1. Introduction

According to the World Health Organization (WHO), cervical cancer is the fourth most common cancer in women worldwide [1]. In 2018, 570000 new cases were estimated with 311000 cases of death. 85% of these cases were in low-income countries. Cervical cancer is the second most common cancer in Moroccan females [2]. The management of locally advanced cervical cancer (Ib2-IVA) is based on concomitant chemoradiotherapy and endocavitary brachytherapy [3]. Adjuvant radiotherapy with or without concomitant chemotherapy is indicated whenever there are anatomo-pathological risk factors in the surgical specimen [4]. When brachytherapy is not feasible (non-catheterizable cervix, large residual tumor, patient's refusal...) an additional 20 to 24 Gy by external radiotherapy is an alternative [5]. Conformational radiotherapy has allowed loco-regional control of the disease at the expense of digestive, bladder and hematopoietic toxicity [6]. Concomitant chemotherapy aggravates acute and late grade III and IV toxicity by 34% and 21%, respectively [7]. In the 2000s, Intensity-Modulated RadioTherapy (IMRT) reduced digestive and hematologic toxicity while maintaining a consistent coverage of the planning target volume [8]. Indeed, the study by Roeske et al. (2000) compared the simulation of three-dimensional radiotherapy (3DRT) treatment with that of IMRT treatment. The latter technique allowed a better conformation of the dose prescribed to the PTV and a reduction of 25% to 13% of the volume of the small bowel which received a dose higher than 45 Gy. Moreover, the IMRT increases the OARs volumes that irradiated by low doses and intermediate doses

between 15 Gy and 30 Gy [9]. Another study by Lukovic et al. (2016) compared a simulation of IMRT and 3DRT adjuvant therapy in patients undergoing cervical or endometrial tumor. The results were in favor of IMRT by ensuring better compliance with PTV (p <0.001) and a significant decrease in the dose of the OARs mainly the V_45Gy of the small bowel (p = 0.005) [10]. Comparison of static and dynamic IMRT by Renard et al. (2012) was significantly in favor of VMAT treatment with better coverage of PTV (p = 0.01), better intestinal savings (p = 0.01) and a reduction in volume receiving 20 Gy (p <0.001). The VMAT also reduced processing time and monitor units (p = 0.0001) [8]. The meta-analysis of Wei et al. (2018) analyzed the results of eight studies comparing the dosimetry of arc-therapy and IMRT in patients with locally advanced tumors between 2008 and 2018. Arc-therapy has resulted in better rectal preservation with a decrease in V_40% (SMD = 0.27, 95% CI = -0.49, -0.05), monitor units (SMD = -9.52, 95% CI = -14.49, -14.35) as well as treatment time (SMD = -10.11, 95% CI = -14.16, -5.96) [11].

The first VMAT treatment in North Africa is carried out at Al Kindy Oncology Center in Casablanca, Morocco, since 2011. The treatment of cervical cancer by arc-therapy is performed when the financial means of the patients allow it. After an MRI evaluation at the end of external radiotherapy and when the brachytherapy is deemed not feasible, an additional 20 Gy by arc-therapy is performed. The objective of this study was to compare 50 Gy dosimetry data between conformal and arc-therapy treatments as well as to evaluate the contribution of 20 Gy supplemental therapy by arc-therapy on both treatment plans.

2. Materials and Methods

The medical records of 20 patients supported for uterine cancer treated exclusively by concomitant chemoradiotherapy without surgery or brachytherapy were selected. The age of the patients was 37 to 74 years with an average of 59.33 years. According to the FIGO 2018 classification, the tumor was classified: IIA = 2 cases, IIB = 4 cases, IIIA = 4 cases, IIIB = 5 cases, IIIC1 = 4 cases and IVA = 1 case. Twelve of the patients studied had a dose of 70 Gy by arc-therapy, the remaining patients had a dose of 50 Gy 3DRT followed by a supplement of 20 Gy arc-therapy treatment. Patients were in a supine position with their arms on their chest, their feet fixed by a footrest and foam under their knees. The bladder was comfortably full and the rectum was empty (3 days of laxatives). A spiral computed tomography (CT) image acquisition in thin-slice scanning with thicknesses of 2.5 mm. The acquisition of the scout scan is acquired between L2-L3 at the top, and 2 cm below the small trochanter at the bottom.

