Medical interventions for high‐grade vulval intraepithelial neoplasia
Abstract
Background
This is an updated version of a review first published in theCochrane Database of Systematic Reviews, Issue 4, in 2011. Vulval intraepithelial neoplasia (VIN) is a pre‐cancerous condition of the vulval skin and its incidence is increasing in women under 50 years. High‐grade VIN (also called usual‐type VIN (uVIN) or VIN 2/3 or high‐grade vulval intraepithelial lesion) is associated with human papilloma virus (HPV) infection and may progress to vulval cancer, therefore is usually actively managed. There is no consensus on the optimal management of high‐grade VIN; and the high morbidity and relapse rates associated with surgical interventions make less invasive interventions highly desirable.
Objectives
To evaluate the effectiveness and safety of medical (non‐surgical) interventions for high‐grade VIN.
Search methods
We searched the Cochrane Gynaecological Cancer Group Trials Register, Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2015, Issue 3), MEDLINE and EMBASE (up to 30 March 2015). We also searched registers of clinical trials, abstracts of scientific meetings, reference lists of included studies and contacted experts in the field.
Selection criteria
Randomised controlled trials (RCTs) that assessed non‐surgical interventions in women diagnosed with high‐grade VIN.
Data collection and analysis
We used Cochrane methodology with two review authors independently abstracting data and assessing risk of bias. Where possible, we synthesised data in meta‐analyses using random effects methods.
Main results
Five trials involving 297 women with high‐grade VIN (defined by trial investigators as VIN 2/3 or VIN 3 or 'high‐grade' lesions) met our inclusion criteria: three trials assessed the effectiveness of topical imiquimod versus placebo; one assessed topical cidofovir versus topical imiquimod; and one assessed low‐ versus high‐dose indole‐3‐carbinol in similar types of participants. Three trials were at a moderate to low risk of bias, two were at a potentially high risk of bias.
Meta‐analysis of the three trials comparing topical imiquimod 5% cream to placebo found that women in the active treatment group were more likely to show an overall response (complete and partial response) to treatment at five to six months compared with the placebo group (Risk Ratio (RR) 11.95, 95% confidence interval (CI) 3.21 to 44.51; participants = 104; studies = 3; I2 = 0%; high‐quality evidence). A complete response at five to six months occurred in 36/62 (58%) and 0/42 (0%) participants in the active and placebo groups, respectively (RR 14.40, 95% CI 2.97 to 69.80; participants = 104; studies = 3; I2 = 0%; high‐quality evidence). A single trial reported 12‐month follow‐up, which revealed a sustained effect in overall response in favour of the active treatment arm at 12 months (RR 9.10, 95% CI 2.38 to 34.77; moderate‐quality evidence), with 9/24 (38%) and 0/23 (0%) complete responses recorded in the active and placebo groups respectively. Progression to vulval cancer was also documented in this trial (one versus two participants in the active and placebo groups, respectively) and we assessed this evidence as low‐quality. Only one trial reported adverse events, including erythema, erosion, pain and pruritis at the site of the lesion, which were more common in the imiquimod group. Dose reductions occurred more frequently in the active treatment group compared with the placebo group (19/47 versus 1/36 participants; RR 7.77, 95% CI 1.61 to 37.36; participants = 83; studies = 2; I2 = 0%; high‐quality evidence). Only one trial reported quality of life (QoL) and there were no significant differences between the imiquimod and placebo groups.
For the imiquimod versus cidofovir trial, 180 women contributed data. The overall response at six months was similar for the imiquimod and cidofovir treatment groups with 52/91 (57%) versus 55/89 (62%) participants responding, respectively (RR 0.92, 95% CI 0.73 to 1.18; moderate‐quality evidence). A complete response occurred in 41 women in each group (45% and 46%, respectively; RR 1.00, 95% CI 0.73 to 1.37; moderate‐quality evidence). Although not statistically different, total adverse events were slightly more common in the imiquimod group of this trial with slightly more discontinuations occurring in this group. Longer term response data from this trial are expected.
