Can chronoradiotherapy offer benefits to cervical cancer patients? A scoping review

ABSTRACT The objective of this scoping review was to synthesize the available evidence and evaluate the effectiveness of chronoradiotherapy interventions in cervical cancer patients. This scoping review was performed by searching in the PubMed, Cochrane Library, Embase, Web of Science, Scopus, Cumulative Index to Nursing and Allied Health Literature (CINAHL), China National Knowledge Infrastructure (CNKI), Wanfang, Wenpu, and Chinese Biomedical Literature (CBM) databases. Databases were searched for studies published in English or Chinese from inception to 21 May 2021, and reference lists of relevant reports were scanned. Two investigators independently screened eligible studies in accordance with predetermined eligibility criteria and extracted data. The included studies were summarized and analyzed. Five studies including a total of 422 patients with cervical cancer were included in the scoping review; four studies were Chinese, and one was Indian. Main themes identified included the efficiency of chronoradiotherapy and relevant toxic and side effects, including diarrhea toxicity, hematologic toxicity, myelosuppression, gastrointestinal mucositis, and skin reactions. Administration of radiotherapy at different times of the day resulted in similar efficacy. However, the toxic side effects of morning radiotherapy (MR) and evening radiotherapy (ER) differed, with radiotherapy in the evening leading to more severe hematologic toxicity and myelosuppression. There were conflicting conclusions about gastrointestinal reactions with chronoradiotherapy, and further studies are needed. Radiation responses may be associated with circadian genes, through the influence of cell cycles and apoptosis.


Introduction
Cervical cancer is the fourth most important malignant tumor impacting women's health (Sung et al. 2021). According to the latest Global Cancer Observatory (GLOBOCAN) estimates 604,000 new cases and 342,000 deaths occurred worldwide in 2020, and the number of cervical cancer cases in young women has increased in recent years (Menon et al. 2018). The incidence of carcinoma in situ is high in women aged 30-35 years, and the incidence of invasive cancer is high in women aged 45-55 years (Menon et al. 2018). Cervical cancer is a major threat to the physical and mental health of women affected.
Timely treatment is an important part of eliminating cervical cancer. At present, commonly used treatment methods include surgery therapy, laser therapy, chemotherapy, and radiotherapy (Cohen et al. 2019). Radiotherapy plays an important role in the comprehensive treatment of cervical cancer (Shelley et al. 2021), and can achieve good therapeutic effect through appropriate combination and coordination of internal and external irradiation. External irradiation mainly resolves the problem of abdominal and pelvic lymph node metastasis. Internal irradiation destroys locally invasive tumors through fully conformal high-dose irradiation.
It is worth noting that during radiotherapy for patients with cervical cancer, the lower abdomen and pelvic organs are likely to be affected by radiation, resulting in uncomfortable symptoms such as radiation enteritis, radiation-induced cystitis, radiation dermatitis, myelosuppression, and diarrhea, reducing the patient's quality of life (Sagi et al. 2019). Achieving the best curative effects with the lowest toxicity, while administering limited doses of radiotherapy, has always been an important goal in the field of tumor radiotherapy (Chan et al. 2017;Ni et al. 2021).
Over the years, the link between circadian biology and disease has gained traction in the clinic, with increasing interest in studying how the time of day might affect clinical outcomes (Crnko et al. 2019;Fishbein et al. 2021;Sulli et al. 2019). Researchers are currently looking into how the time of day might affect radiotherapy outcomes to see if chrono modulation may be beneficial (Gu et al., 2020;Sapienza et al. 2021). Chronotherapy is based on the correlation of a variety of treatment methods and the body clock system, to find and select the minimal impact to the cells of the body's normal tissue, but the strongest duration of therapy effect on tumor cells, reduce adverse reactions, and enhance the curative effect, expand the body's greatest tolerance, improve patient quality of life for the purpose of a cure (Cardinali et al. 2021). Additionally, some studies have also discovered that there are circadian differences in the susceptibility of adverse malign (Dong et al. 2020;Eriguchi et al. 2003;Yao et al. 2010). Chronoradiotherapy is based on biological rhythms and has recently become a new trend in tumor radiotherapy (Liu and Jin 2019). This technique is based on differences in biological rhythms between normal tissues and tumor tissues, and selects the most sensitive period for tumor cells, avoiding the sensitive period of normal tissues to improve curative effects and reduce adverse reactions (Vansteensel et al. 2008). A systematic review demonstrated that chronoradiobiology has a significant effect on the skin response and recovery status of breast cancer patients after radiotherapy to the whole breast or chest wall (Nelson et al. 2022). In addition, the current effect of chronoradiobiology in cancer treatment can be concluded that it can decrease the toxic side effects of radiotherapy, such as reducing the gastrointestinal and genitourinary toxicity of prostate cancer, enhancing the overall survival of brain metastases patients, and improved its therapeutic impact (Harper and Talbot 2019). Meanwhile, many researchers investigated chronoradiotherapy for cervical cancer and other tumors in the 1960s (Lévi et al. 2010;Shukla et al. 2010). In some studies, the curative effect of morning was the same as that in the evening, although opinions differ about which period can better reduce adverse effects such as radiation dermatitis, diarrhea, and myelosuppression (Harper and Talbot 2019;Hassan et al. 2021;Yasser et al. 2022).
Researchers have performed several studies on the intervention of chronoradiotherapy (Bollinger et al. 2014;Brolese et al. 2021;Johnson et al. 2019). However, as there are considerable heterogeneities in the intervention plans and outcome indicators, it is not possible to evaluate the evidence through meta-analysis. A scope review is an evidence-based research method that can be used to explore the scope, extent, and nature of a class of studies, summarize and generalize research results, and identify shortcomings in existing research. The objective of this study was to use the scope review method to analyze the methodology and effects of chronoradiotherapy in patients with cervical cancer by using a scope review method, summarize the deficiencies of current studies, and provide recommendations for the future development of chronoradiotherapy.

