Prognostic value of tumor volume reduction during radiotherapy in patients with locally advanced cervical cancer in different risk groups

Objective: To evaluate the risk factors of patients with locally advanced cervical cancer (LACC) undergoing radical radiotherapy (with or without concurrent chemotherapy) and to assess the prognostic value of tumor volume regression (TVR) based on magnetic resonance imaging (MRI) in different risk groups. Methods: A retrospective analysis was performed on 176 individuals diagnosed with stage IIA-IVA cervical cancer (CC) who underwent radical intensity-modulated radiotherapy in our center between January 2012 and December 2020. The tumor volume before radiotherapy (TVp) and before brachytherapy (TVmid) were evaluated based on three-dimensional MRI images, TVR = (TVp - TVmid)/TVp×100%. Kaplan-Meier curves were used to assess patient’s overall survival (OS) and progression-free survival (PFS). Prognostic factors were identi�ed using Cox proportional hazards models. Results: For the entire cohort, patients with TVR ≥ 94% had better 5-year OS (82.7% vs 49.8%, p<0.001) and 5-year PFS (82.5% vs 51.1%, p<0.001) compared to TVR < 94%. Patients with TVR ≥ 94% were more likely to receive concurrent chemoradiotherapy (CCRT) than those with TVR < 94% (70.1% vs 40.5%, p<0.05). Among patients undergoing CCRT, those with a TVR ≥ 94% had a better prognosis than those with a TVR < 94%. However, among patients who received RT alone, those with TVR ≥ 94% had better PFS but no statistically signi�cant difference in OS. Likewise, among patients with CYFRA21-1 < 7.7 ng/ml, patients with TVR ≥ 94% had a better prognosis. However, TVR was not a prognostic factor in patients with CYFRA21-1 ≥ 7.7 ng/ml. Both CYFRA21-1 (OS, PFS interaction, p<0.001) and FIGO stage (PFS interaction, p=0.035) were found to signi�cantly impact predictive effects of TVR.


Introduction
Cervical cancer (CC) is the most prevalent form of malignancy affecting the female reproductive tract [1], and an estimated two-third of patients present with locally advanced cervical cancer (LACC) at the time of diagnosis [2].The current standard of care for LACC patients is concurrent chemotherapy combined with external beam radiation therapy (EBRT) followed by intracavitary brachytherapy (ICBT) [3,4].With the development of Magnetic Resonance imaging (MRI) technology, we can calculate the tumor volume of cervical cancer before EBRT and ICBT separately; and the ratio of the difference between the two, to the volume before EBRT is de ned as Tumor Volume Regression (TVR) (4,5).Advances in MRI technology in oncology applications have led to the development of precise MRI-based region-of-interest (ROI)-based three-dimensional (3D) tumor volume measurements that correlate with treatment outcomes [5,6].
Current studies have shown that in LACC patients receiving radical radiotherapy, TVR is an important prognostic factor [7].However, the optimal cut-offs of TVR for prognostication reported by different studies vary widely [8][9][10].Moreover, baseline characteristics and treatment details of patients are also not homogenous across different studies, making it challenging to derive an appropriate TVR cut-off, that can be generalized for applicability to routine patients in the clinic.
There also remains pronounced disease-related heterogeneity even among patients exhibiting equivalent TVR levels.The reported 5-year overall survival (OS) rates of CC patients with International Federation of Gynecology and Obstetrics (FIGO) stages II, III, and IV disease are 65-69%, 40-43%, and 15-20% respectively [11,12].Other parameters related to treatment outcomes in CC patients include age, tumor size, and levels of different tumor markers [13,14].Studies exploring the prognostic signi cance of TVR in LACC patients with differing risks of recurrence and mortality are lacking.In addition, whether TVR is a prognostic factor in patients who receive radiotherapy alone as well as concurrent chemo-radiotherapy is yet to be examined.
Given the above, this study aims to identify independent predictors associated with survival outcomes in LACC patients and to explore the prognostic relevance of TVR during radical radiotherapy (with or without concurrent chemotherapy) in patients with different risks of recurrence and death.