The small trial comparing two doses of indole‐3‐carbinol contributed limited data. We identified five ongoing randomised trials of various interventions for high‐grade VIN.
Authors' conclusions
Topical imiquimod appears to be a safe and effective treatment for high‐grade VIN, even though local side‐effects may necessitate dose reductions. However, longer term follow‐up data are needed to corroborate the limited evidence that response to treatment is sustained, and to assess any effect on progression to vulval cancer. Available evidence suggests that topical cidofovir may be a good alternative to imiquimod; however, more evidence is needed, particularly regarding the relative effectiveness on longer term response and progression. We await the longer‐term response data and the results of the five ongoing trials.
PICOs
Plain language summary
Comparison of non‐surgical treatments for women diagnosed with high‐grade VIN (precancerous changes of the vulva related to HPV‐infection)
Background
This is an update of a Cochrane review previously published in 2011. Vulval intraepithelial neoplasia (VIN) is a skin condition affecting the vulval skin, which, if left untreated, may become cancerous. Distressing symptoms include itching, burning, and soreness of the vulva or painful intercourse. There may be discolouration and various other visible changes to the vulval skin. There are two types of VIN: the most common type (now known as usual‐type VIN or uVIN) is associated with infection of the cells of the vulva with a virus called human papilloma virus (HPV or wart virus), whereas the other type (known as differentiated‐type VIN) is not associated with this viral infection. As HPV infection is common, uVIN is becoming more common in younger women (under 50 years of age). At the moment treatments are aimed at relief of distressing symptoms and to ensure that the condition does not become cancerous.The most common treatment option for women with this condition has been surgery to remove the affected skin areas. Surgery, however, does not guarantee a cure, can be disfiguring, and may result in physical and psychological problems in younger women who are sexually active.
Potential non‐surgical treatment options include imiquimod, indole‐3‐carbinol, cidofovir, IFN‐α and HPV vaccines. These mainly work by enhancing the body's immune system. The purpose of this review was to assess the effectiveness and safety of these non‐surgical treatments.
Methods
The previous version of this review included four randomised controlled trials. We updated the literature search from September 2010 to March 2015 and identified one new completed trial and five ongoing trials to add to the review.
Findings
In total, we included five randomised controlled trials involving 297 women. Three trials assessed imiquimod compared with placebo, one trial assessed imiquimod compared with cidofovir, and one compared two different doses of indole‐3‐carbinol. We pooled data from the three similar trials involving 104 women and found imiquimod to be more effective in clearing high‐grade VIN lesions by six months than placebo. Most studies did not include longer term follow‐up, but findings from one study suggested that women in whom VIN was completely cleared at six months were likely to sustain this response by 12 months. This single study showed no difference in rates of progression to cancer between study groups. We are uncertain about these longer‐term findings and would like them to be corroborated by other trials. We found limited evidence on side‐effects. However, evidence from one study found that side‐effects, such as pain and itching of the skin over the vulva, occurred more frequently among women in the imiquimod group compared with the placebo group, and were usually managed by reducing the frequency of applications.
The trial comparing imiquimod with cidofovir involved 180 women. These topical treatments appeared to be similarly effective at six months. However, there were no longer term results available for this trial.
The trial of indole‐3‐carbinol was a small trial of only 13 women that compared two different doses of the medication and we could not draw any conclusions about this treatment.
We found no evidence on the effectiveness of other treatments, such as HPV vaccines to treat high‐grade VIN; however, we identified five ongoing trials that may provide important evidence in the future.
Conclusions
Imiquimod appears to be effective and reasonably safe for the treatment of VIN, and cidofovir shows considerable promise, but more research is needed. In particular, more evidence is needed on longer term effectiveness of both treatments, and on the risk of VIN progressing to vulval cancer after treatment.
