Pharmacological interventions for the prevention of insufficiency fractures and avascular necrosis associated with pelvic radiotherapy in adults

Abstract

This is the protocol for a review and there is no abstract. The objectives are as follows:

The overall objective is to assess the effects of pharmacological interventions for prevention of insufficiency fractures associated with pelvic radiotherapy in adults.

Primary objective

• To assess the effects of pharmacological interventions on insufficiency fractures and avascular necrosis of the femoral head after curative pelvic radiotherapy in adults.

Secondary objectives

• To assess the effects of pharmacological interventions on bone mineral density and fracture risk in adults after curative pelvic radiotherapy.

• To assess the effects of pharmacological interventions on quality of life (QoL) and bone symptoms in adults after curative pelvic radiotherapy.

• To assess the effects of pharmacological interventions on unplanned hospital stay and mortality in adults undergoing curative pelvic radiotherapy.

• To identify adverse effects of pharmacological interventions.

• To compare different types of pharmacological interventions.

Background

Description of the condition

Radiotherapy‐related bone disease is increasingly recognised as an important, yet under‐researched area. In the UK, 17,000 patients per year are treated with pelvic radiotherapy (West 2009) for gynaecological, colorectal, prostate and bladder cancers. It is estimated that 150,000 to 300,000 people across the developed world are treated annually (Andreyev 2005; Hauer‐Jensen 2003).

An insufficiency fracture is a type of stress fracture identified on magnetic resonance imaging (MRI) after radiotherapy and associated with minimal or no trauma. Pelvic radiotherapy can cause microvascular occlusion (blockage of small blood vessels) in bone, which results in bone necrosis (cell death) and altered osteoblastic function (osteoblasts are bone‐forming cells) and eventually bone fragility (Hopewell 2003). Reported bone abnormalities after pelvic radiotherapy include bone marrow signal changes, insufficiency fractures (Baxter 2005) and femoral head avascular necrosis (necrosis due to interrupted blood supply). Reported incidences of insufficiency fracture after pelvic radiotherapy range between 2.7% and 89% (Bliss 1996; Blomlie 1996) with femoral head avascular necrosis occurring in up to 0.5% to 1% (Bliss 1996; Kwon 2008); these fractures have been noted in those receiving pelvic radiotherapy for gynaecological (endometrial/cervical) cancers (Ikushima 2006, Shih 2013), as well as for prostate (Igdem 2010), anal and rectal cancers (Herman 2009; Kim 2012; Dzik‐Jurasz 2001). The timing of development of fractures is variable; reports in the literature describe fractures diagnosed between 2 and 63 months after completion of radiotherapy, with reported median time to development of 6 to 20 months (Erickson 2000; Ikushima 2006; Kwon 2008; Schmeler 2010). Approximately 43% to 77% of patients are symptomatic (Kwon 2008; Abe 1992) and experience pain that can impact their quality of life, resulting in long‐term morbidity.

Chemotherapy may be used alongside pelvic radiotherapy as curative treatment and is known to increase radiation toxicity, including bone toxicity (Jenkins 1995; Kirwan 2003; Kim 2012). Steroids are known to be associated with osteoporosis and increased risk of fracture (Bauer 2000; Ono 1992). Chemotherapy regimens often include co administered steroids, which may be responsible for the associated increase in insufficiency fractures and osteonecrosis (death of bone cells due to interrupted blood supply) (Bauer 2000).

Risk factors such as osteoporosis (Kim 2012), older age (Park 2011; Schmeler 2010), low body weight (Oh 2008; Tokumaru 2012) and postmenopausal status (Ikushima 2006; Abe 1992) have also been associated with increased risk of insufficiency fracture after pelvic radiotherapy. Higher radiation dose, completion of treatment and use of concurrent chemotherapy all increase the chances of cancer cure; however, these factors are also associated with an increased incidence of toxicity, including risk of insufficiency fractures (Oh 2008).

