Introduction

Cytotoxic chemotherapy is an integral component in the management of various gynaecological cancers either as adjuvant therapy after primary treatment, that is, surgery or radiation, or as primary or upfront therapy called neoadjuvant chemotherapy (NACT) for advanced stage prior to surgery (epithelial ovarian cancer, EOC) or radiation (cervix cancer). The rationale behind using NACT in advanced EOC is to reduce tumour size making inoperable advanced disease operable, increasing the optimal debulking rate and reducing the post-operative morbidity as compared to primary surgery . In the case of carcinoma of the cervix, the use of NACT is based upon the principle that (i) chemotherapy may shrink the primary tumour making malignant cells sensitive to subsequent radiotherapy (RT), (ii) uncompromised blood flow in radiation-naïve patients results in higher chemotherapy drug concentration at the tumour site compared to patients pretreated with radiation and (iii) chemotherapy can eradicate micro-metastatic disease. However, a delay of the definitive treatment, that is, radiation, and selection of resistant clone are potential disadvantages of NACT . Apart from locally advanced (FIGO, IIB–IVA) cervix cancer, the role of NACT has also been explored in patients with early stage (FIGO, IB–IIA) prior to surgery or radiation. We have made an attempt to review the present status of NACT in various gynaecological cancers with a focus on EOC and carcinoma of the cervix.

Cancer ovary

EOC remains the major cause of gynaecological cancer-related mortality in developed countries reflecting advanced stage (III–IV) at presentation. A primary debulking surgery (PDS) with the goal of optimum cytoreduction followed by paclitaxel plus carboplatin-based chemotherapy is currently the standard treatment approach. Various retrospective and prospective studies have established an inverse relationship between residual tumour diameter and patient’s survival . Patients without visible residual tumour have a better survival than those with a residual mass as large as <0.5 cm, who in turn have a better outcome than those with 0.5–1.5-cm residual tumour . Therefore, an aggressive surgical approach in order to achieve optimum cytoreduction has been recommended . It remains debatable whether the better outcome is due to surgeon’s expertise or tumour location and its biology ( Table 1 ). For example, in practice, in some patients, bilateral salpingo-oophorectomy and omentectomy alone can render optimal cytoreduction. In others, bowel resection, peritoneal/diaphragmatic stripping or en bloc resection of the ovaries, uterus and sigmoid colon may be required for optimal debulking, and this may be associated with considerable morbidity. Further, aggressive surgery can be performed with minimal morbidity in some patients by some surgeons; however, for many surgeons and patients, morbidity can be substantial with serious operative (haemorrhage, shock, fistula formation and death) and prolonged post-operative recovery and complications approaching up to 70% . This may also delay post-operative chemotherapy.

The definition of optimum debulking has undergone a change over the last three decades, from residual disease as ≤2 cm by Griffith et al. in 1978 to ≤ 1cm by the Gynecologic Oncology Group in the last decade to ‘no visible residual tumour’ in recent studies . The vast majority of literature published from North America and Europe have shown that 15–30% of patients can be optimally debulked (no visible tumour) to microscopic residual disease . In view of this, many investigators have used upfront NACT as an alternative to primary surgery with the goal of improving surgical quality. Table 2 compares the potential advantages of primary debulking surgery (PDS) and upfront NACT.

Cancer ovary

EOC remains the major cause of gynaecological cancer-related mortality in developed countries reflecting advanced stage (III–IV) at presentation. A primary debulking surgery (PDS) with the goal of optimum cytoreduction followed by paclitaxel plus carboplatin-based chemotherapy is currently the standard treatment approach. Various retrospective and prospective studies have established an inverse relationship between residual tumour diameter and patient’s survival . Patients without visible residual tumour have a better survival than those with a residual mass as large as <0.5 cm, who in turn have a better outcome than those with 0.5–1.5-cm residual tumour . Therefore, an aggressive surgical approach in order to achieve optimum cytoreduction has been recommended . It remains debatable whether the better outcome is due to surgeon’s expertise or tumour location and its biology ( Table 1 ). For example, in practice, in some patients, bilateral salpingo-oophorectomy and omentectomy alone can render optimal cytoreduction. In others, bowel resection, peritoneal/diaphragmatic stripping or en bloc resection of the ovaries, uterus and sigmoid colon may be required for optimal debulking, and this may be associated with considerable morbidity. Further, aggressive surgery can be performed with minimal morbidity in some patients by some surgeons; however, for many surgeons and patients, morbidity can be substantial with serious operative (haemorrhage, shock, fistula formation and death) and prolonged post-operative recovery and complications approaching up to 70% . This may also delay post-operative chemotherapy.

The definition of optimum debulking has undergone a change over the last three decades, from residual disease as ≤2 cm by Griffith et al. in 1978 to ≤ 1cm by the Gynecologic Oncology Group in the last decade to ‘no visible residual tumour’ in recent studies . The vast majority of literature published from North America and Europe have shown that 15–30% of patients can be optimally debulked (no visible tumour) to microscopic residual disease . In view of this, many investigators have used upfront NACT as an alternative to primary surgery with the goal of improving surgical quality. Table 2 compares the potential advantages of primary debulking surgery (PDS) and upfront NACT.