Authors' conclusions
Summary of findings
| Imiquimod compared with placebo for high‐grade VIN | |||||
| Patient or population: women with high‐grade VIN Settings: outpatient Intervention: imiquimod 5% cream Comparison: placebo | |||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of Participants | Quality of the evidence | |
| Assumed risk (risk in study population) | Corresponding risk | ||||
| Placebo | Imiquimod | ||||
| Response to treatment at 5‐6 months ‐ Overall response | 24 per 1000 | 285 per 1000 | RR 11.95 (3.21 to 44.51) | 104 | ⊕⊕⊕⊕ |
| Response to treatment at 5‐6 months ‐ Complete response | 0 per 1000 | not estimable | RR 14.40 (2.97 to 69.80) | 104 | ⊕⊕⊕⊕ |
| Response to treatment at 12 months ‐ Overall response | 87 per 1000 | 791 per 1000 | RR 9.10 (2.38 to 34.77) | 47 | ⊕⊕⊕⊝ |
| Response to treatment at 12 months ‐ Complete response | 0 per 1000 | not estimable | RR 18.24 (1.12 to 296.41) | 47 | ⊕⊕⊕⊝ |
| Progression to vulval cancer at 12 months | 56 per 1000 | 28 per 1000 | RR 0.48 (0.05 to 4.93) | 47 | ⊕⊕⊝⊝ |
| Pain ‐ Any grade | 269 per 1000 | 922 per 1000 | RR 3.43 (1.80, 6.52) | 52 | ⊕⊕⊕⊕ |
| Dose reductions | 28 per 1000 | 218 per 1000 | RR 7.77 (1.61 to 37.36) | 83 | ⊕⊕⊕⊕ |
| The risk in the cidofovir group is based on the assumed risk on the comparison group and the relative effect of the intervention and its 95% CI. | |||||
| GRADE Working Group grades of evidence | |||||
| 1 Downgraded due to imprecision 2 Downgraded due to sparse data (few events) | |||||
| Imiquimod compared with cidofovir for high‐grade VIN | |||||
| Patient or population: women with high‐grade VIN Settings: outpatient Intervention: imiquimod 5% cream Comparison: 1% cidofovir gel | |||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of Participants | Quality of the evidence | |
| Assumed risk (risk in study population) | Corresponding risk | ||||
| cidofovir | imiquimod | ||||
| Response to treatment at 6 months ‐ Overall response | 618 per 1000 | 569 per 1000 (451 to 729) | RR 0.92 (0.73 to 1.18) | 180 | ⊕⊕⊕⊝ |
| Response to treatment at 6 months ‐ Complete response | 461 per 1000 | 461 per 1000 | RR 1.00 (0.73 to 1.37) | 180 | ⊕⊕⊕⊝ |
| Pain ‐ Any grade | 516 per 1000 | 598 per 1000 | RR 1.16 | 168 | ⊕⊕⊕⊝ |
| Fatigue ‐ Any grade | 607 per 1000 | 759 per 1000 | RR 1.25 (1.02 to 1.55) | 168 (1 study) | ⊕⊕⊕⊝ |
| Headache ‐ Any grade | 440 per 1000 | 656 per 1000 | RR 1.49 (1.12 to 1.98) | 168 (1 study) | ⊕⊕⊕⊝ |
| Total serious adverse events | 369 per 1000 | 465 per 1000 | RR 1.26 (0.88 to 1.81) | 168 (1 study) | ⊕⊕⊕⊝ |
| Treatment discontinuation | 126 per 1000 | 168 per 1000 | RR 1.33 (0.65 to 2.74) | 176 (1 study) | ⊕⊕⊕⊝ |
| *The risk in the cidofovir group is based on the assumed risk on the comparison group and the relative effect of the intervention and its 95% CI. | |||||
| GRADE Working Group grades of evidence | |||||
| 1 Downgraded due to imprecision | |||||
Background
This is an updated version of a review first published in theCochrane Database of Systematic Reviews, Issue 4, in 2011. The terminology of VIN has evolved over the years with our understanding of the biology and natural history of the condition (Wilkinson 2014). For the purpose of this updated review, the term high‐grade VIN includes lesions also referred to in the literature as VIN 2, VIN 3, usual‐type VIN (uVIN) (2004 terminology; Sideri 2005) and vulval high‐grade squamous intraepithelial lesions (HSIL) (2014 terminology; ISSVD 2014; see also Table 1).
| ISSVD 1986 | ISSVD 2004 | LAST 2012 |
| VIN 1 | Flat condyloma or HPV effect | LSIL |
| VIN 2 | VIN, usual type (uVIN) a. VIN, warty type b. VIN, basaloid type c. VIN, mixed (warty/basaloid) type | HSIL |
| VIN 3 | ||
| Differentiated VIN | VIN, differentiated type (dVIN) |
Table derived from ISSVD 2014.