Patients
Between January 2012 and December 2020, 176 patients were diagnosed with histo-pathologically con rmed CC (stage IIA-IVA CC at diagnosis) and were restaged in retrospect in accordance with the 8th edition of the FIGO system.To be eligible for inclusion in this study, patients had to meet the following criteria: 1) patients with histologically diagnosed cervical squamous cell carcinoma or adenocarcinoma; 2) patients had undergone pelvic MRI examinations before and during radiotherapy (before ICBT, at 40-45 Gy of EBRT).Patients were excluded if: 1) they had undergone any antitumor treatment prior to their initial evaluation at our hospital; 2) they did not complete planned radical radiotherapy; or 3) they exhibited a small initial tumor volume with fewer than 3 ROI lays and 3D imaging could not be established.This retrospective study was approved by the Institutional Review Board of our hospital, and all patients agreed to the study and signed informed consent.

Treatment strategy
All patients underwent a combination of External Beam Radiation Therapy (EBRT) and high-dose brachytherapy.Clinical target volume (CTV) for EBRT included cervical mass and whole of the cervix, uterus, part of vagina, parametrium, draining lymph nodes (internal iliac, external iliac, common iliac, and presacral).The dose to CTV was 4860-5040 cGy in 27-28 fractions and involved lymph nodes were considered for Simultaneous Integrated Boost (SIB) to a dose of 5670-6160 cGy in 27-28 fractions.After 20 fractions of EBRT, all patients were started on brachytherapy, to the dose at the point A of the pelvic dose reference point of 2600-2800 cGy in 4 fractions (once weekly).Concurrent chemotherapy regimens for these patients included cisplatin (CDDP 40 mg/m 2 ) weekly for 6 cycles or cisplatin and taxane (CDDP 75 mg/m 2 + paclitaxel 175 mg/m 2 ) 3 weekly for 2-3 cycles.In total, 111 (63%) patients received cisplatinbased concurrent chemoradiotherapy (CCRT).

Tumor volume (TV) assessments
Tumor volume (TV) was estimated using an ROI-based approach.Using AccuContour V3.02 software (Manteia Technologies, Xiamen, China) to track the tumor area on a trackball on each MRI-T2 sequence with a computer workstation, the tumor volume before radiotherapy (TVp) and the tumor volume during radiotherapy (TVmid) were calculated.TVmid is the MRI-assessed tumor volume before brachytherapy (after receiving 40-50 Gy of EBRT).TVR was de ned as follows: TVR = (TVp-TVmid)/TVp×100.All volumetric assessments were performed simultaneously by two radiologists with more than 10 years of experience.

Statistical analysis
Optimal cut-off values were established using Receiver Operating Characteristic (ROC) curves.Overall survival (OS) and progression-free survival (PFS) were the primary and secondary endpoints for the present analysis, respectively.OS was de ned as the interval between histological diagnosis and allcause mortality, while PFS was de ned as the interval between initial presentation and disease progression or all-cause mortality.The Kaplan-Meier method was used when estimating survival outcomes.Univariate and multivariate analyses were conducted using Cox proportional hazards models.

ROC curve analyses
ROC curve analyses yielded an optimal cut-off value of 94% for TVR (Youden index: 0.35) and an AUC of 0.69.At the 94% cut-off value, the speci city and sensitivity values were 0.84 and 0.51, respectively.The respective optimal cut-off values for tumor size and tumor volume were 5.35 cm and 25 cm 2 , while the optimal CA125 and CYFRA21-1 cut-off values were 14.6 μmol/L and 7.7 ng/ml, respectively.The optimal baseline albumin (pre-treatment albumin) cut-off value was 37 g/L (Figure 1).

