The Impact of Chronic Pelvic Pain and Bowel Morbidity on Quality of Life in Cervical Cancer Patients Treated With Radio (Chemo) Therapy. A Systematic Literature Review

Introduction

Globally, cervical cancer (CC) remains a major public health problem.^1,2 For example, in the year 2022, an estimated 660,000 new cases and 350,000 deaths due to CC were recorded.¹ Notably, over 80% of the global burden of CC is disproportionately concentrated in low- and middle-income countries (LMICs)^1–6 which have only 5% of the global cancer resources.⁷ That is to say, the global burden of CC reflects significant global health inequities including but not limited to limited access to vaccination, screening, and treatment services.⁸

CC is a prime cause of cancer-related mortality and morbidity in Uganda and is associated with significant disruptions in the quality of life (QoL) of the women effected.^4,9 CC accounts for about 4100 incident cases and 2300 deaths annually in Uganda.^1,10 Exacerbating the problem is that the majority (over 80%) of CC cases in Uganda are diagnosed in late advanced stage when a cure is no longer possible.¹¹

Globally, radiotherapy (RT), usually with concurrent chemotherapy (CT), is currently the radical standard choice of treatment for CC for both curative and palliation intent.¹² Similarly, RT/CT is currently the gold standard treatment for CC in Uganda, given with or without surgery for both curative and palliation intent. It has been shown that CT (usually Cisplatin-based agent) acts as a radio-sensitizer to optimize local response of the cancerous cells to RT and/or or vice versa.^13,14 However, Bjelic-Radisic et al³ reported that CT increases the risk of additional toxicities, including Chronic Pelvic Pain (CPP) and bowel morbidities that cause significantly diminished QoL among cervical cancer survivors (CCS).

However, pelvic irradiation with or without CT has been shown to be associated with both acute- and long-term toxicities that cause both acute and chronic pelvic pain and bowel morbidities. Acute-related toxicities include mucositis and diarrhoea. Long-term treatment-related toxicities include bowel morbidities such as impaired anorectal function, chronic diarrhoea or proctitis, pelvic and insufficiency fractures,^15–18 and pelvic pain.¹⁹ However, there exist wide variations in the prevalence rates of these toxicities.

The American College of Obstetricians and Gynaecologists (ACOG)²⁰ Practice Bulletin No. 5 defines CPP as non-cyclic persistent pain lasting for six or more months, that localizes to the anatomic pelvis, anterior abdominal wall at or below the umbilicus, the lumbosacral back, or the buttocks and is of sufficient severity to cause functional disability or lead to medical care. Vistad et al²¹ define CPP as pain that persists longer than the time of natural healing, located in hips, groins, lower back, radiating pain, pain at rest or activity and/or pain influencing daily activities. It encompasses insufficiency fractures, chronic radiation enteritis (CRE), proctitis, cystitis, lumbosacral plexopathies, chronic radiation myelopathy, lymphoedema pain, burning perineum syndrome, and osteoradionecrosis. To note, CRE is inflammation of the intestines following RT and is associated with disabling symptoms like nausea, vomiting, appetite loss, diarrhoea or constipation (bowel obstruction), abdominal cramps, bleeding tendencies and sometimes anaemia. These profoundly compromise the QoL of the patient and their family.

CPP has been shown to have negative implications on domains of QoL of a patient including cognitive, behavioural, sexual and emotional consequences as well as causing morbidities, including of the lower urinary tract, bowel, pelvic floor and sexual or gynaecological functioning.^22,23 In Uganda, no published empirical study examining the burden of CPP and chronic bowel morbidity among CC patients treated with chemoradiation can be traced. The extent to which the topic has been studied on the regional and global landscape is also not well understood. This review could identify the extent to which the topic has been studied and identify important evidence gaps and inform future studies.

Aim of the Review

To systematically-:

1. Appraise available evidence about chronic pelvic pain and bowel morbidity in cervical cancer patients treated with radiotherapy with or without chemotherapy.
2. Examine the impact on quality-of-life chronic pelvic pain and bowel morbidity on QoL of cervical cancer patients treated with radiotherapy with or without chemotherapy.