Description of the intervention

Potential pharmacological interventions to prevent pelvic radiotherapy－induced insufficiency fractures are based on standard treatments for optimal bone health. These include adequate bone mineralisation using combined calcium and vitamin D supplements or vitamin D monotherapy; prevention of bone resorption (breaking down of bone) using bisphosphonates (drugs that impair the function and activity of bone‐resorbing cells, which are called osteoclasts), hormone manipulation (oestrogen and testosterone preparations and selective oestrogen receptor modulators (drugs that reduce bone resorption by binding to the oestrogen receptor in women)) or denosumab (an antibody drug that reduces the formation, function and survival of osteoclasts); and medications that promote bone formation (teriparatide). Calcitonin and strontium also affect bone resorption and formation and are used in osteoporosis treatment.

These interventions may be employed before or during radiotherapy with the goal of preventing insufficiency fractures.

How the intervention might work

Insufficiency fracture is usually related to underlying weakened bone, and the risk is increased in patients with osteoporosis, rheumatoid arthritis, fibrous dysplasia (a condition wherein parts of bone are replaced by fibrous connective tissue), Paget’s disease (a disorder characterised by areas of bony overgrowth), osteogenesis imperfecta ('brittle bone disease'), osteomalacia (condition with inadequate mineralisation of bone－Rickett's in children) or hyperparathyroidism (overactive parathyroid glands leading to raised parathyroid hormone (PTH), which is harmful to bone) (Blake 2004; Lourie 1982; Pentecost 1964; Hosey 2008).

The pathophysiology of radiotherapy‐induced insufficiency fracture is not well understood, although data suggest that the incidence is increased in patients with osteoporosis (Park 2011; Kim 2012). Interventions that target osteoporosis could therefore potentially be effective.

Calcium and vitamin D optimise mineralisation of bone. Furthermore, trials with bisphosphonates that demonstrate reduction in fracture risk in postmenopausal women were carried out in the presence of optimal calcium and vitamin D levels (reviewed in NICE TA160 and NICE TA161).

Bisphosphonates, denosumab, calcitonin (a hormone produced by the thyroid gland, which opposes the actions of PTH), strontium (a drug with an antiresorptive effect) and teriparatide (a recombinant PTH) have been demonstrated to reduce the incidence of fracture in patients with osteoporosis by preventing bone resorption or promoting bone formation or a combination of the two (reviewed in NICE TA160 and NICE TA161). Hormone replacement therapies (oestrogen and testosterone) can be used to improve bone density if evidence of hormonal deficiency is noted.

Although no specific data are available on treatment for radiotherapy‐induced insufficiency fracture, if patients undergoing pelvic radiotherapy have low vitamin D or hormone levels or underlying osteoporosis, providing optimal bone strength with a combination of the above could theoretically reduce the incidence of insufficiency fracture and avascular necrosis.

Insufficiency fractures are associated with increased mortality and morbidity (Taillandier 2003; Bliuc 2009). The aim of pharmacological intervention therefore is to prevent insufficiency fractures from occurring during or after radiotherapy, thus potentially reducing mortality and morbidity and improving quality of life and patient‐reported outcome measures.

Why it is important to do this review

Recognition that pelvic insufficiency fractures are a consequence of pelvic radiotherapy is increasing. Insufficiency fractures can lead to significant and prolonged morbidity in terms of pelvic/back pain and immobility, which, in turn, is associated with a variety of complications, including infection and pressure sores.

The clinical features of pelvic insufficiency fractures may be confused with those of metastatic or recurrent disease, leading to potentially unnecessary investigations, interventions and anxiety for patients, all of which have a consequent impact on resources.

Once an insufficiency fracture has been identified, treatment is generally conservative and includes analgesia and rehabilitation. Resolution of symptoms can take between 1 month and 35 months, and a minority of patients remain persistently symptomatic (Ikushima 2006; Blomlie 1996; Huh 2002; Ogino 2003).

Few data are available regarding mortality rates specifically associated with pelvic insufficiency fractures associated with pelvic radiotherapy. However, mortality rates of 14% and 23% for pelvic insufficiency fractures in general have been reported at 1 year in older patients (Mears 2011; Taillandier 2003). It has been well documented that mortality is significantly increased during the first year after a hip fracture (Baxter 2005). Evidence suggests that increased mortality risk can persist for some years (Bliuc 2009) and that rates of mortality associated with insufficiency fractures and displaced pelvic fractures are similar in older patients (Mears 2011). Other, less common bone complications of pelvic radiotherapy include osteolysis and avascular necrosis of the femoral head (Kwon 2008).

