Cervical cancer is a significant global health issue affecting approximately 600,000 women each year [1]. Cervical cancer is managed through a multimodal treatment approach that includes surgery, chemotherapy, and radiation therapy [2]. The treatment landscape for cervical cancer has evolved significantly, with chemoradiation, comprising external beam radiotherapy (EBRT) and intracavitary brachytherapy (BT), emerging as the standard of care for locally advanced cases [3].

Despite substantial advancements in treatment strategies, the occurrence of recurrences remains a formidable challenge in the management of cervical cancer [4]. Although extensive research and studies have been done on the pattern of late recurrences, limited research currently exists on the underlying causes of early recurrences in cervical cancer patients. The duration of EBRT to BT and the overall treatment time (OTT) have emerged as potential factors influencing treatment response and the occurrence of early recurrences in cervical cancer patients [5].

EBRT, delivering radiation to the pelvis, is often followed by BT, a localized form of radiotherapy targeting the tumor directly. The sequencing of BT within the overall treatment schema, traditionally administered post-EBRT, is also extensively researched, with concurrent approaches explored for optimization. The intricate interplay of these factors necessitates a comprehensive evaluation of treatment parameters and their impact on early recurrences, considering patient-specific and tumor-related variables. Additionally, several factors have been identified as potential contributors to early recurrences in cervical cancer [6-9]. An advanced stage at diagnosis, nodal metastasis, younger age, presence of comorbidities, immunosuppression, has consistently been linked to an elevated risk of recurrence [6-9].

Despite extensive research on various risk factors associated with cervical cancer recurrences, there remains a significant gap in the literature regarding the influence of treatment duration on early recurrence in cervical cancer patients. Limited studies have specifically investigated these treatment time parameters and their impact on recurrence rates [10-12]. While these studies have explored the OTT, the duration between EBRT and BT, treatment gaps in between, and their correlation to response and early recurrence have not been extensively studied.

This study aims to fill this existing knowledge lacuna by investigating the impact of treatment time parameters, specifically the durations of EBRT to BT and overall treatment, on response and early recurrences in cervical cancer patients. The study also aims to provide a comprehensive analysis of the influence of these temporal variables, recognized as integral components of cervical cancer treatment, on the occurrence of early recurrences.

A total of 288 patients details who had received EBRT and BT for cervical cancer were analyzed. The patient characteristics are listed in Table 1.

The most common stage was stage IIB, with 137 patients (47.6%). The predominant radiation dose administered was 50 Gy in 25 fractions, received by 245 patients (85.1%). The most common chemotherapy given was Cisplatin, with 249 patients (86.5%) receiving regimen. Among the various BT doses, the most frequent one was HDR BT at 7.5 Gy in 3 fractions, administered to 210 patients (72.9%). The predominant histological type observed was squamous cell carcinoma (89.9%).

Out of the entire cohort of patients, the response assessment at the 3rd month showed that 266 patients (92.4%) had a complete response, 13 patients had a partial response (4.5%), and nine patients (3.1%) had progressive disease. Out of the 288 patients analyzed at 6 months, a total of 23 (7.9%) early recurrences were observed within 6 months of completing therapy.

Among the observed recurrences, eight manifested as local only occurrences, involving the cervix, parametrium, and vagina. Four recurrences were regional involving the pelvic and para-aortic nodes. Two patients had a locoregional recurrence. Distant metastasis occurred in nine patients, with five presenting with liver metastases, three with lung metastasis, and one with both lung and supraclavicular node metastases.

Among the patients who did not have a recurrence and those who had an early recurrence, no significant association was found between stage (p = 0.683), type of chemotherapy (p = 0.750), mean EBRT equivalent dose of 2 Gy (EQD₂) (p = 0.996), mean BT EQD₂ (p = 0.994), and mean total EQD₂ (p = 0.987) with status of recurrence. The characteristics between the recurrence and no recurrence group are outlined in Table 2.

The number of days of gap between EBRT and BT differed significantly between the patients who did not have a recurrence and those who had an early recurrence (no recurrence group, 10.4 ± 4.2 days; early recurrence group, 12.3 ± 4.5 days; p = 0.031), as determined by an independent t-test. Furthermore, a notable difference was observed in the OTT between the two groups (no recurrence group, 61.6±11.5 days; early recurrence group, 73.8±8.8 days; p < 0.001) (Fig. 1).

Out of all the patients, a total of 165 patients had a gap of 10 or fewer days and 123 patients had a gap of more than 10 days between the completion of EBRT and the start of BT. Out of the 123 patients with a gap of more than 10 days, 21 experienced skin and mucosal reactions, causing a delay in treatment; 95 presented late due to logistics issues. Additionally, four patients did not receive anaesthesia clearance due to deranged hematological parameters, and three patients had neutropenia after chemoradiation, requiring antibiotics and supportive care.