The delineation of the target volumes and organs at risk OAR was the same for both techniques by following the recommendations of ESTRO and ICRU. Gross Tumor Volume (GTV) is clinically defined and by MRI. It includes cervical, vaginal, uterine, parametrial tumor extensions and macroscopically affected lymphadenopathies. The Clinical Target Volumes (CTV) includes in addition to the GTV the whole uterus, the parameters up to the wall and the vagina according to the stage of its invasion. Ganglion CTV includes internal and external iliac areas, obturators and primitive iliac. Pre-sacral ganglion areas are included in CTV if pelvic lymph nodes or parametres are reached, and inguinal areas are taken in CTV if the vagina is invaded in its 1/3 below. The planning target volume PTV1 includes CTV with a margin of 1.5 cm in 3DRT and 1 cm in VMAT. The PTV2 corresponds to the GTV with a margin of 10 mm. The delineated OARs are the rectum, the bladder in its entirety, the femoral heads. The small bowels with the peritoneal cavity is contoured only for series treated by arc-therapy.

The Treatment Planning System (TPS) used for all the treatment plans is Eclipse version 13.5 of Varian Medical System. VMAT arc-therapy consisting of two coplanar arcs from 180.1° to 179.9° and from 179.9° to 180.1° with clockwise and counterclockwise rotation, respectively. Collimator angle was selected between 30 and 45 degrees to cover the entire PTV with photon beam energy of 6MV. The 3DRT planning consisted of the four-field box.

The prescribed dose was 50Gy (25 fractions of 2 Gy) to PTV1 given by 3DRT or by arc-therapy. A supplement of 20 Gy is added to PTV2 by arc-therapy. The primary objective of the constraints was a good coverage of the planning target volumes by 95% reference isodose. Dose constraints for OARs are summarized in Table 1.

Table 1: OARs dose constraints.

From Dose-Volume Histograms (DVH), we noted for the PTV the D_98%, D_95%, D_50%, D_5%, D_2% the V_99% and V_total. For the rectum, bladder and small bowel we collected the V_10Gy, V_20Gy, V_30Gy, V_40Gy, V_50Gy, V_60Gy and D_max. The femoral heads will be evaluated on V_15Gy and D_max. The dosimetric values of both techniques were exploited by the IBM SPSS Statistics 25 system.

2.1 Monitoring and toxicity

During radiotherapy, a weekly consultation was conducted to evaluate the toxicity and acute complications of the treatment. Then, at the end of the first series, a clinical examination and an MRI were done. Once the brachytherapy was considered not feasible the 2nd series of radiotherapy was performed. A follow-up consultation was conducted every three months in the first two years and then every six months for five years. An MRI of control was requested at the first consultation then annually.

3. Results

The coverage of the planning target volume by 3DRT and VMAT is summarized in Table 2. These results show that there is no difference between these two techniques. For, the homogeneity index was close to 0 (0.068 for 3DRT vs 0.090 for VMAT). As for the conformity index, it tended to 1 (0.99 for 3DRT vs. 0.98 for VMAT) with a slightly significant p = 0.039. For organs at risk, Arc-therapy had reduced the bladder irradiated volumes by doses greater than 50 Gy (p = 0.01). It allowed a better rectal saving concerning volumes V₃₀, V₄₀ and V₅₀ significantly (Table 3). When with femoral heads, there is no significant difference between conformal radiotherapy and arc-therapy.

Table 2: Dosimetric comparison of RT3D and VMAT treatment plans of 50 Gy for PTV.

Table 3: Dosimetric comparison of RT3D and VMAT treatment plans of 50 Gy for OARs.

The addition of a 20 Gy complement dose by arc-therapy after 50 Gy by 3DRT allowed PTV2 coverage to be similar to that achieved by arc-therapy alone (Table 4). In addition, this supplement did not bring any significant benefit to the organs at risk. Indeed, the Arc-therapy allowed a better bladder, rectal and small bowels savings with clearly significant p (Table 5).

Table 4: Dosimetric comparison of RT3D and VMAT treatment plans of 70 Gy for PTV.

Table 5: Dosimetric comparison of RT3D and VMAT treatment plans of 70 Gy for OARs.