Currently, almost 2 million cancer survivors can be found in England, and this figure is projected to rise to 4 million over the next 20 years (Maddams 2012). Long‐term consequences of cancer treatment vary significantly in severity and prevalence, but as the number of cancer survivors increases, strategies to reduce the risk of developing these problems become more relevant. For patients receiving pelvic radiotherapy, there is a need to identify possible therapeutic interventions that may reduce the incidence of radiation‐induced pelvic insufficiency fracture. A systematic review of published studies examining the effects of these interventions has not previously been undertaken and could inform the development of clinical guidelines, which, in turn, would benefit both patients and healthcare systems.

 

Objectives

The overall objective is to assess the effects of pharmacological interventions for prevention of insufficiency fractures associated with pelvic radiotherapy in adults.

Primary objective

• To assess the effects of pharmacological interventions on insufficiency fractures and avascular necrosis of the femoral head after curative pelvic radiotherapy in adults.

Secondary objectives

• To assess the effects of pharmacological interventions on bone mineral density and fracture risk in adults after curative pelvic radiotherapy.

• To assess the effects of pharmacological interventions on quality of life (QoL) and bone symptoms in adults after curative pelvic radiotherapy.

• To assess the effects of pharmacological interventions on unplanned hospital stay and mortality in adults undergoing curative pelvic radiotherapy.

• To identify adverse effects of pharmacological interventions.

• To compare different types of pharmacological interventions.

Methods

Criteria for considering studies for this review

Types of studies

Randomized controlled trials (RCTs), including conference abstracts of RCTs, from which sufficient data can be obtained.

We expect to find few RCTs on pharmacological interventions; therefore, non‐randomised studies with concurrent comparison groups will also be included:

• Quasi‐randomised trials, cluster RCTs, non‐randomised trials, prospective cohort studies, and case series of 30 or more participants.

Types of participants

Adults, of any gender, aged 18 or older, undergoing radical pelvic radiotherapy (external beam, brachytherapy or both) as part of their anticancer treatment for a primary pelvic malignancy, including gynaecological (cervix or uterus), lower gastrointestinal (anal or rectal) and urological (prostate or bladder) malignancies. Patients with bone metastases will be excluded.

Types of interventions

Pharmacological interventions may be provided at any stage before or during pelvic radiotherapy.

Pharmacological interventions will include one or more of the following:

• Calcium supplements;

• Vitamin D supplements;

• Bisphosphonates: alendronate, alendronic acid, etidronate, ibandronate, risedronate, zolendronate, pamidronate;

• Selective oestrogen receptor modulators: raloxifene;

• Hormone replacement: oestrogen replacement therapy, hormone replacement therapy;

• Combined oestrogen and progesterone oral contraceptive pill;

• Testosterone replacement: testosterone undecanoate, testosterone, Sustanon;

• Strontium ranelate;

• Teriparatide;

• Denosumab; and

• Calcitonin.

Trials may examine providing pharmacological interventions in comparison with not providing pharmacological interventions or may compare alternative types of interventions. We will ensure that pooling of data for pharmacological interventions is appropriate and does not combine drugs that are different in composition. This potentially involves multiple comparisons. This review will analyse those comparisons studied to date but in the future may be split to analyse each individual pharmacological intervention compared with placebo or standard care.

Types of outcome measures

Primary outcomes

• Insufficiency fractures and avascular necrosis developing within 5 years after completion of pelvic radiotherapy as determined by accepted radiological appearances on MRI/computed tomography (CT) imaging.

Secondary outcomes

• Bone mineral density changes as determined by dual‐energy x‐ray absorptiometry (DEXA) (bone density scan), quantitative CT, quantitative MRI or ultrasound scanning and changes in fracture risk assessed using the FRAX score (method for calculating fracture risk) within 5 years after completion of radiotherapy.

