Effect of three therapeutic strategies for FIGO stage IB2/IIA2 cervical Cancer CURRENT STATUS: POSTED

Background: To evaluate the long-term efficacy and three Methods : 206 patients with stage IB2/IIA2 cervical cancer were selected in this retrospective study. The patients were classed into three groups according to the primary therapy: primary surgical treatment (PST), neoadjuvant chemotherapy followed by radical surgery (NAC+RS), and concurrent chemoradiotherapy (CCRT). We observed the inter-group differences in patient characteristics, surgery approaches, postoperative rick factors, supplemental therapies and overall survival (OS), disease-free survival (DFS) and acute and late toxicities. Results: Less patients in NAC+RS group had deep cervical stromal invasion than those in PST group (p=0.024). No differences in lymph node metastasis, intravascular tumor embolus, vaginal margin and the need of postoperative supplement treatment were observed between PST and NAC+RS ( P =0.734, P =0.704, P =0.487 and P =0.714, respectively). With a median follow-up time of 57 months, the 3-year DFS and OS in PST, NAC+RS and CCRT were 85.6%, 79.2%, 85.7% and 87.5%, 84.9%, 85.7% ( P =0.424 and P =0.856, respectively). The most frequently observed acute toxicities were hematologic side effects. No significant inter-group differences in leukopenia, neutropenia, thrombocytopenia and anemia were observed (all P >0.05). No patient experienced grade 3-4 hepatotoxicity and nephrotoxic. Late toxicity ≥grade 3 mainly consisted of lower extremity lymphedema (4/104, 3.8%), bowel obstruction (3/104, 2.9%) and thrombosis (1/104, 1.0%) in PST, lower extremity lymphedema (5/53, 9.4%) and bowel obstruction (1/53, 1.9%) in NAC+RS and proctitis (4/49, 8.2%) and femoral head necrosis (1/49, 2.0%) in CCRT. No grade 5 toxicities were observed. There was no significant difference in cumulative late adverse effects rate in the three groups ( P =0.777). The patients in NAC+RS had increased hospitalization cost than that in PST ( P =0.000) and CCRT ( P =0.000) and prolonged hospitalization time than that in PST ( P =0.000) and same as that in CCRT ( P =0.07).

NAC+RS would need longer hospitalization time and cost more. Nevertheless, we believe it should be further explored in prospective trials.

Background
Cervical cancer is one of the common malignant tumors that affect the health of females all over the world [1]. Concurrent chemoradiotherapy has been the standard treatment of locally advanced cervical cancer (LACC) since 1999 [2][3][4][5][6]. However, 25% to 40% of patients still experience relapse, and some experience distant failure despite local control after chemoradiation [7]. Patients with tumors measuring >4 cm in the largest diameter have a worse prognosis compared to those with smaller tumors, regardless of treatment [8,9]. Additionally, the optimal therapeutic strategies for patients with stage IB2/IIA2 cervical cancer remains controversial. Since the 1980s, neoadjuvant chemotherapy (NAC) followed by radical surgery (RS) or Concurrent chemoradiotherapy (CCRT) has been proposed and carried out for LACC [10][11][12]. The rationale for NAC is that this approach would reduce tumor volume, kill subclinical lesions, increase tumor resectability, eliminate micrometastases, and has received widespread attention. In addition, chemotherapy given in the neoadjuvant setting might be more effective, partly because it is delivered to uncompromised tumor blood supply and to a population of chemosensitive tumor cells. Therefore, it has emerged as an alternative option of treatment based on several studies that have shown a significant benefit of NAC+RS over radiotherapy alone or concurrent chemotherapy in terms of overall survival (OS) and disease free survival (DFS) [13,14]. On the other hand, some studies have reported inconsistent findings regarding the outcomes of NAC [15,16].
Therefore, the aim of this study was to evaluate the long-term efficacy and toxicities of three As anti-emetic agents, the combination of a steroid and ondansetron hydrochloride or granisetron hydrochloride was administered before chemotherapy. Prophylactic use of recombinant granulocyte colony-stimulating factor was not allowed.