Methods

Design

This was a systematic review of published peer reviewed research evidence.

Ethical Considerations

This was a review of secondary data. This meant that the study did not require ethical review and approval from an Institutional Review Board (IRB). To note, all the papers included in this review had an ethics statement stating that they had obtained ethical approval from a recognised IRB. The review was conducted and reported in accordance with the PRISMA guidelines.²⁴

Search Strategy

The review was conducted between April 2021 and May 2021 and was updated in September 2024. The authors performed a systematic search in trusted online databases for peer reviewed subject- and content-specific literature. Four databases, Hinari “Research4Life”, Google Scholar, CINAHL and PubMed were searched for eligible articles. A uniform search strategy was applied to each of the databases using the search terms, “Prevalence” OR “Severity” AND “radiotherapy-induced chronic pelvic pain” OR “Bowel morbidity” OR “bowel dysfunction” AND “quality of life” AND “cervical cancer” AND “English articles” AND “full text articles” AND “peer reviewed” AND “Published 2008 to 2024”. The search was filtered for articles which were peer-reviewed, in English, full and open access articles published between 2008 and 2024. A supplementary parallel Google search was performed to retrieve eligible papers, yielding an additional seven papers. The retrieved papers were first screened on title and abstract and then full-text for eligibility for inclusion in the review. Results of the search are summarised in Figure 1.

Figure 1 Flow diagram showing search strategy underpinning the review. Adapted from Page MJ, McKenzie JE, Bossuyt PM, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ. 2021;372:n71. Creative Commons.24 Abbreviations: CC, Cervical Cancer; CINAHL, Cumulative Index to Nursing and Allied Health Literature; CT, Chemotherapy; QoL, Quality of Life; RT, Radiotherapy.

Assessment of Methodological Quality of the Studies

The articles were each subjected to a thorough methodological critique for quality using appropriate validated Critical Appraisal Skills Programme (CASP) checklists. The articles were all found to be of good quality. The papers were initially independently assessed by GN followed by PE. Decision on the papers eligible for inclusion and exclusion and their quality scores was reached through consensus. To note, GN had identified 31 eligible papers for inclusion but two were deemed ineligible for inclusion following assessment of the papers by PE. The two ineligible papers examined different types of gynaecological and pelvic cancers including cancer of the cervix, vagina, prostate, endometrium/uterus, rectum and bladder but findings were not disaggregated by diagnosis and gender.

To note, the 11-item CASP checklist for descriptive/cross-sectional studies and the 10-item CASP checklist for systematic/literature/records reviews were used to assess the selected articles. The questions are designed to be answered with “Yes”, “Can’t tell” or “No”. Each “Yes” response was scored as 1 point. A response of “Can’t tell” or “No” was scored as zero (0) points. The total possible maximum score for each question item in the CASP checklist was 11. The range of scores (0–11) were then assigned a rating of the article as very good (score ≥9–11), good (score 7–8), average (score 5–6) and then weak (score less than 5). All the studies (articles) selected for review had a score ≥8 and so were of good or very good quality (Table 1–4).

Table 1 CASP25 Scoring for Qualitative and Quantitative Studies (n = 26)

Table 2 Systematic/Literature Review Quality Assessment Using Critical Appraisal Skills Programme (CASP) checklist44

Table 3 Summary of CASP Checklist Methodological Quality Scores of Descriptive Studies (n=26)

Table 4 Summary of CASP Checklist Methodological Quality Scores of Systematic/Literature Reviews (n=3)

Results

Characteristics of the Articles Reviewed

The regional distribution of the studies used in the review (n = 29) is shown in Table 5. To note, the studies were conducted in four continents with most being undertaken in high-resourced countries. For example, eleven (n = 11) studies were conducted in Europe,^{6,18,21,28,31,32,34–38} eight (n = 8) in Asia,^{12,13,26,27,33,39,42,43} one (n = 1) in North America,²⁹ three (n = 3) in Africa,^5,7,30 and six (n = 6) were multi-continental; including three conducted in Europe, Asia and North America^3,40,41 and three (n = 3) reviews of global literature.^15,45,46 To note, all the three studies done in Africa were from high-income or middle-income countries, ie South Africa (n = 2)^5,30 and Nigeria (n = 1).⁷

Table 5 Methodological Characteristics of Studies Included in the Review

Figure 2 shows regional distribution of eligible articles included in the review.

