Cervical cancer (CC) represents the fourth leading cause of cancer death in women, with 311,000 deaths in 2018 worldwide (1). Treatment depends mainly on the stage of the tumor at diagnosis, as assessed by the International Federation of Gynecology and Obstetrics (FIGO) 2009 staging system (2). Definitive chemoradiotherapy (CRT) has represented the gold standard of treatment in locally advanced cervical cancer since 1999, with a gain in overall survival (OS) and disease-free survival (DFS) compared to radiotherapy alone. Despite these results, the 5-year overall survival still remains around 70% in this subgroup of patients (3).

Several studies were conducted using neoadjuvant chemotherapy or concurrent chemoradiotherapy followed by radical surgery in order to try to improve outcomes of patients with locally advanced cervical cancer (4–10). The GYNECO 02 trial demonstrated no therapeutic impact of radical surgery following CRT in patients with clinical and radiological complete response after neoadjuvant treatment (8). Cetina et al. compared the role of brachytherapy and radical surgery after CRT, showing no differences in outcomes between the two therapeutic options (9). Indeed, radical surgery after neoadjuvant treatment could be useful removing chemo- and radio-resistant tumor foci, obtaining pathological response to the pre-operative therapy, and determining pathological assessment in the view of a more tailored patient treatment (11, 12).

Several technical innovations have been introduced in the clinical routine of the radiation oncologist (13). Intensity-modulated radiotherapy (IMRT), such as volumetric arc radiotherapy or helical tomotherapy, allows an increase of the dose to the target volume and a reduction of the dose to the organs at risk (OARs), with less acute and late toxicity (14, 15). Therefore, the use of on-board cone-beam or fan-beam CT (image-guided RT, IGRT) in daily practice allows for a daily check of the patient’s setup and a reduction of the margins and consequently of the treatment volumes. Furthermore, conventional IMRT techniques allow the simultaneous delivery of different doses to different target volumes within a single fraction (Simultaneous Integrated Boost - SIB).

The phase I and II LARA-CC-1 trial was set up to investigate a regimen based on gross tumor volume (GTV)-accelerated fractionation and lymph node extended-field (LNEF) irradiation followed by radical surgery. The total dose of 45Gy (2.25Gy/fraction) to macroscopic tumor and 40Gy (2Gy/fraction) to lymph node station was established as the recommended dose, with a complete pathological response to treatment rate of 38.6% (16, 17). In this setting, a subsequent dose escalation study demonstrated that the SIB-IMRT technique is feasible and safe, but it’s unable to safely escalate dose beyond levels already achieved with three-dimensional conformal radiotherapy technique (18).

In this scenario, we retrospectively analyze the efficacy and tolerability of simultaneous integrated boost volumetric modulated arc therapy (SIB-VMAT) associated to cisplatin-based chemotherapy in our preoperative setting of patients with locally advanced cervical cancer.

We retrospectively analyzed the data of 148 patients affected by histologically proven cervical carcinoma with IB2-IVB FIGO 2009 stage. Median age was 49.5 years (range 20-78). One hundred six patients (71.6%) were FIGO Stage IIB, and 62.2% had radiographically positive lymph nodes at staging imaging. We included in our analysis one patient with IVB FIGO stage because of pelvic peritoneal metastasis which were encompassed by the clinical target volume. The majority of tumors were squamous carcinoma (N=128, 86.5%). Patients’ baseline characteristics and treatment details are summarized in Table 1.

Chemoradiation was well tolerated with good compliance. As described in Table 2, no grade 3 or 4 gastrointestinal or genitourinary toxicity were reported. Five patients developed a Grade 3 neutropenia which led to a temporary treatment interruption of a median of 8.5 days (range 0-10).

After imaging restaging, all pts successfully underwent radical surgery.

Pathological response was assessed in all patients receiving surgery: 68 patients (46%) showed pathological complete response (pCR) and 32 patients (21.6%) had a microscopic residual disease. Pathological nodal involvement was observed in 23 patients (15.5%) divided as follow: four patients of the pCR group, four patients of the pR1 group, and 15 patients of the pR2 group. (Table 3)

According to the pathological response to treatment, adjuvant chemotherapy was administered in 40 patients (27%) with pR1-2 and/or nodal involvement, while five patients (3.4%) with pR2N0 underwent endovaginal brachytherapy.

As of July 2021, the median follow-up period was 59 months (range 27-100 months) in the overall series.

At the time of the analysis, the 1-year and 3-year local control (LC) were 88.5% and 78.5%, respectively (median LC: not reached), while the 1-year and 3-year metastasis-free survival (MFS) were 82.9% and 74.5%, respectively (median MFS: not reached). Death due to disease was recorded in 13 patients, with 3-year overall survival (OS) rates of 88.9% (median OS: not reached).

Patients with pathological nodal involvement experienced a statistically significant worse LC, OS, and MFS rate compared to those without positive lymph nodes after neoadjuvant CRT (P <.0001).

Concerning long-term toxicity, 13 patients (8.8%) developed grade 2 genitourinary toxicity, while no late gastro-intestinal or haematological toxicity were documented (data not shown).