Abbreviations: ISSVD ‐ International Society for the Study of Vulvar Disease; LSIL ‐ low‐grade squamous intraepithelial lesions; HSIL ‐ high‐grade squamous intraepithelial lesion
Description of the condition
Vulval intraepithelial neoplasia (VIN) is a term used for chronic pre‐cancerous skin conditions affecting the vulva. It can affect women at any age but the peak incidence occurs under the age of 50 (De Sanjose 2013; Jones 2005; Nygard 2014). There are two distinct types, a type associated with HPV‐infection (the usual‐type or uVIN) and a rarer type related to chronic skin conditions such as lichen sclerosis (the differentiated‐type or dVIN). Although clinicopathological overlap occurs in a small proportion of cases (< 1%) (De Sanjose 2013; McCluggage 2009), this review concerns HPV‐related VIN.
VIN is diagnosed by histological examination of a vulval biopsy and may be graded as low‐grade (VIN 1) or high‐grade (VIN 2/3) depending on the thickness of epithelium containing undifferentiated cells. Low‐grade lesions are usually, but not always, associated with low‐risk HPV types (Srodon 2006) and have little known risk of invasive carcinoma (Wilkinson 2014), whereas high‐grade VIN is associated with high‐risk HPV types, particularly HPV 16 (De Sanjose 2013; Reyes 2014), which are associated with vulval and other anogenital carcinomas. Newer terminology, with VIN 1 renamed as low‐grade squamous intraepithelial lesions (LSIL), and VIN 2/3 or uVIN renamed as high‐grade squamous intraepithelial lesions (HSIL), has not yet been widely adopted in the United Kingdom (UK) (ISSVD 2014; Wilkinson 2014; Table 1).
HPV‐related VIN (uVIN) has a variable appearance on clinical examination, frequently presenting as multifocal raised plaques or papules which may be white, brown or red (Preti 2015; Reyes 2014). Women usually present with distressing vulval symptoms, including itching, pain, burning, and dyspareunia (painful intercourse). Therefore, impaired sexual functioning and psychological morbidity are frequent associated features (Dominiak‐Felden 2013; Shylasree 2008). Recurrence after treatment is common, with studies reporting recurrence rates of 28% to 51% (Fehr 2013; Jones 2005; ; Van Esch 2013; Wallbilich 2012).
VIN is associated with a risk of progression to vulval cancer and uVIN precedes almost all vulval squamous cell carcinomas (SCC) in younger women (Reyes 2014; Sideri 2005; Van der Avoort 2006). There is evidence that the incidence of vulval SCC in younger women is increasing, driven primarily by the increasing incidence of uVIN (De Vuyst 2009; Dittmer 2011; Joura 2000; Lai 2014; ;Reyes 2014). In England there has been a statistically significant increase in the age‐standardised risk of vulval cancer from approximately 2 to 2.5 per 100,000 women from 1990 to 2009 (Lai 2014), in agreement with similar trends noted in other countries (Dittmer 2011; Jones 1997; Joura 2000; Judson 2006). In addition, the reported incidence of vulval cancer after treatment of VIN ranges from 2% to 6% (Fehr 2013; Jones 2005; Van Seters 2005; Wallbilich 2012), and for untreated VIN ranges from 9% (Van Seters 2005) to 16% (Jones 2005).