Evaluation during treatment and Follow-up
All patients were evaluated once a week during treatment. At the completion of treatment, patients were evaluated clinically and radiologically using a contrast-enhanced CT scan or MRI of abdomen and pelvis. Then patients were follow-up every 3 months during the first 2 years, every 6 months from 3 to 5 years, and every 1 year thereafter. Acute and late treatment-related morbidities were assessed according to the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. The surgical approach, hospitalization time and treatment cost were also recorded.

Statistical analysis
Statistical comparisons of inter-group differences in characteristics and the post-operatic adjuvant therapy rate, as well as the incidence of acute and late toxicity, were performed using the Chi-square test or Fisher exact test. Hospitalization time and treatment cost in three groups were compared by variance analysis. Survival was analyzed using the Kaplan-Meier method and log-rank test. All data were analyzed using the SPSS Statistics 22.0. P < 0.05 was considered statistically significant.  High-risk factors (HRFs) predictive of supplement treatment Less patients in NAC + RS group had deep cervical stromal invasion than those in the PST (P = 0.024).

Patients And Baseline Characteristics
No differences in lymph node metastasis, intravascular tumor embolus and vaginal margin were observed between PST and NAC + RS group (P = 0.734, P = 0.704 and P = 0.487, respectively). There was no difference in the rate of postoperative supplement treatment (P = 0.714) ( Table 2).  (Fig. 1).

Patterns Of Treatment Failures
There     Table 4. significantly less in the NAC group compared to the DS ( directly with surgery) group (P = 0.002), but there was no difference in lymph node metastasis (P = 0.698) or positive parametrial involvement (P = 0.469) [18]. The rate of postoperative radiotherapy in the NAC group was lower than that of the DS group, although the difference was not significant (58.9% vs. 63.3%, P = 0.472). In the present study, the rate of deep stromal invasion in NAC group was significantly lower than that in the PST group, while no significant difference was detected in lymph node metastasis between the two groups. This finding is consistent with the literature [18] and indicates that NAC is effective in reducing risk factors of recurrence. A meta-analysis by Kim et al. showed that the use of NAC in FIGO stage IB1-IIA cervical cancer decreased the incidence of risk factors such as large tumor size (≥ 4 cm) and lymph node metastasis when compared to radical surgery in all studies and randomized controlled trials (RCTs) [19]. As a result, NAC reduced the need for adjuvant radiotherapy. In our study, although the NAC group was superior to the PST group in terms of deep stromal invasion, the groups did not differ significantly with respect to other high-risk factors. Additionally, we observed no inter-group differences in the rates of supplemental radiotherapy and chemotherapy. We might thus consider that the standards used to determine the need for adjuvant treatment may not have been uniform.
Additionally, a local tumor with a largest diameter > 4 cm is itself a risk factor for recurrence.
Therefore, the gynecologic oncologist may still opt for supplemental therapy even in the absence of  [20]. In the present study, the main acute adverse effect was hematology toxicity but no significant differences in the three groups were observed. The inconsistence to other studies may be attributed to different chemotherapy regimens. Accumulative incidence of grade 3-4 late adverse effects in the three groups were not high and the inter-group difference was not significant.
Impact on long term toxicity and quality of life remained to be proven.
Several retrospective analyses suggest that prolonged RT treatment duration has an adverse effect on outcome [21][22][23][24][25]. Extending the overall treatment beyond 6 to 8 weeks can result in approximately a 0.5-1% decrease in pelvic control and cause specific survival for each extra day of overall treatment time. Thus, it is generally accepted that the entire RT course (including both EBRT and brachytherapy components) should be completed in a timely fashion (within 8 weeks). In the present study, the average overall treatment time was less than 8 weeks and met the requirement of designed proposal. Although there was no study to explore the impact of treatment time of NAC followed by RS on tumor control, we found that NAC + RS prolonged the treatment time and as a result increased the hospitalization cost than that in patients treated with CCRT. The impact of treatment time and expenditure on clinical outcome remained to be proven.
This study has some limitations. One limitation is that it is a small sample single-center retrospective study. The follow-up period is not enough. Because the original text did not provide enough data, no analysis was done about response rate, which is the most important prerequisite for improvement of curative effects. Quality of life was not prospectively measured. Randomize trials need to be conducted to explore the effect on clinical outcome in patients with different treatments.

Conclusion
Preoperative NAC decreased the incidence of deep cervical stromal invasion but had no effect on