Surgery represents the standard treatment for early stage cervical carcinoma, while exclusive chemoradiation followed by brachytherapy is considered the gold standard for locally advanced cervical cancer (3, 21–25). Despite the benefit on overall survival due to radical CRT, local relapse and distant metastasis represented the main cause of failure in LACC treatment (26). Furthermore nodal involvement represents one of the main factors influencing survival (27–29).

Several studies concerning radical surgery after CRT were conducted with the aim of evaluating the efficacy and safety of this kind of treatment and its impact on improving local control. As demonstrated by Classe et al., surgery allows evaluation of the pathological response to therapy and improves local control in the case of partial pathological response (6). This finding is closely associated with the clinical trend and allows for the evaluation of personalized prognostic profiles that lead to the definition of specific surveillance procedures or further treatments. A 2018 Meta-analysis showed that radical surgery following CRT seemed to reduce the risk of local recurrence compared to radical CRT followed by brachytherapy (30). Probably the data are due to the eradicating role that surgery could have on the residual cervical cancer or on the residual lymph node involvement after CRT.

Ferrandina et al. showed that the addition of concomitant boosts in accelerated fractionation modality to whole pelvis CRT followed by radical surgery results in a high rate of pathologically assessed complete response (50.5%) and a very encouraging local control rate, with an acceptable rate and profile of toxicity (31). The high tolerability and efficacy of this accelerated regimen was also confirmed by Macchia et al. in 2012, with a total of 59.1% complete/microscopic response to treatment (17).

In our series, pathological complete response rate combining both pCR and pR1 was 67.6%. These encouraging results could be related to the technological improvement that has led to the use of an accelerated regimen which allowed us to an intensification of the total dose at site of macroscopic disease through the use of SIB-VMAT and a reduction of treatment time with an increase in the effectiveness. This hypothesis is also supported by a previous study in which 45 Gy as a concomitant boost CRT delivered by a 3D technique did not seem sufficient to increase pCR rate (17).

As far as the primary and secondary endpoints are concerned, we reported 3-year local control, metastasis-free, and overall survival of 78.5%, 75%, and 89%, respectively. These rates are in the range reported in previous studies using different multimodal therapeutic approaches to LACC patients (3, 17, 18, 31, 32).

The retrospective nature represents a limit of the present paper, and has to be considered in toxicity evaluation. Another limitation of the study, moreover, is represented by the impossibility of performing a statistical analysis between the different stages of the disease, due to the limited number of patients: this could be a bias, considering the wide difference in prognosis of the different stages of disease.

No grade 3-4 acute GI and genitourinary toxicity were reported in our series, while only five patients (3.4%) developed grade 3 haematological toxicity that led to temporary treatment interruption. With the limits inherent in the risk of under-reporting, the rate of late toxicity appears quite encouraging comparing to standard treatment, with only 8.8% of genitourinary grade 3 complication. Indeed, several studies on exclusive CRT have reported severe late toxicity ranging from 10 to 18.3% with a predominant pattern of intestinal toxicity (13% grade 3–4 complications), and vaginal toxicity (20% grade 3–4 complications) (33–35).

The reduction of acute GI toxicity compared to literature data could be related to the introduction of intensity modulated techniques and the development of more efficient image-guided radiotherapy protocols (13).

Patients with pathological nodal involvement after CRT experienced statistically significant worse outcomes in terms of local control, metastasis-free survival, and overall survival. These results underscore the need to stratify patients into risk classes in order to pave treatment pathways tailored according to the predicted outcome. Recently, a radiomics model for LACC patients undergoing neoadjuvant CRT was developed analyzing T2-weighted 1.5 T MRI acquired before treatment start, appearing to be a reliable tool in pCR prediction after neoadjuvant CRT (36). Taken into consideration that our study showed a 46% pathological complete response, these response prediction models could play a fundamental role in the management of patients with LACC by identifying patients who could benefit from lower doses, resulting in less toxicity. Based on this assumption, new dose delivery and targeting paradigms could be proposed and better treatment outcomes may be achieved, as already demonstrated in rectal and cervical cancer (36–38).

Neoadjuvant chemoradiation seems to be a promising strategy in the management of locally advanced cervical cancer, with a high rate of pathologically assessed complete response and a very encouraging local control rate with acceptable toxicity. The worst outcome in patients with persistent pathological nodal involvement after neoadjuvant CRT underscored the need for further investigations with the aim of improving outcomes in this subgroup of patients.

In this scenario, it must be acknowledged that the ongoing LARA 4.0 prospective multicentric phase II trial (Eudract number: 2020-002300-40; www.eudract.emea.europa.eu) is testing the efficacy tolerability of simultaneous integrated boost on primary and positive lymph nodes in neoadjuvant CRT for patients with locally advanced cervical cancer.

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

The studies involving human participants were reviewed and approved by Comitato Etico dell’Università Cattolica del Sacro Cuore - Policlinico Universitario A. Gemelli - Roma. The patients/participants provided their written informed consent to participate in this study.

Conceptualization, AN and RA; methodology, LB; validation, GM and MAG; formal analysis, AN and RA; investigation, AN; data curation, SR, AN, NB, MC, and LT; writing—original draft preparation, AN; writing—review and editing, RA, GM, and MAG; visualization, GM, LB, and GF; supervision, VV and MAG; project administration, RA and AN. All authors have read and agreed to the published version of the manuscript.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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