Figure 2 Regional distribution of articles included in the review.

Regarding study design, thirteen (n = 13) studies were longitudinal,^{6,12,13,27,30–32,34,35,39–41,43} ten (n = 10) were cross-sectional,^{3,5,7,18,21,29,33,36–38,} one (n = 1) randomised controlled trial,²⁶ three (n = 3) were reviews^15,45,46 and two (n = 2) retrospective studies of prospectively collected data^28,42 (Table 4).

Discussion

This review aimed to systematically appraise literature about the burden of bowel morbidity and CPP and their effects on QoL in patients treated with RT or RT/CT. Findings suggest that bowel morbidity and CPP are common symptoms in RT or RT/CT-treated CC patients and profoundly compromise QoL. The review further reveals there is scant published research evidence about these two common issues in LMICs. For example, of the 29 papers reviewed, only three were from Africa, while no paper was identified in South America. This highlights a huge evidence gap on the topic. Again, very few of the studies reviewed studied CPP, which is shown to be a common complaint in patients receiving, or who have received, pelvic irradiation.

CPP and Its Effects on QoL of CC Patients

QoL has been defined as a person’s self-reported perception of physical, psychosocial and sexual well-being.³⁶ It is thought that the toxicity of treatment in women receiving RT or RT/CT could be due to RT as some authors report they did not find any significant differences between RT/CT and RT treated groups.³⁶ However, conflicting findings also exist. For example, Bjelic-Radisic et al³ reported that CT increases treatment related toxicities when concurrently administered with RT. Nonetheless, RT/CT is now the most widely used modality of CC treatment for both early-stage disease for curative intent and for palliation of CC symptoms. In fact, it is estimated that 52% of cancer patients will require RT for optimal treatment while a further 23% need re-treatment.⁴⁵ It is likely that these figures are an underestimate of the number needing retreatment for example because of relapse.

Pain is a common symptom experienced by CC patients. Its aetiology has been cited in many studies as linked to the CC itself and its invasive treatments. Numerous studies report the prevalence of pain among CCSs ranges between 40% and 70%.^7,31,37 This finding is corroborated by a study conducted in South Africa by Ntinga and Maree.⁴⁷ Sadly, CPP is often underreported and under described,²¹ and inevitably poorly treated as seen in a number of other studies.^19,48,49

Vistad et al²¹ in their study of CPP after RT in survivors of locally advanced CC found 38% of the women they studied in Norway met the criteria for CPP and CPP had a significant link to bladder and bowel morbidity. These findings are corroborated by Donovan et al²⁹ in the US, who found 36% of CCSs reported pelvic pain. However, wide variations in the prevalence of pelvic pain are observed in the literature. For example, Le Borgne et al³⁸ in their study in France, found prevalence rates of lower back pain and peripheral neuropathies were lower at 14.6% and 17.2% respectively. It is unclear as to why these wide variations exist.

CPP has been shown to have a negative impact on women’s QoL. CT/RT usually causes chemotherapy-induced peripheral neuropathy (CIPN) which causes nerve pain, sensory discomfort like numbness, fatigue and psychological problems (anxiety, worry and depression) all of which could exacerbate poor QoL among patients and even their family. For example, Vistad et al²¹ found participants who had CPP significantly had a lower QoL, higher levels of anxiety and depression, and more severe bladder and bowel morbidity compared to their counterparts without CPP. Furthermore, Tian et al¹⁷ found poor sleep quality was prevalent in 52.63% and 64.47% of CC patients before and after RT respectively while Sumdaengrit et al¹³ found emotional changes, difficulty sleeping, worrying and feeling irritable were frequently reported by CC participants.