• Changes in bone turnover markers, including serum alkaline phosphatase, bone‐specific alkaline phosphatase, serum osteocalcin, serum type 1 procollagen (C‐terminal/N‐terminal: C1NP or P1NP), urinary hydroxyproline, urinary total pyridinoline (PYD), urinary free deoxypyridinoline (DPD), urinary collagen type 1 cross‐linked N‐telopeptide (NTX), urinary or serum collagen type 1 cross‐linked C‐telopeptide (CTX), bone sialoprotein (BSP) and tartrate‐resistant acid phosphatase 5b.

• QoL measured using a scale that has been validated through reporting of norms in a peer‐reviewed publication, including participant‐reported bone symptoms and participant outcomes.

• Mortality, specifically cancer‐related and overall mortality.

• Adverse effects and compliance with pharmacological interventions, including those related to a specific agent or route of delivery.

Search methods for identification of studies

Electronic searches

The following electronic databases will be searched:

• The Cochrane Central Register of Controlled Trials (CENTRAL);

• The Cochrane Gynaecological Cancer Collaborative Review Group's Trial Register;

• MEDLINE;

• EMBASE;

• AMED;

• BNI and CINAHL; and

• DARE.

The MEDLINE search strategy is presented in Appendix 1. For databases other than MEDLINE, the search strategy will be adapted accordingly. All relevant articles will be identified on PubMed, and by using the 'Related articles' feature, a further search will be carried out for newly published articles. Reports in all languages will be sought and translations carried out if necessary.

Searching other resources

Unpublished and grey literature MetaRegister (www.controlled‐trials.com), Physicians Data query (nci.nih.gov), www.clinicaltrials.gov and www.cancer.gov/clinicaltrials will be searched for ongoing trials. If ongoing trials that have not been published are identified through these searches, the principal investigators will be approached with requests for relevant data. Conference proceedings and abstracts will be searched through ZETOC (zetoc.mimas.ac.uk) and WorldCat Dissertations.

Handsearching

We will handsearch the citation lists of included studies, key textbooks and previous systematic reviews and will contact experts in the field to identify further reports of trials. We will also handsearch reports of conferences.

Suggested reports of conferences to be handsearched:

• Gynecologic Oncology (Annual Meeting of the American Society of Gynecologic Oncologists);

• International Journal of Gynecological Cancer (Annual Meeting of the International Gynecologic Cancer Society);

• British Journal of Cancer;

• British Cancer Research Meeting;

• Annual Meeting of the European Society of Medical Oncology (ESMO); and

• Annual Meeting of the American Society of Clinical Oncology (ASCO).

Data collection and analysis

Selection of studies

We will download all titles and abstracts retrieved by electronic searching to a reference management database (e.g. Reference Manager, Endnote) and will remove duplicates. Two review authors (QUM, KG) will examine the remaining references independently. We will exclude those studies that clearly do not meet the inclusion criteria, and we will obtain copies of the full text of potentially relevant references. Two review authors (QUM, KG) will independently assess the eligibility of retrieved studies. Disagreements will be resolved by discussion between the two review authors and, if necessary, with a third review author (CCH). Reasons for exclusion will be documented. Multiple reports of the same study will be linked to ensure that no data are included in the meta‐analysis more than once.

Data extraction and management

A data collection form will be devised for the study that will facilitate data collection from the included studies. The data form will be piloted and modified as required. Two review authors will undertake the process of data extraction independently, with discrepancies discussed between them and a third review author if required. For each trial, the following information will be recorded:

• Author, year of publication and journal citation (including language);

• Country;

• Setting;

• Inclusion and exclusion criteria;

• Study design, methodology;

• Study population:

  • Total number enrolled;

  • Patient characteristics, gender;

  • Age; and

  • Comorbidities.

• Details of bone health:

  • Bone mineral density using validated measures;

  • Fracture risk assessment derived from a validated tool (e.g. FRAX score); and

  • Biochemical measures (including vitamin D, alkaline phosphatase, calcium, phosphate, P1NP and CTX). 

• Cancer details:

  • Type and stage;

  • Previous surgery; and

  • Treatment details (external beam radiotherapy dose/volume/fractionation and details of brachytherapy, chemotherapy and surgery).  

• Pharmacological intervention details:

  • Type of intervention;

  • Timing of intervention in relation to radiotherapy;

  • Route of intervention;

  • Length of intervention;

  • Quantity delivered; and

  • Adverse effects.