Recurrence and progression of VIN have been associated with smoking (Fehr 2013), multifocality (more than one lesion) (Fehr 2013; Van Esch 2013), positive surgical margins (Jones 2005; Wallbilich 2012), and large lesion size (Wallbilich 2012). In addition, higher recurrence and progression rates have been reported in immunocompromised women (Fehr 2013; Van Esch 2013; Wallbilich 2012), supporting the increasing interest in the immunological aspects of VIN, both as predictors of recurrence and progression, and to facilitate new immunotherapeutic approaches (Van Esch 2012; Van Esch 2015).
Description of the intervention
High grade VIN lesions were historically managed by aggressive surgical excision including partial or total vulvectomy, until the 1970s when, based on a better understanding of the condition, surgery for VIN became less extensive and local excision became the standard treatment (Wilkinson 2014). Other treatment options included ablative techniques such as electrocautery, cryotherapy, and laser ablation (Cox 2007). Surgical excision remains the standard of care for small, well‐circumscribed lesions but is not optimal for treating multifocal lesions, which are common and more problematic (Stern 2012, BASHH guidelines 2014). Due to the high recurrence rate, the disfiguring nature of more extensive surgical procedures, and the negative impact on sexuality and quality of life (Aerts 2012; Andreasson 1986), less invasive, medical interventions are highly desirable.
Medical (non‐surgical) treatments utilised prior to the 1990s have largely been disregarded due, either to their inefficacy, or to their unacceptable side effect profile. These include chemotherapy drugs assessed in the 1980s such as 5‐fluorouracil (Sillman 1985), bleomycin (Roberts 1980) and trinitrochlorobenzene (Foster 1981). Interferon‐α therapy (IFN‐α), was also investigated in the 1980s and early 1990s with initially promising results (Spirtos 1990); however, its high cost and serious local side effects limited its use.
Imiquimod, an immune response modifier, is currently approved for the treatment of genital warts (Moore 2001), with uVIN being an unlicensed indication for imiquimod use in the UK (BASHH guidelines 2014). Some researchers consider imiquimod the treatment of choice for uVIN (Van Seters 2008). The previous version of this review pooled data from three randomised trials (Mathiesen 2007; Sterling 2005; Van Seters 2008) and found moderate‐quality evidence that imiquimod treatment was substantially more effective than placebo in achieving a response to treatment at five to six months (Pepas 2011). However, safety and quality of life data were sparse, as were longer term response and progression data.
Photodynamic therapy (PDT), which has ablative and non‐surgical effects, was evaluated for VIN in the late 1990s with varying results (Dougherty 1998; Fehr 2001; Hillemanns 2000). Proponents of this modality report that it is well‐tolerated and has the advantage over surgical procedures in that the appearance of the vulva is preserved (Fehr 2001), We found no RCTs on PDT in the original version of this review.
Prophylactic HPV vaccines, which aim to reduce precancer and invasive cancer of the cervix, may offer protection against developing VIN, but the evidence is currently inconclusive (Couto 2014; Miltz 2014). However, non‐randomised studies (NRSs) conducted in women with VIN have reported clinical responses and symptomatic improvement with experimental therapeutic HPV vaccines (Baldwin 2003; Davidson 2003; Fiander 2006; Kenter 2009). Therefore, vaccination may have a role to play in the treatment of VIN, either alone or in combination with other modalities.
Cidofovir, a potent antiviral agent, may also be effective in treating VIN (Tristram 2005). The previous version of this review identified an ongoing phase 2 trial of cidofovir versus imiquimod (RT3VINa) which had not yet reported results, but whose preliminary data are now included in this update (Tristram 2014). Other potentially useful medical interventions, include the phytochemical indole‐3‐carbinol (I3C), a natural compound derived from the breakdown of glucosinolates. This compound is present in large concentrations in cruciferous vegetables (cabbage, broccoli, brussel sprouts, and cauliflower). Two studies of I3C have found it to be somewhat effective in treating high‐grade cervical intraepithelial neoplasia (CIN) (Bell 2000) and VIN (Naik 2006); however, the latter data are extremely limited (Pepas 2011).