3.3 Evolutions and toxicities

All patients completed their radiotherapy protocol. No acute complications of grade III or IV were recorded during the first series. A case of cystitis and neutropenia grade III has been reported after 50 Gy in a patient's FIGO stage IVA. The median follow-up after the end of radiotherapy was 45 months. The progression was marked by a locoregional recurrence rate of 30% (25% in the Arc-therapy arm vs 37% in the 3DRT arm) and by a metastasis of 8.33% in the arc-therapy arm. Locoregional and metastatic relapses were more frequent in stage III compared to stage II (46.15% vs 33.33%). A case of chronic grade III cystitis was reported in a patient's FIGO stage IVA. We also recorded a death rate of 30% (25% in the Arc-therapy arm vs 37% in 3DRT arm).

4. Discussions

In a Japanese study, Roeske et al. (2003) compared arc-therapy with 3DRT. This study did not report any significant difference in terms of coverage of the PTV (D_95% = 94.5% vs 95.1% and D_98% = 102.1% vs 102%). For the complement by arc-therapy on the high-risk CTV, it recommended a PTV greater than one centimeter considering the important mobility of the uterus in intra and inter-fractions [12]. Several other studies have confirmed these results [13, 14, 15]. In our series the complement by arc-therapy after 50Gy was done with a 1 cm PTV2 around the high risk CTV. The results found are similar in both arms. They allow a homogeneous coverage and a good conformation of the target volumes.

In our series the complement by external radiotherapy was decided after the end of the 50Gy and consequently it was not possible to deliver on the tumor volume at high risk that 70 Gy in 35 sessions of 2 Gy. This approach does not allow to reach the recommended high-risk CTV doses of 80 to 90 Gy. Indeed, in a purely theoretical approach Guerrerro et al. were able to deliver doses equivalent to 60, 70 and 80 Gy in the tumor with fractions 2.4, 2.8 and 3.2 Gy in 25 sessions taking into account the biological equivalent dose on OARs [16]. Currently, in arc-therapy the Simultaneous Integrated Boost (SIB) is promising that the sequential boost in terms of dose distribution on the target volume (p <0.05) [17].

In a comparative study of the adjuvant treatment of gynecologic cancers by 3D radiotherapy and IMRT (45 to 50.4 Gy), Lukovic et al. (2016) showed that IMRT significantly reduces the volume of all organs at risk [18]. Indeed, the V₄₅ was reduced by 77% for the bladder and 63.7% for the rectum. In our study the arc-therapy reduced the V₅₀ of the bladder by 85%. For the rectum the contribution of the arc-therapy was largely significant on the DVH by reducing V₃₀ by 26.6%, V₄₀ by 36.6% and V₅₀ by 89%.The results of our study show that after 50 Gy of 3D radiotherapy a 20 Gy supplement by arc-therapy is not as beneficial as the exclusive arc-therapy at 70 Gy. Indeed, the arc-therapy has minimized considerably irradiation of organs at risk. For the small bowel, it reduced toxicity by reducing V₄₀ by 61.4%, V₅₀ by 75% and V₆₀ by 77%. For the bladder and rectum the arc-therapy also reduced the V₅₀ and V₆₀ by 25 to 46%. Similar results have been published by Portelance et al. [19] regarding the reduction of 30-70% doses to OARs by IMRT compared to conventional radiotherapy.

Grade III gastrointestinal acute toxicity and grade III and IV hematologic toxicities [20] were reported by Dang et al. (2018). It represented respectively 8.1%, 39% and 5.4%. In our series we recorded 5% grade III acute hematologic toxicities. According to published studies, late gastrointestinal toxicity was 3% to 4%. For cystitis grade III, it ranged from 2% to 5.6%. Whereas, for grade III proctitis, it was around 11%. In our study, we recorded only 5% grade III cystitis [21, 22, 23].

5. Conclusion

This work aims to compare dosimetry treatment plans by conformal radiotherapy and arc-therapy for cervical cancer. The results obtained show that the arc-therapy allows a better conformity, coverage and homogeneity of the PTV. It also allows better preservation of organs at risk such as the rectum; bladder and small bowel thus reducing the acute and late toxicities of treatment. Arc-therapy would be a better therapeutic alternative when brachytherapy is not feasible. It could improve the patient’s life quality.

Conflicts of Interest

All authors declare no conflict of interest.

Acknowledgements

We would like to thank all the staff of the Oncology and Diagnostic Treatment Center Al Kindy in Casablanca who

helped us to realize this Study.

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