The log-odds of progressive disease (PD) relative to complete response (CR) was 0.069. The odds ratio was 1.06 implying that, for each additional day of OTT, the odds of PD relative to CR increase by a factor of 1.068 (p = 0.041). The log-odds of partial response relative to CR was 0.022. The odds ratio was 1.02 implying that, for each additional day of OTT, the odds of PD relative to CR increase by a factor of 1.068 (p = 0.324).

Logistic regression analysis was done to explore the association between the odds of recurrence and the increase in OTT. The coefficient for OTT and recurrence was 0.071 (standard error = 0.016, Z = 4.33, p < 0.001). The odds ratio for OTT and recurrence was 1.07 (95% CI, 1.04–1.10). The logistic regression model was statistically significant, highlighting the association between OTT and the likelihood of recurrence (p < 0.001) suggesting that the odds of recurrence are 7% higher for each one-unit increase in OTT. Similarly, the logistic regression done to evaluate the association of the number of days of gap between EBRT and BT to recurrence was statistically significant. The odds ratio of 1.095 (95% CI, 1.07–1.12) indicates that the odds of recurrence are 9.5% higher for each one-unit increase in the gap (p < 0.001). An ROC curve analysis was done to compare the no recurrence group and early recurrence group based on OTT. The AUC was 0.817, and the analysis showed a statistically significant association (p < 0.001) (Fig. 2).

Cervical cancer is a significant health concern worldwide, and the combination of EBRT and BT has emerged as a standard treatment approach [2]. The present study investigated the influence of overall treatment duration and the gap between EBRT and BT on treatment response and early recurrences in chemoradiation-treated cervical cancer patients. The analysis of our study cohort, comprising patients with varying tumor stages and histological subtypes, revealed several findings. Our results showed an association between longer overall treatment durations and a higher risk of early recurrences. It is possible that longer treatment durations may lead to treatment resistance, allowing for the emergence of resistant tumor cell clones [14].

The impact of OTT has shown a decrease in pelvic control by 7%–8% for each week of extended treatment [15]. Another possible cause for this could also be due to accelerated repopulation of cells once they are exposed to radiation or chemotherapy [16]. Further investigation is warranted to understand the underlying mechanisms driving this association and to identify strategies to mitigate the risk of early recurrences in patients with longer treatment durations.

In addition to overall treatment duration, we explored the impact of the gap between EBRT and BT sessions on treatment outcomes. Interestingly, our findings indicated that patients with longer gaps between these treatments exhibited poorer treatment responses and outcomes, although it was not statistically significant. This observation suggests that a prolonged interval between EBRT and BT may compromise the effectiveness of treatment. Several factors may contribute to this association. Tumor repopulation during the treatment gap, reoxygenation of hypoxic tumor cells, and repair of sublethal radiation damage are potential mechanisms that could influence treatment response and recurrence rates [17]. The tumor microenvironment during the gap period may also play a role in treatment outcomes. Several patient-related factors may contribute to an increased gap between EBRT and BT [18]. These factors include a poor performance status of the patient following EBRT, the presence of side effects resulting from EBRT such as neutropenia, radiation mucositis, and dermatitis. Additionally, logistic factors, such as the unavailability of a BT facility in the hospital or nearby medical centers, can also contribute to the extended time interval between the two treatments [19].

Optimizing treatment durations and intervals is essential in achieving improved treatment responses and reducing the risk of early recurrences. However, it is crucial to emphasize the importance of personalized treatment planning in cervical cancer patients. Individualized approaches should consider various patient-specific factors, such as tumor characteristics, patient tolerance, and treatment response, to tailor treatment durations and intervals accordingly [20]. Striking a balance between delivering an adequate radiation dose to the tumor and minimizing treatment-related toxicities is crucial in achieving optimal treatment outcomes.

Furthermore, the findings of our study have important implications for treatment protocols and guidelines in cervical cancer. Currently, there is a lack of consensus regarding the optimal treatment durations and intervals. Our study highlights the need for standardized treatment protocols that consider individual patient factors and incorporate evidence-based recommendations. Future prospective studies with larger patient cohorts are warranted to validate our findings and provide further evidence for treatment optimization in cervical cancer.

While our study provides valuable insights into the influence of overall treatment duration and the gap between EBRT and BT on treatment response and early recurrences, several limitations should be acknowledged. The retrospective design of the study introduces inherent biases and limitations in data collection. Prospective studies with larger patient cohorts and standardized treatment protocols are needed to further validate our findings. Additionally, our study focused solely on chemoradiation-treated cervical cancer patients, and the generalizability of the findings to other treatment modalities or patient populations should be explored in future research.

In conclusion, our study reveals unexpected associations between overall treatment duration, the gap between EBRT and BT, and treatment outcomes in chemoradiation-treated cervical cancer patients. Longer overall treatment durations were associated with a higher risk of early recurrences, highlighting the need for further investigation and optimized treatment strategies. Future prospective studies with larger patient cohorts and standardized treatment protocols are warranted to validate these findings and further explore the underlying mechanisms.