• Comparison:

  • Definition and details.

• Details of bone symptoms:

  • Validated toxicity scores;

  • Validated participant‐reported outcome measure scores; and

  • Other symptom‐based questionnaires/interview scores.

• Details of QoL measures including participant‐reported outcomes;

• Details of clinical outcomes, including unplanned hospital stay and mortality;

• Risk of bias in study (see later);

• Duration of follow‐up;

• Outcomes: For each outcome, we will extract the outcome definition and unit of measurement (if relevant). For adjusted estimates, we will record variables adjusted for in analyses; and

• Results: We will extract the number of participants allocated to each intervention group, the total number analysed for each outcome and the missing participants.

Results will be extracted as follows:

• For time‐to‐event data (survival and disease progression), we will extract the log of the hazard ratio [log(HR)] and its standard error from trial reports. If these are not reported, we will attempt to estimate the log(HR) and its standard error using the methods of Parmer 1998;

• For dichotomous outcomes (e.g. insufficiency fractures, adverse events or deaths, if it is not possible to use a hazard ratio), we will extract the number of participants in each treatment arm who experienced the outcome of interest and the number of participants assessed at endpoint, to estimate a risk ratio; and

• For continuous outcomes (e.g. QoL measures), we will extract the final value and the standard deviation of the outcome of interest and the number of participants assessed at endpoint in each treatment arm at the end of follow‐up, to estimate the mean difference between treatment arms and its standard error.

If reported, we will extract both unadjusted and adjusted statistics.

Where possible, all data extracted will be those relevant to an intention‐to‐treat analysis, in which participants will be analysed in the groups to which they were assigned.

We will note the time points at which outcomes were collected and reported.

Data will be independently extracted by two review authors (QUM, KG) onto a data extraction form specially designed for the review. We will resolve differences between review authors by discussion or by appeal to a third review author (CCH) if necessary.

Assessment of risk of bias in included studies

We will assess the risk of bias in included studies using the Cochrane Collaboration's tool (Higgins 2011). This will include assessment of:

• Selection bias: random sequence generation and allocation concealment;

• Performance bias: blinding of participants and personnel (patients and treatment providers);

• Detection bias: blinding of outcome assessment;

• Attrition bias: incomplete outcome data;

• Reporting bias: selective reporting of outcomes; and

• Other possible sources of bias.

Two review authors (QUM, KG) will apply the risk of bias tool independently, and differences will be resolved by discussion or by appeal to a third review author (CCH). We will summarise results on a risk of bias graph and in a risk of bias summary. Results of meta‐analyses will be interpreted in the light of findings with respect to risk of bias.

Individual 'risk of bias' items are detailed in Appendix 2.

Measures of treatment effect

We will use the following measures of the effects of treatment:

• For time‐to‐event data, we will use the hazard ratio, if possible;

• For dichotomous outcomes, we will use the risk ratio;

• For continuous outcomes, we will use the mean difference between treatment arms; and

• Standardised mean difference will be used to compare studies in which outcomes are measured on different scales, for example, bone symptoms and toxicity scores.

Unit of analysis issues

Two review authors (QUM, KG) will review unit of analysis issues according to Higgins 2011, and differences will be resolved by discussion. These include reports wherein:

• Groups of individuals are randomly assigned together to the same intervention (i.e. cluster‐randomized trials);

• Individuals undergo more than one intervention (e.g. in a cross‐over trial, or simultaneous treatment of multiple sites on each individual); or

• Multiple observations describe the same outcome (e.g. repeated measurements, recurring events, measurements of different body parts).

Studies with multiple control groups will be handled by combining all relevant control groups into a single group for comparison with the intervention. Studies with multiple intervention groups will be combined into a single group for comparison with the control group, if possible. If this is not possible, a pair‐wise comparison will be performed with shared intervention or control groups divided out approximately evenly among comparisons. For dichotomous outcomes, both the number of events and the total number of participants will be divided up. For continuous outcomes, only the total number of participants will be divided up, and the means and standard deviations will be left unchanged.