Review questions
(1) What are the methods of chronoradiotherapy are used in patients with cervical cancer? (2) What is the application effect of chronoradiotherapy in patients with cervical cancer?

Search strategy
The search strategy aimed to locate both published primary studies and reviews in databases with peer reviewed literature. A search of the literature was completed utilizing online databases including PubMed, Cochrane Library, Embase, Web of Science, Scopus, Cumulative Index to Nursing and Allied Health Literature (CINAHL), China National Knowledge Infrastructure (CNKI), Wanfang, Weipu, and Chinese Biomedical Literature (CBM). The following specific subject (MeSH) headings and free text words were used to identify reviews of the effects of chronoradiotherapy in patients with cervical cancer: Uterine Cervical Neoplasms [MeSH] cervical carcinoma*, cervix carcinoma*, cervical cancer*, cervical neoplasms*, uterine cervical neoplasms*, uterine cervix tumor*; morning radiotherapy, evening radiotherapy, chronoradiotherapy. The search period ran from the establishment of each database to March 15, 2022.

Inclusion and exclusion criteria
Inclusion criteria were: (1) The study included cervical cancer patients, aged ≥18 years; (2) The study involved the chronoradiotherapy intervention measures for patients with cervical cancer; (3) The types of studies were randomized controlled trials, quasi-experimental studies, qualitative research, cohort studies, mixed studies, or case control studies. Exclusion criteria were: (1) The studies were not published in Chinese or English; (2) Reviews, literature abstracts, literature reviews, etc.; and (3) The full text was not available.

Study screening and selection
Study screening and selection was completed in a twostep process. Two reviewers will independently evaluated and screened all the titles and abstracts of the studies retrieved using the above literature search strategy in order to identify papers that potentially met eligibility criteria and to evaluate the quality of all included studies using the Newcastle-Ottawa Scale (NOS) (Wells et al. 2010). In case of disagreement, the two review authors discussed the disagreement to come to reach a consensus; if no consensus could be reached, another reviewer was consulted.

Data extraction and analysis
Data were extracted from papers included in the scoping review by two independent reviewers, using a data extraction tool designed in Microsoft Excel. The data extracted included first author name, year of publication, study country, study design, and intervention characteristic (i.e., intervention components and strategies). Additionally, key findings relevant to the review question were extracted. Any discrepancies were resolved by a third reviewer.

Literature study results
The process of identification, selection and exclusion of full text studies was visualized in a Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flow diagram Figure 1). Findings are presented in a narrative form with a description of the chronoradiotherapy interventions for cervical cancer patients. Initially, 418 records were identified in the electronic database search. After excluding duplicates (n = 40), the titles and abstracts of the remaining 378 records were screened. A further 373 records were excluded because they were clearly irrelevant. The remaining studies were deemed potentially relevant, and their full texts were evaluated. Five studies were ultimately included in the scoping review.