Furthermore, research suggests that CPP and bowel morbidities post RT could negatively affect rehabilitation, increase suffering and negatively influence QoL. In fact, several other negative symptoms including anxiety, depression, fatigue, insomnia, sexual and sexuality problems, social problems, and extended lost work days have been reported by studies done among CCSs after RT/CT. Insomnia has been reported to be a common symptom in CC patients receiving RT or RT/CT in many studies.^5,6,47,50 These findings underscore the crucial role of CPP in the pathophysiology and exacerbation of physical, emotional and psychological morbidity among RT-treated CC patients. The prevalence of insomnia, however, varies quite widely across studies. Insomnia was the most commonly reported symptom in a South African study by Ntinga and Maree,⁴⁷ followed by pain and fatigue. Goker et al⁵⁰ found fatigue was most prevalent followed by pain and insomnia. Pasek et al⁶ reported insomnia was the commonest followed by fatigue and diarrhoea. Whereas Sabulei and Maree⁵ found insomnia, pain and fatigue showed a downward trend from baseline throughout treatment, research elsewhere found contrary findings ie these symptoms registered an upward trend.

Everhov et al¹⁶ in the US, found that disabled CCSs have significantly more depression than working patients, and the prevalence of delayed return to work was at 71% among those treated with RT. These finding support those of Vistad et al²¹ who found CPP is associated with higher overall mental and somatic morbidity. Earlier studies found that significant psychological impairment; eg, feelings of guilt, self-blame, fear of recurrence, and anxiety and sexual functioning impairment were related to CC treatment, including RT.^51–53

While it is likely that CPP and bowel morbidity have a close link in the aetiology of insomnia and fatigue, the studies reviewed lack data about to what extent CPP and bowel morbidity account for the aetiology of fatigue and insomnia and their overall effect on QoL. This underlines a need for future longitudinal studies to examine these predictor variables to have a better evidence-supported understanding of the salient cause-effect relationships that exist.

In their population-based study of 243 gynaecological cancer survivors who had received pelvic irradiation, Kollberg et al¹⁹ found dyspareunia (painful intercourse) affected 67% of the study participants. 55%, 40%, and 36% reported superficial pain, deep pain and both types of dyspareunia respectively. Previous studies have linked dyspareunia to a shortened vagina following pelvic irradiation.^52,54,55 These findings reveal disruptions on the sexuality and sexual functioning, an essential QoL domain. Jensen et al⁵⁴ in their longitudinal study assessing sexual functioning following primary or postoperative RT for 118 CC patients found sexual dysfunction persisted up to two years after RT treatment with 50% reporting severe disabling distress. Numerous large sample studies report similar findings.^{31,48,51,56–60}

Swelling of the feet (lymphoedema pain) is another symptom that negatively impacts women’s QoL during or following RT or RT/CT.^32,47 Other longitudinal studies report worsening of lymphoedema from start of treatment and onwards,^61,62 except Bjelic-Radisic et al³ who reported that lymphoedema improved during follow-up. Le Borgne et al³⁸ found voiding (bowel) problems and lymphoedema were more prevalent among long-term CCSs (5–15 years) unlike other symptoms which improved over time during treatment. Findings are corroborated by another study conducted in China.⁴⁹ This calls for clinical settings to be more aware of these issues and make practical efforts to identify and address these issues in order to improve the QoL of patients.

Bowel Morbidity and Its Effects on the QoL of Patients

Bowel morbidity in patients receiving or who have received RT or RT/CT manifesting as incontinence, diarrhoea, tenesmus, constipation, rectal dysfunction, chronic radiation enteritis-(CRE), bloating, flatulence, urgency, rectal bleeding and per-rectal mucus is a great concern and predictor of poor QoL among CCSs receiving RT singly and/or in combination with CT. Bowel morbidity was reported in 20 of the 29 studies in this review^{3,5,13,18,21,26–30,32–35,37,38,40–42,46} as well as in numerous studies elsewhere^63–67 while CRE is reported, as occurring in 19–20% of patients.³⁷ In contrast, a cross-sectional study of 105 Greek women found treatment type (RT or RT/CT) had no effect on total QoL.³⁶

Dahiya et al²⁷ in their longitudinal study assessing the QoL of 67 Indian women before and after RT/CT in CC found the mean global health score after six months of treatment was 59.52, which was significantly higher than the pre-treatment score of 50.15 (P< 0.00007). Similarly, physical, cognitive and emotional functioning improved significantly (P<0.05) after treatment. Fatigue, pain, insomnia and appetite loss improved whereas episodes of diarrhoea which is common in CRE increased after treatment.