Dealing with missing data

We will not impute missing outcome data for the primary outcome. If data are missing, or if only imputed data are reported, we will contact trial authors to request data on outcomes only among participants who were assessed.

Assessment of heterogeneity

Clinical heterogeneity will be assessed by examining types of participant, interventions and outcomes in each study. Meta‐analyses will be conducted only if studies are reporting similar comparisons for the outcome measures.

We will assess heterogeneity between studies by visual inspection of forest plots, by estimation of the percentage of heterogeneity between trials that cannot be ascribed to sampling variation (Higgins 2003), by completion of a formal statistical test of the significance of the heterogeneity (Deeks 2001) and, if possible, by subgroup analyses. If evidence of substantial heterogeneity is found, the possible reasons for this will be investigated and reported.

Assessment of reporting biases

We will examine funnel plots corresponding to meta‐analyses of the primary outcome to assess the potential for small study effects, such as publication bias if a sufficient number of studies are identified (e.g. more than 10).

Data synthesis

If sufficient clinically similar studies are available, we will pool their results in meta‐analyses using Cochrane Review Manager Software (RevMan 5.1).

• For time‐to‐event data, we will pool hazard ratios using the generic inverse variance facility of RevMan 5.1.

• For any dichotomous outcomes, we will calculate the risk ratio for each study, and all will be pooled; and  

• For continuous outcomes, we will pool the mean differences between treatment arms at the end of follow‐up if all trials measure the outcome on the same scale; otherwise we will pool standardised mean differences. 

If any trials have multiple treatment groups, we will divide the ‘shared’ comparison group into the number of treatment groups and the number of comparisons between each treatment group, and we will treat the components of the split comparison group as independent comparisons.

We will use the random‐effects model with inverse variance weighting for all meta‐analyses (DerSimonian 1986).

Subgroup analysis and investigation of heterogeneity

Subgroup analysis will be undertaken, if data allow, on studies as follows:

• Comparison by participant age;

• Comparison by participant gender;

• Comparisons by primary tumour site;

• Comparisons by type of radiotherapy, including external beam conformal radiotherapy, intensity‐modulated radiotherapy (IMRT), brachytherapy and combinations of these;

• Comparisons by cancer treatment modalities, including external beam radiotherapy, brachytherapy, chemotherapy, surgery and combinations of these;

• Comparison by use of steroids; and

• Comparison by baseline bone mineral density or fracture risk (FRAX) score.

We will consider factors such as age, stage, type of intervention, length of follow‐up and risk of bias status in interpretation of any heterogeneity.

Sensitivity analysis

Sensitivity analysis will be performed if relevant issues are identified during the review process. If sensitivity analyses identify particular decisions or missing information that greatly influence the findings of the review, we will attempt to resolve uncertainties and to obtain extra information by contacting trial authors and requesting individual patient data. If this cannot be achieved, the results will be interpreted with an appropriate degree of caution. Studies at high risk of bias will be excluded from the meta‐analysis as part of the sensitivity analysis.

Appendices

Appendix 1. MEDLINE search strategy

Medline Ovid

 1   exp Fractures, Bone/ 2   fracture*.mp. 3   (bone* adj5 (break or broke*)).mp. 4   Femur Head Necrosis/ 5   femur head necrosis.mp. 6   avascular necrosis.mp. 7   (bone* adj5 (fragility or fragile)).mp. 8   1 or 2 or 3 or 4 or 5 or 6 or 7 9   exp Radiotherapy/ 10 (radiotherap* or brachytherapy or IMRT).mp. 11 (radiat* or irradiat*).mp. 12 radiotherapy.fs. 13 9 or 10 or 11 or 12 14 drug therapy.fs. 15 Calcium, Dietary/ 16 exp Vitamin D/ 17 exp Diphosphonates/ 18 exp Selective Estrogen Receptor Modulators/ 19 exp Hormone Replacement Therapy/ 20 exp Contraceptives, Oral/ 21 exp Testosterone/ 22 (calcium or vitamin D or bisphosphonate* or alendronate or alendronic acid or etidronate or ibandronate or risedronate or zolendronate or pamidronate or (selective adj (oestrogen or estrogen) adj receptor modulator*) or raloxifene or hormone replacement or ((oestrogen or estrogen) adj replacement therapy) or oral contraceptive pill or testosterone or sustanon or strontium ranelate or teriparatide or denosumab or calcitonin).mp. 23 14 or 15 or 16 or 17 or 18 or 19 or 20 or 21 or 22 24 8 and 13 and 23

key:

mp = Title, abstract, original title, name of substance word, subject heading word, protocol supplementary concept, rare disease supplementary concept, unique identifier