How the intervention might work
VIN is associated with failure to mount an effective cell‐mediated immunity (CMI) response to clear HPV infection, particularly interferon‐Ɣ‐producing T cells, which results in viral persistence (Van Esch 2012). Therefore, most medical interventions to treat VIN aim to enhance the body's immune response to directly or indirectly destroy affected cells. Topically applied imiquimod does this by binding to cell receptors, leading to the activation of dendritic cells and the secretion of pro‐inflammatory cytokines, such as tumour necrosis factor (Van Esch 2012). IFN‐α activates cytotoxic T‐cells (Van Esch 2012). With such topical agents, a local reaction of redness and blistering is necessary to eliminate the lesion; however, such reactions may be associated with significant discomfort (Todd 2002).
Vaccination aims to stimulate the systemic immune system to eliminate the virus. Prophylactic HPV vaccines are highly immunogenic,leading to increased antibodies and T‐cell response (Stanley 2010). Other types of HPV vaccines have been developed, for example recombinant vaccines encoding modified HPV16/18 oncogenes (E6, E7) (Baldwin 2003; Davidson 2003) and synthetic peptide vaccines (Kenter 2009). Few studies have shown a relationship between induction of immunity and clinical outcome; however, a complete response in women with VIN was correlated with higher numbers of HPV16‐specific T‐cells in a phase 2 study of a peptide vaccine against HPV16 oncoproteins (Kenter 2009).
Cidofovir is a deoxycytidine monophosphate analogue with potent antiviral activity against a broad range of DNA viruses including HPV. Cidofovir probably mediates its effects by causing death in HPV‐infected cells (Tristram 2005).
HPV has been shown to increase cellular 16‐alpha‐hydroxyestrone, a known carcinogen (Newfield 1998). Dietary I3C acts as a potent inducer of 2‐hydroxylation of oestradiol in rodents and humans, decreasing production of the carcinogen, 16‐alpha‐hydroxyestrone and increasing production of the anti‐proliferative metabolite 2‐hydroxyestrone (Newfield 1998).
PDT causes direct destruction of lesions using the interaction between a tumour‐localising photo‐sensitiser and light of an appropriate wavelength to bring about molecular oxygen‐induced cell death. It is usually used in conjunction with a topical cream containing 5‐aminolaevulinic acid (ALA), since the resultant chemical reaction reduces incidental damage to surrounding normal tissues (Dougherty 1998). In addition to lesion destruction, PDT also induces local inflammation and activates T cells (Van Esch 2012).
Why it is important to do this review
Currently there is no consensus on the optimal management of high‐grade VIN. Surgical interventions are associated with high recurrence rates, possibly because non‐visible lesions are missed, but also due to the commonly multifocal nature of the disease, and have significant physical and psychosexual implications. However, the evidence regarding the effectiveness and safety of non‐surgical interventions is limited or incomplete. VIN and vulval cancer are being increasingly diagnosed in younger women for whom surgical options are unlikely to be readily accepted. The previous version of this review called for more high‐quality trials on medical treatment options for VIN (Pepas 2011). We continue to update this review on the medical alternatives to surgery, to inform women's choices, to support clinical guidelines, and to stimulate VIN research.
Objectives
To evaluate the effectiveness and safety of medical interventions for high‐grade VIN.
Methods
Criteria for considering studies for this review
Types of studies
Randomised controlled trials (RCTs).
Types of participants
Women aged over 18 years with a confirmed histological diagnosis of high‐grade VIN (to include VIN 2, VIN 3, uVIN, or HSIL). Women with unifocal or multifocal disease were included; those with a histological diagnosis of Paget's were excluded. Trials that studied the management of vulval carcinoma were excluded.
Types of interventions
Medical (non‐surgical) agents used to treat high‐grade VIN. These could be administered by any route to include:.
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topical immune modulators, e.g. imiquimod;
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systemic immunotherapy, e.g. vaccines;
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antiviral agents, e.g. cidofovir;
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natural compounds, e.g. I3C, green tea catechins;
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any other medical intervention, excluding those targeted exclusively at symptomatic control.
We included trials that compared a single agent to placebo or a varying dose of a single agent.
We considered direct comparisons of different types of interventions and also comparisons of interventions and control.