Bowel injury is often due to impaired anorectal function following RT or RT/CT treatment. Hsu et al³³ found diarrhoea, bloody stools, intestinal dysfunction and abdominal pain were significantly higher in the RT-treated group. Kuku et al³⁷ in their medical records review of 541 women treated with RT with or without CT for CC and endometrial cancer identified 152 women who reported significant new bowel symptoms after pelvic radiation. 19% of participants in the CC group had a radiation-induced bowel injury requiring surgical intervention compared with five (6.7%) in the endometrial cancer group. Bowel morbidity is also reported by Bjelic-Radisic et al³ who found pelvic irradiation with or without other therapy was more associated with symptoms of diarrhoea. Studies also report that RT-treated patients reported greater intestinal dysfunction or bowel morbidity eg voiding and abdominal symptoms.^33,38,66

Furthermore, to note, the prevalence of bowel dysfunction varies quite widely in the literature. In their study, Vistad et al²¹ reported a prevalence of 19% for defecation urgency and 60% of their study subjects (CCSs) previously treated with RT had bowel problems. Le Borgne et al³⁸ reported a slightly lower prevalence of incontinence of 14.6% compared with Hazewinkel et al⁶⁴ who found the prevalence of defecation urgency in women who had completed radiation therapy for CC was 49%.

The effect of RT and/or CT/RT treatment on the overall QoL of women is also widely documented in both cross-sectional and longitudinal studies in the literature. In their longitudinal study of 121 CC patients, Greimel et al³¹ reported participants in the surgery/RT group reported significantly worse QoL outcomes (lower scores on physical, role, cognitive, and social functioning) compared with participants in the surgery group or surgery/CT group. The severity of symptoms such as nausea/vomiting, pain, appetite loss, frequent urination (P < 0.019), urine leakage (P < 0.015), and the feeling of tightness in the vagina (P < 0.018) was significantly higher in irradiated participants. Regarding the sexual functioning QoL domain, patients in the surgery/RT group reported a significantly lower sexual activity rate compared with women in the surgery group or those in the surgery/CT group (P < 0.05).

In another longitudinal study, Kirchheiner et al³⁵ found global health status and physical and role functioning showed a highly significant decline during CT/RT treatment (P < 0.001) and declined further to near the baseline levels three months after end of treatment. Compared to the reference population (CT group), global health status (GHS) and emotional and role functioning remained impaired in the CT/RT group. Other studies report poor or lower GHS, social, emotional and functional status and higher symptom and financial suffering in patients treated with RT or RT/CT.^7,42,46 The most frequently reported PRS predictors of poor QoL during active treatment were fatigue (78%), diarrhoea (68%), urinary frequency (60%) and nausea (54%). Findings are consistent with those of other studies.^{3,5,32,34,37,38} Pasek et al⁶ in their longitudinal study found that physical, emotional role and financial functioning were poor during and after RT and profoundly compromised QoL of the participants. Bjelic-Radisic et al³ found that pelvic irradiation alone or with other therapy (surgery or CT) was associated with most symptoms of diarrhoea. Compromised QoL was also observed in 13 other domains of QoL, namely physical, role, emotional, cognitive, social functioning, global health/QoL, fatigue, nausea and vomiting, pain, appetite loss, constipation, symptom experience and sexual enjoyment. Mikkelsen et al¹⁸ found QoL was lower in participants who received CT/RT.

It can be argued that whereas chemotherapy increases the sensitivity of CC cells to RT, CT/RT combination is associated with a higher symptom burden. Sumdaengrit et al¹³ found diarrhoea and rectal irritation were the most distressful symptoms for the participants, while Heijkoop et al¹⁹ found diarrhoea and bowel cramps increased markedly during RT treatment and profoundly impacted the QoL of the participants, particularly reducing their score in the global health and functioning status domains.