Upfront NACT

This approach utilizes three to four cycles of chemotherapy followed by interval debulking surgery (IDS); optimal cytoreduction (≤1 cm) in 60–94% of patients has been reported. Operative morbidity is reduced with decreased blood loss, decreased intensive care unit (ICU) and post-operative hospital stay and reduction in post-operative infections. Overall (OS) and progression-free survival (PFS) of such patients is comparable to those treated with the standard approach, that is, PDS followed by chemotherapy. Prior to NACT, core biopsy of the primary tumour or one of the metastatic sites must be performed and is considered the gold standard. Fine-needle aspiration cytology (FNAC) along with a CA-125/CEA ratio >25 is also acceptable .

Patient selection : In most studies, the criteria used for selection of patients for NACT include poor performance status (ECOG 3–4), higher age (>70 years), patients with significant co-morbid conditions rendering anaesthesia highly risky, massive pleural effusion or large volume ascites, features of subacute intestinal obstruction, those with evidence of liver or splenic and pleural deposits etc. .

Upfront debulking surgery versus NACT: randomized trials

Table 3 presents the trial design, eligibility criteria and end points used in the four randomized trials . Of these, results of EORTC study were published in 2010. In this multicentre study, 670 patients with advanced ovarian cancer were randomized between PDS versus NACT. After three cycles of chemotherapy, 90% of patients in the NACT arm underwent IDS. A Median survival of 29 or 30 months was reported regardless of the initial assigned group. In the multivariate analysis, complete resection of all macroscopic tumours at IDS was the strongest prognostic factor .

The results of another trial CHORUS (NACT or upfront surgery) were presented in 2013 during the Annual Meeting of American Society of Clinical Oncology. A total of 552 patients with stage III–IV EOC were randomized. The primary outcome was overall survival, the secondary outcome being toxicity and quality of life (QOL). Complete resection was achieved in 16% of patients in the PDS arm versus 40% in the NACT arm. Grade 3–4 post-operative adverse events were 24% versus 14%, and deaths (5.5% vs. 0.5%) within 28 days of surgery were more in the PDS arm. The median survival was 22.8 and 24.5 months, respectively . Data from the JCOG trial were presented in part recently at the American Society of Clinical Oncology meeting (2014). The frequency of bowel or organ resection was lower in the NACT arm ( p < 0.01), and operative morbidity, for example, blood/ascites loss ( p < 0.01) and albumin transfusion ( p < 0.01) were lower in the NACT arm. The authors concluded that NACT is less invasive compared to the PDS arm; survival data are likely to be mature in the year 2016 .

QOL in patients treated with NACT

QOL is one of the important parameters for evaluating cancer treatment outcomes. Few studies have shown better QOL in patients treated with NACT . In the EORTC study, survival and QOL after NACT followed by IDS was similar to survival and QOL after PDS followed by chemotherapy. However, institutions with good QOL compliance had better survival outcomes . Future prospective randomized clinical trials comparing NACT with PDS should address QOL issues in both groups apart from comparing survival, morbidity, mortality and optimal debulking rate.

Role of Imaging: A number of investigators have used computed tomographic (CT) scan to identify patients likely to benefit from PDS. CT scan criteria used to define unresectability or to predict suboptimal debulking in these studies include parenchymal liver metastasis, diffuse peritoneal thickening, bowel mesentery involvement, extensive diaphragmatic disease, disease at porta hepatis, splenic hilum, peritoneal carcinomatosis with greater than the estimated 1000-g metastatic load, diaphragmatic plaques >2 cm or bulky suprarenal para-aortic nodes . However, false-positive rates of CT scan to predict surgical outcome can be as high as 60% when a single site is taken into account . Few major studies, their sensitivity, specificity, positive predictive value and negative predictive value are given in Table 4 . Suidan et al. recently reported results of a prospective, non-randomized trial of two centres involving 669 patients. Based on three clinical criteria (age ≥60 years, CA-125 ≥ 500 U/ml and performance status by the American Society of Anesthesiologists as 3 and 4) and six radiological criteria (e.g., suprarenal retroperitoneal lymph nodes >1 cm, diffuse small bowel adhesions/thickening, lesion (s) > 1 cm small bowel mesentery, lesion >1 cm at the root of the superior mesenteric artery, lesion >1 cm in the peri-splenic area and lesion >1 cm in the lesser sac), they developed a predictive model in which the suboptimal rate was directly proportional to the predictive value score .

Table 4

Prediction of surgical cytoreduction by CT scan: a review of literature.

Author (Ref.)	n	Sensitivity	Specificity	PPV	NPV	Remarks
Nelson et al. (1993)	34	92.3%	79.3%	67%	96%	Low PPV indicates that a substantial number of patients who were thought to have suboptimal debulking underwent optimal cytoreduction. Nineteen percent of the patients were of early stage.
Meyer et al. (1995)	28	58%	100%	100%	76%	Only 18 out of 28 patients were of advanced stage. A score of ≥3 identified patients in whom optimal debulking was not possible.
Bristow et al. (2000)	41	100%	85%	85%	100%	A predictive index score of ≥4 had the highest overall accuracy in predicting surgical outcome at 92.7%. Complex scoring model.
Dowdy et al. (2004)	87	52%	90%	68%	82%	Diffuse peritoneal thickening and large-volume ascites predicted suboptimal surgical resection
Qayyum et al. (2005)	137 (CT + MRI)	76%	99%	94%	96%	CT and MRI are equally effective in detection of inoperable tumour and prediction of suboptimal debulking
Everett et al. (2005)	56	–	–	–	–	Three sites were associated with suboptimal debulking: omentum, parietal peritoneum and ascites.

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