Patient characteristics
The baseline clinical characteristics of the 176 LACC patients included in the present study are summarized in Table 1.In total, 134 (76.1%) of these patients exhibited a TVR ≥ 94%, while the remaining 42 (23.9%)exhibited a TVR < 94%.No signi cant differences were observed between these two subsets of LACC patients with different regression rates with respect to patient's age, FIGO stage, pathological type, TV, CA125 levels, or CYFRA21-1 levels (p>0.05).Patients undergoing CCRT were more likely to have a better TVR compared to those receiving RT alone (70.1% vs 40.5%, p<0.05).

Survival analyses
The median follow-up duration for the entire cohort in this study was 52 months (range: 20-105 months).

Analysis of different risk subgroups of LACC patients
Patients were divided into high-risk and low-risk groups based on a set of prognostic factors.High-risk group included patients with age ≥ 60 years, FIGO stage: IIIA-IVA, CYFRA21-1 level ≥ 7.7 ng/ml and pretreatment albumin < 37 g/L.Remaining patients were considered as low risk category.Across both risk groups, patients with higher TVR tended to have better outcomes (Figure 3.A).Among the 111 patients who received CCRT, those with TVR ≥94% had better OS and PFS than those with TVR <94% (Figures 4A  and B).However, among the 65 patients who received RT alone, those with TVR ≥94% had better PFS but no statistically signi cant difference in OS (Figures 4C and D).Similarly, among 138 patients with CYFRA21-1 < 7.7 ng/ml, patients with TVR ≥94% had a better prognosis (Figures 4E and F); however, TVR was not a prognostic factor in patients with CYFRA21-1 ≥ 7.7 ng/ml (Figures 4G and H).
Further subgroup analyses indicated that CYFRA21-1 levels (OS and PFS interaction, p <0.001) and FIGO stage (PFS interaction, p=0.035) signi cantly affected the protective bene ts associated with the observed TVR levels.Other variables exhibited no signi cant impact on the association between TVR and survival outcomes (Figure 3B).

