.Poor general condition. 2.Uncontrolled infections. 3.Thrombocytopenia. 4. Bleeding diathesis.5.Terminal or sub terminal kidney functions.6. Severe coronary heart disease(NYHA stage 3&4).7.Liver cirrhosis Child B &C. 8.Anemia (Hemoglobin<10) DATA ANALYSIS: The outcomes of individual groups analyzed as- *PRIMARY OUTCOME: margin clearance in cytoreduction surgery, postoperative recovery rate, intraoperative complications, duration of surgery, pain relief, symptom relief. *SECONDARY OUTCOME: Wound complications, hospital stay and recurrence rate were Tabulated and statistical significant calculated by GRAPH-PAD SOFTWARE.

In our study among the 60( Sixty) patients selected for the study as per inclusion and exclusion criteria, of which Gr-A( 30) underwent 6 cycles of chemotherapy with Paclitaxel and Carboplatin followed by Interval Debulking Surgery while Gr-B(30) underwent Primary Debulking surgery.In our study the majority of patients in the NACT group were in FIGO stage 3&4, the age group 50-60 yrs(48%) and ~96% were post menopausal, 75% of patients in the NACT arm had as ascetic fluid positive for M-cells and was statistically significant on comparison with the PDS. The  multiple mesenteric nodules, omental caking and bladder/ bowel invasion was seen in NACT group and showed significant difference to the PDS group. In NACT group with complete all six cycles of chemotherapy with Paclitaxel and Carboplatin,  revealed 73% reduction was seen in the incidence of omental caking and peritoneal nodules as compared to the PDS group and was statistically significant.The incidence of optimal cytoreduction (R0 + R1) in NACT group was relatively higher,the incidence of recurrence was much lower in the NACT as compared to the PDS but patients receiving NACT reported anaphylaxis, neutropenia( treated with Filgrastin) and anemia. Among the markers (CEA ,Ca19.9, Ca125) in NACT the CA125 levels before and after NACT showed  statistically significant (p<0.001).The overall survival was  in both groups with( 80% -NACT group & 86.7% -PDS group),Progression Free Survival was (79.3% in NACT group & 86.7% in PDS group)but no statistical significance. The Overall Survival in both groups was dependent on the stage of tumor (better with stage 1&2 as compared to advanced malignancy),was decreased in patients with existing co-morbidities. Progression Free Survival showed  in relation with histological type, grade of tumor and was most favorable in  Mucinous Adenocarcinoma.

Table-1

Dewdney et al. represented few cycles neoadjuvant chemotherapy given prior to tumor cytoreductive surgery in  suitable  patients with advanced ovarian cancer  achieved 70%-80% and 40% ~ 50% achieved clinical complete remission. McClug et al. confirmed neoadjuvant chemotherapy has several advantages.In line with several studies, we observed a dramatic increase in optimal cytoreductive rates in patients treated with NACT-IDS compared to PDS. However no survival benefits were observed. Progression free survival showed no difference either with NACT. The majority of studies have  demonstrated similar progression free survival (PFS) and overall survival (OS) between patients treated with NACT and PDS.

In our study, the patients’ base-line characteristics were well balanced. We found a higher rate of optimal  cytoreduction for patients in the NACT group, but showed no improvement in PFS and OS compared to patients in the PDS group (median PFS:19.3 months vs 13.8 months, P = 0.586; median OS: 25.3 months vs 19.4months, P = 0.812). This observation is consistent with the results observed in the majority of previous studies.

With the improvement of surgical techniques, several previous ‘unresectable’ tumors could now be removed meticulously. In the 2018 SGO annual meeting on women’scancer, Dr. Beryl suggested a new prospective. Recognition of chemoresistant properties based on initial tumor biology and molecular phenotype in advance is complicated.

The role of Neoadjuvant chemotherapy in advanced epithelial ovarian carcinoma with metastatic deposits is reinforced in our study.But in case of early stage tumors with respectable mass, no advantage in terms of progression free survival was observed. Further studies regarding platinum sensitivity would enhance patient selection for NACT in early stage cancers.

LIMITATIONS:1. Follow up was limited to one year. 2.Quality of life could not be assessed for patients receiving NACT.3.Recruited patients mostly had advanced stage disease( stage 3&4) associated with poorer prognosis.

In conclusion, among patients with epithelial ovarian cancers, overall survival after Neoadjuvant Chemotherapy with Paclitaxel and Carboplatin is similar to those undergoing primary debulking surgery followed by adjuvant chemotherapy. Although, Neoadjuvant chemotherapy is associated with better margin resection in advanced ovarian cancer, especially those with Omental caking and peritoneal metastases. It is not inferior to primary debulking surgery in terms of progression free survival. In order to decide outcomes it depends upon factors like stage of disease, associated co morbidities and presence of metastatic deposits.Complete cytoreduction remains the most important prognostic factor and must remain the final goal with either mode of treatment.

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