Research elsewhere, notably in South Africa, found bowel problems (urgency, diarrhoea, pain, constipation, and appetite loss, nausea and vomiting) negatively impacted QoL.⁵ However, contradictory findings also exist. For example, Heijkoop et al³² found RT-induced bowel morbidity was associated with reduced global health and functioning status while Sabulei and Maree⁵ found the GHS of the participants improved significantly compared to the functioning scores, while financial difficulties were common. The differences in the observations could be due to different study designs used in each of the studies, for example, Heijkoop et al³² used a longitudinal design while Sabulei and Maree⁵ used a cross-sectional design. Interestingly, du Toit and Kidd,³⁰ in their earlier South African longitudinal study found that RT resulted in an improvement in pain and bowel (gastrointestinal) symptoms. It is unclear as to whether patient- and treatment-related differences or limited sample sizes are possible predictors of the observed differences. This suggests a need for large studies of longitudinal designs to examine both short-term and long-term effects.

Strengths and Limitations of the Review

This study has important strengths worth mentioning. First, the study is informed by rich literature retrieved through a systematic rigorous search performed in trusted databases that publish high quality peer reviewed work. The methodological critique applied to select and appraise eligible articles is also strong, this increases the dependability and credibility of the findings. Secondly, the evidence used in the review was pooled from studies that used different study designs, hence some triangulation of the study findings. Thirdly, based on the findings, this is one of the first systematic reviews to examine, in detail, CPP and bowel morbidity and their impact on QoL of CCSs treated with RT or RT/CT. Hence, the review is novel to some extent.

However, the review has a few limitations to acknowledge. First, the literature search was conducted in just four databases. It is likely some papers published and indexed in other databases could have been missed. Hence, findings may not be a true reflection or representative of the available published research on the topic. Second, we know that bowel morbidity and CPP may develop later, several months or years following RT treatment, requiring longitudinal studies with longer duration of follow-up to better examine late adverse events. Most of the studies used in this review had a short duration of follow-up and small sample sizes, while some used cross-sectional design and lacked baseline and follow-up data. Third, to a large extent, findings in this review are skewed towards high-income countries (HICs), with very few studies conducted in LMICs. In addition, most of the studies had small sample sizes. Moreover, the findings from the studies done in HICs may not be wholly generalised to the situation in LMICs due to potential contextual differences such as dosages and the quality of radiotherapy treatment and sociocultural nuances, all which could influence patients’ symptom experience. Fourth, the heterogeneity of the data, eg uncontrolled treatment modalities, poses an additional limitation. These make it hard to make a more realistic balanced discussion of the findings and draw generalisable deductions.

Conclusion

This review found that CPP and bowel morbidity are common symptoms in CCSs treated with RT or RT/CT. The review found there exists a strong relationship between these morbidities and poor QoL among CCSs. Studies reported disruptions in nearly all domains of QoL of an individual, including global, physical, emotional/psychological, financial, sexual, social, and role functioning as a result of being treated with RT or RT/CT for CC. To note, research evidence, particularly from large sample longitudinal studies with extended periods of follow-up is sparse, as are studies from LMICs. There is a need for more longitudinal population-based (large sample size) studies with extended follow-up periods to examine late adverse effects of RT treatment. In addition, studies in which treatment modalities are controlled would give findings that are more accurate.

Research employing qualitative designs is also needed to capture lived experiences of patients treated for CC which may be missed by quantitative design. Interventions for timely and effective assessment and management of CPP and bowel morbidity need to be given a priority as in clinical settings, and as evidenced in the literature, the failure to manage these morbidities profoundly compromises the QoL of patients, and may even worsen the outcome.

Strengths and Limitations of the Study

This is a worldwide systematically appraised review of original peer-reviewed evidence.

The review integrates mixed methodologies evidence. The heterogeneity of the data makes it difficult to generalise findings across different contexts. Most of the studies lacked baseline data, had small sample sizes and or had short follow-up times and hence had limited ability to examine late adverse events.