Literature study characteristics
The characteristics of five of the included studies are shown in Table 1. These studies were published between 2010 and 2019 and were conducted in China (four studies) or India (one study). The sample sizes of the studies ranged from 28 to 229, participants, with a collective total of 442 participants with cancer ranging from stage IIB to stage ⅣA. The radiation time for cervical cancer patients include morning group from 8 am to 11 am and evening group from 9 pm to 11pm. All five studies were evaluated using the National Cancer Institute Common Toxic Criteria Version 3.0 (Trotti et al. 2003) and the Radiation Therapy Oncology Group criteria (Cox et al. 1995). The radiotherapy sites included the anterior and posterior pelvic cavity and intravaginal close-range irradiation and external irradiation. Radiotherapy doses included 50 Gy 25 times/ fraction.

Discussion
At present, the treatment methods of cervical cancer mainly include surgery and radiotherapy. Chemotherapy is widely used in comprehensive treatment combined with surgery and radiotherapy and in the treatment of advanced recurrent cervical cancer. Currently targeted therapy, immune therapy and its combination therapy can be used for recurrence or metastasis of cervical cancer systemic treatment, comprehensive treatment of cervical cancer is not the superposition of several methods of blind implementation and ought to plan step by step, in principle, early cervical cancer is given priority to with surgical treatment, locally advanced cervical cancer is given priority to with radiotherapy, chemotherapy is complementary. The NCCN guidelines emphasize that surgical treatment is suitable for patients with stage IIA or below, radiotherapy is suitable for all stages of cervical cancer, and external irradiation can be performed by anterior and posterior perforation field, pelvic four-field, threedimensional conformal, intensity modulated radiotherapy (Fowler et al. 2022).
The objective of this scoping review was to map the large body of literature and describe the therapeutic range of chronoradiotherapy in cervical cancer. By focusing on existing reviews of chronoradiotherapy in cervical cancer, it aimed to synthesize the ways in which interventions have been conceptualized and their components described. Overall, the literature included in our review demonstrate that patients with cervical cancer had similar responses to radiation, irrespective of whether the treatment was administered in the morning or the evening. However, differences in radiation toxicity, particularly hematologic toxicity, myelosuppression, and diarrheal toxicity, were reported. Notably, there were no significant differences in skin responses to radiotherapy at the different time points (J. . Biological rhythms affect normal biological processes such as the cell cycle and hormone secretion (Y. . In recent years, biological rhythms have been taken into account in the treatment of tumors. Based on biological rhythms, radiotherapy is given at the best time when tumor cells and normal cells are radiosensitive, so as to reduce low-toxicity side effects without reducing efficacy. This prolongs survival rate and improves the quality of life of patients. It is well known that each stage of the cell cycle corresponds to a different degree of radiosensitivity. The second growth (G2) and mitosis (M) phases of the cell cycle are most sensitive to radiation, while cells in the synthetic (S) phase are least sensitive. Cells in first growth (G1) phase are more sensitive than cells in the S phase, but less sensitive than cells in G2/M phase (Bermúdez et al. 2021;Pawlik et al. 2004;Terasima et al. 1963). In a randomized controlled study of chronoradiotherapy for cervical cancer, Chang et al. found that there were significant negative correlations between the expression of circadian genes, Per1, Per2, Clock, and the G2/M phase fraction, and a positive correlation between their expression and cell apoptosis (Chang et al. 2016). That means circadian genes can affect radiation response by influencing cell cycle and apoptosis. The degree of apoptosis in the irradiated cells was lowest in the early active phase (equivalent to target cells at G1). However, another study found that the Clock protein did not show significant rhythmicity; probably due to the small sample size of the study (Li et al. 2015).
It has been demonstrated that more than 70% of patients develop acute gastrointestinal symptoms while undergoing pelvic radiotherapy, and 80% of patients with cervical cancer experience radiationinduced diarrhea (Demers et al. 2014;Visich et al. 2010). The mechanisms of radiation-induced gastrointestinal reactions are unclear. In a study of intestinal crypts in mice, a distinct circadian rhythm was observed in the number of apoptotic cells in the crypts at different times of radiotherapy, demonstrating that radiotherapy-induced apoptosis was time dependent. Irradiation of intestinal crypts in the G2/M phase leads to severe induction of apoptosis, and the number of apoptotic cells in the G1 phase is the least. Therefore, the toxic and side effects of treatment in the G2/M phase are more serious than those in the G1 phase (Ijiri et al. 1990). One study found a higher incidence of radiation-induced intestinal mucositis in the morning than in the evening (Shukla et al. 2010). Two other studies verify that the toxicity of diarrheal is more severe if radiotherapy is given in the morning (Chang et al. 2016;Shukla et al. 2010). Chang et al. found that the incidence of diarrhea (both overall [I-IV] and high [III-IV] grade) was significantly more frequent if treatment was administered in the morning than in the evening (Chang et al. 2016). Furthermore, different of gastrointestinal symptoms were found when cervical cancer patients were irradiated in the morning or evening, which may result from the effect of different circadian rhythms on the mucosa of the human intestine (Abu et al. 2020;Li and Li 2015;Lu et al. 2019). These results suggest that the circadian rule of radiotherapy can directly affect the mucosal response of the small intestine. Further clinical trials are needed to prove that by adjusting the timing of radiotherapy, intestinal damage caused by radiation can be reduced.
Because the bone marrow in human body is concentrated in the pelvic bone and lumbosacral bones, exposure of the whole pelvic region to radiation in patients with locally advanced cervical cancer is likely to damage the bone marrow tissue. This may induce myelosuppression and cause blood toxicity reaction following in radiation therapy, diminishing the effect of the radiation therapy and reducing quality of life (Bjarnason et al. 2009). Effects of chronotherapy on myelosuppression and hematotoxicity in patients with cervical cancer were analyzed in the current scoping review. Three studies consistently demonstrated that radiotherapy at night was associated with more severe myelosuppression and hematotoxicity (Chang et al. 2016;Li and Li 2015;Lu et al. 2019). Cells in the S stage of the biorhythm cycle are resistant to radiotherapy, while radiotherapy in normal tissues at the peak of the S stage can reduce the toxic effects of radiotherapy in normal tissues. Bone marrow cells are at the peak of the S stage during early radiotherapy (Bermúdez et al. 2021;Bjarnason et al. 2009). Due to the resistance of S-stage cells to radiotherapy and low radiosensitivity of radiotherapy to bone marrow cells, the incidence of myelosuppression and hematotoxicity in the early radiotherapy group was low, while that in the late radiotherapy group was high. Therefore, myelosuppression and blood toxicity caused by radiotherapy are a non-negligible problem in clinical practice. This means that the time at which radiotherapy is administered should be adjusted, and protocols for the early recognition, monitoring, and treatment of these side effects should be strengthened.