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The present study was conducted to explore the risk factors of LACC patients undergoing radical radiotherapy (with or without concurrent chemotherapy), and to assess the prognostic value of MRIbased TVR in different risk groups of patients.Our study showed that the FIGO stage, CYFRA21-1 levels, pre-treatment albumin levels, and TVR were independently associated with treatment outcomes in LACC patients.This study is the rst to have speci cally explored the predictive utility of TVR in different risk groups of LACC patients, showing that TVR is an important prognostic factor in patients with CRYFA21-1 < 7.7ng/ml undergoing CCRT.However, in patients with CRYFA21-1 ≥ 7.7 ng/ml who received RT alone, the difference in TVR had no signi cant effect on outcomes.
In this study, MRI images were used to determine TV before treatment and during radiotherapy (before ICBT, after 40-50 Gy of EBRT) to determine the TVR.Mayr et al. [10] analyzed 114 CC patients and found that patients with residual TV >20% at 40-50 Gy were strongly associated with poorer prognosis.Our study also found that patients with residual TV >6% (or TVR <94%) before ICBT had poor prognosis.However, only 45 patients in the Mayr et al. study received concurrent platinum-based chemotherapy, which may be the main reason for the difference in the signi cant absolute value of TVR.Therefore, we conducted a subgroup analysis of patients with and without concurrent chemotherapy and found that in patients receiving CCRT, TVR had important prognostic value in both OS and PFS.This is consistent with a number of previous studies [9,10,15].It is worth noting, however, that among patients who received RT alone, TVR was not signi cantly associated with OS.This suggests that treatment options may affect the prognostic value of TVR, and that TVR is more useful to prognosticate patients receiving standard CCRT.
In multivariate analyses, pretreatment TV and maximum tumor diameter were not signi cantly associated with prognosis of LACC patients.In contrast, TVR, which takes the pretreatment tumor burden into account and serves as a surrogate for the therapeutic sensitivity of a given tumor, was independently associated with outcomes [16].Similarly, CCRT had prognostic value in univariate analysis.However, when TVR was included, CCRT was not statistically signi cant in multivariate analysis.This may be because in our study, more patients receiving CCRT had TVR ≥ 94%.Therefore, it is suggested that we need to consider treatment options when analyzing the prognostic value of TVR.
Although previous studies have shown that TVR is signi cantly associated with prognosis in CC patients, the cut-off values used by different studies vary widely [8-10] and most of the previous studies have set the median as the continuous tumor reference cut-off.Therefore, Sun et al. [15] used a more scienti c 'Youden index' as the cut-off value and found that among 217 LACC patients who received CCRT, patients with TVR ≥ 82.19% had a better prognosis.We also used the Youden index to determine the optimal cutoff value for patients and found that this was different from the results of previous studies.This may be related to the heterogeneity of study population in different studies, different radiotherapy and chemotherapy regimens, socio-economic conditions of the patients, and difference in the radiotherapy technology used.In addition, our study found that stratifying patients into 3 subgroups based on TVR is of prognostic signi cance.Therefore, although it may be di cult to have a single cut-off value of TVR that is applicable to the whole population, but it de nitely appears to have an inverse correlation with the risk of relapse and death in patients.
LACC is a highly heterogeneous disease, and even among patients exhibiting equivalent TVR levels, there also may be pronounced residual disease-related heterogeneity.The FIGO stage is directly related to prognosis and guides the strati cation of patients to different treatment regimens [11,12].Wagner et al. [17] retrospectively analyzed 18,649 CC patients from the SEER database and found that TV was an independent prognostic factor across all FIGO stages.Therefore, TVR being an important independent prognostic factor in LACC patients, its value in different FIGO stage-groups needed to be veri ed.Serum albumin level, commonly used to assess nutritional status, is also an important prognostic factor for advanced cancer and merits inclusion in prognostic subgroup analyses [18][19][20].Our ndings not only demonstrate that FIGO stage and pre-treatment albumin are independent prognostic factors in LACC patients, but also con rm that TVR has signi cant prognostic value different subgroups based on the FIGO stage and pre-treatment albumin levels.
Previous studies have found that pretreatment CYFRA21-1 levels can be considered a useful prognostic marker for cervical cancer [21].However, the prognostic value of TVR in LACC patients with different levels of CYFRA21-1 remains unknown [22].In this study, we found that in patients with CYFRA21-1 < 7.7ng/ml, TVR was an independent prognostic factor.However, in patients with higher CYFRA21-1, TVR was not effective in predicting the prognosis of LACC patients.It may be that both CYFRA21-1 and TVR are independent prognostic factors in LACC patients [21,22], and we also found that CYFRA21-1 level could modify the prognostic value of TVR for the survival of cervical cancer patients.This requires us to pay more attention to the level of CYFRA21-1 when considering the effect of TVR on the prognosis of LACC patients in future.
There are certain limitations to this study.Firstly, this was a retrospective analysis and it is thus subject to certain inherent limitations.Secondly, this was a single-center study, hence it necessitates additional validation of these results in future large-scale multicenter studies for generalized applicability.If these ndings remain signi cant even during external validation, it might pave a way to the construction of a high-performance and clinically useful predictive model.Overcoming these limitations will thus be an important area for future research.

Conclusion
In summary, TVR was identi ed as an independent predictor of treatment outcomes in LACC patients.When categorized to different risk subgroups, in LACC patients with CRYFA21-1 < 7.7ng/ml and concurrent chemotherapy, TVR was an important prognostic factor.However, TVR was not statistically different among patients with CRYFA21-1 ≥ 7.7 ng/ml who received RT alone.

Figures
Figures

Figure 1 Results
Figure 1

Table 2 :
Con icts of InterestAll other authors declare that he/she has no con ict of interest.International of Gynecology and Obstetrics.Tumor size: the largest diameter of the tumor.The FIGO stages are based on the 8th edition of the FIGO staging.Univariate analysis of prognostic factors.