 

Appendix 2. Risk of bias

(1) Random sequence generation

·         Low risk of bias (e.g. participants assigned to treatments on basis of a computer‐generated random sequence or a table of random numbers).

·         High risk of bias (e.g. participants assigned to treatments on basis of date of birth or clinic ID‐number or surname, or no attempt is made to randomly assign participants).

·         Unclear risk of bias (e.g. not reported, information not available).

(2) Allocation concealment

·         Low risk of bias (e.g. allocation sequence could not be foretold).

·         High risk of bias (e.g. allocation sequence could be foretold by participants, investigators or treatment providers).

·         Unclear risk of bias (e.g. not reported).

(3.1) Blinding of participants and personnel

·         Low risk of bias if participants and personnel were adequately blinded.

·         High risk of bias if participants were not blinded to the intervention that they received.

·         Unclear risk of bias if this was not reported or was unclear.

(3.2) Blinding of outcomes assessors

·         Low risk of bias if outcomes assessors were adequately blinded.

·         High risk of bias if outcomes assessors were not blinded to the interventions that participants received.

·         Unclear risk of bias if this was not reported or was unclear.

(4)    Incomplete outcome data

We will record the proportion of participants whose outcomes were not reported at the end of the study. We will code a satisfactory level of loss to follow‐up for each outcome as:

·         Low risk of bias if fewer than 20% of participants were lost to follow‐up and reasons for loss to follow‐up were similar in both treatment arms;

·         High risk of bias if more than 20% of participants were lost to follow‐up or reasons for loss to follow‐up differed between treatment arms; and

·         Unclear risk of bias if loss to follow‐up was not reported.

(5) Selective reporting of outcomes

·         Low risk of bias (e.g. review reports all outcomes specified in the protocol).

·         High risk of bias (e.g. it is suspected that outcomes have been selectively reported).

·         Unclear risk of bias (e.g. It is unclear whether outcomes had been selectively reported).

(6) Other bias

·         Low risk of bias: if you do not suspect any other source of bias and the trial appears to be methodologically sound.

·         High risk of bias: if you suspect that the trial was prone to an additional bias.

·         Unclear risk of bias: if you are uncertain whether an additional bias may have been present.

Non‐randomised studies

We will assess the risk of bias in non‐randomised controlled trials in accordance with four additional criteria concerning cohort selection and comparability of treatment groups.

(1) Relevant details of criteria for assignment of participants to treatments

·         Low risk of bias (e.g. Yes).

·         High risk of bias (e.g. No).

·         Unclear risk of bias.

(2) Representative group of participants who received the experimental intervention

·         Low risk of bias if representative of adults undergoing pelvic radiotherapy.

·         High risk of bias if groups of participants were selected.

·         Unclear risk of bias if selection of group was not described.

(3) Representative group of participants who received the comparison intervention

·         Low risk of bias if drawn from the same population as the experimental cohort.

·         High risk of bias if drawn from a different source.

·         Unclear risk of bias if selection of group is not described.

(4) No differences between the two groups or differences controlled for, in particular with reference to age, gender, type/dose of radiotherapy, use of chemotherapy, performance status

·      Low risk of bias if at least two of these characteristics were reported.

·      High risk of bias if the two groups differed and differences were not controlled for.

·      Unclear risk of bias if fewer than two of these characteristics were reported even if no other differences were noted between the groups and other characteristics were controlled for.

What's new

Date	Event	Description
21 September 2016	Amended	Contact details updated.

History

Protocol first published: Issue 6, 2013

Date	Event	Description
27 March 2014	Amended	Contact details updated.

Contributions of authors

All the named review authors have been involved in the development of this protocol.

Declarations of interest

None known

Edited (no change to conclusions)