Limitations
This scoping review has some limitations. First, the results of this review are limited by the paucity of studies that could be included in the pooled meta-analyses due to heterogeneity in study designs and inconsistent outcome reporting. Only one study clarified the random allocation method used, while the rest mentioned random allocation but did not describe their specific methods. None of the studies described the blinding methods used or methods of allocation concealment. Most of the studies were based on small sample sizes, and the small number of studies and the inconsistent radiotherapy regimens with respect to timing and doses may have affected the accuracy of the results. Finally, the scoping review only included studies conducted in Asian countries, which may have affected results that are sensitive to different regions and times. Therefore, the results of the current analysis should be interpreted with caution, and more high-quality, multicenter, large randomized controlled trials are needed for further verification.

Conclusions
The effectiveness of morning and evening treatment effects were similar, but differences were noted in the toxicity and side effects profile, with radiotherapy in the evening leading to more severe hematologic toxicity and myelosuppression. The chronoradiotherapy studies included had conflicting conclusions about gastrointestinal reactions, and further studies are needed. Further large, high-quality, prospective studies are needed to strengthen our understanding of chronotherapy. At present, the application of chronotherapy in the treatment of cervical cancer is limited. Further large, high-quality, prospective studies are needed to strengthen our understanding of chronotherapy. When patients with cervical cancer exhibit radiotoxic reactions, we suggest that clinical experts provide symptomatic care as necessary, such as weekly routine blood monitoring during radiotherapy, and the administration of drugs to increase white blood cells or platelets if required. The use of antibiotics to prevent infection should also be considered.

Disclosure statement
No potential conflict of interest was reported by the authors.

Funding
This study was supported by Scientific Research Project of Tianjin Educational Committee 2020KJ144.