Types of outcome measures
Primary outcomes
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Response to treatment (based on clinical and histological evidence of resolution, regression, persistence or progression).
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Recurrence of VIN.
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Progression to vulval cancer.
Secondary outcomes
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Superficial dyspareunia.
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Quality of life (QoL), as measured by a validated scale.
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Sexual function using a validated tool. (e.g. Sabbatsberg sexual self rating scoring; Garrat 1995; Naransingh 2000).
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Adverse events of local treatment classified according to CTCAE 2006, including:
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skin reactions (erythema, excoriation, pruritis, erosion, papular rash);
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severe skin reactions (hypopigmentation, hyperpigmentation, crusting, erosions, indurations, urticaria);
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oedema and discharge;
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pain and tenderness;
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bleeding.
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Search methods for identification of studies
We sought papers in all languages and, where necessary, had them translated.
Electronic searches
See: Cochrane Gynaecological Cancer Group methods used in reviews. The original searches for the review were conducted from January 1950 to September 2010 and the Cochrane Gynaecological, Neuro‐oncology and Orphan Cancers' Trial Search Coordinator (TSC) updated these searches in July 2014 and again in March 2015 using the following electronic databases.
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The Cochrane Gynaecological Cancer Collaborative Review Group's Trial Register
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Cochrane Central Register of Controlled Trials (CENTRAL), Issue 3, 2015
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MEDLINE to March 2015
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EMBASE to March 2015
The MEDLINE, EMBASE and CENTRAL search strategies are presented in Appendix 1, Appendix 2 and Appendix 3 respectively.
All relevant articles found were identified on PubMed and using the 'related articles' feature, a further search was carried out for newly published articles.
Searching other resources
Unpublished and Grey literature
We searched clinical trials registries, including www.controlled‐trials.com/rct, www.clinicaltrials.gov, www.cancer.gov/clinicaltrials and the World Health Organization international clinical trials registry platform (ICTPR; http://www.who.int/ictrp) for ongoing trials.
Hand‐searching
We handsearched the following conference proceedings for the original review.
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Gynecologic Oncology (Annual Meeting of the American Society of Gynecologic Oncologist).
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International Journal of Gynecological Cancer (Annual Meeting of the International Gynecologic Cancer Society).
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British Journal of Cancer.
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British Cancer Research Meeting.
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Annual Meeting of European Society of Medical Oncology (ESMO).
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Annual Meeting of the American Society of Clinical Oncology (ASCO)
Reference lists and Correspondence
For the original review, we contacted the investigators of Tristram 2014 (at the time, an ongoing trial), Sterling 2005 and Van Seters 2008, who provided additional useful information, as did various experts in the field who reviewed the manuscript prior to publication. Similarly for this update, we contacted the investigators of Tristram 2014 and all ongoing trials for further information and to confirm the expected completion dates of these trials.
Data collection and analysis
Selection of studies
We downloaded all titles and abstracts retrieved by electronic searching to the reference management database Endnote. Duplicates were removed and the remaining references examined by two review authors (for the original review: LP and SK; and for the update: LP and TL). We excluded references that clearly did not meet the inclusion criteria and obtained copies of the full text of potentially relevant references. The eligibility of retrieved papers was assessed independently by two reviewers (for the original review: LP and SK; for the update: TL and LP). Disagreements were resolved by discussion between the two review authors and when necessary by two other authors (AN and SK). Reasons for exclusion were documented.
Data extraction and management
For included studies, we extracted data as recommended in chapter 7 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011a). This included data on the following:
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author, year of publication and journal citation (including language);
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country;
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setting;
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inclusion and exclusion criteria;
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study design, methodology;
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study population;
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total number enrolled;
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patient characteristics;
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age;
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co‐morbidities;
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previous treatment.
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VIN details:
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unifocal or multifocal lesion;
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grade;
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size of lesion;
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local immune modulator intervention details:
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dose;
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duration;
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and/or
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details of dose and duration of any other therapy used;
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type of therapy;
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dose (if appropriate);
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duration (if appropriate);
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risk of bias in study (see below);
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duration of follow‐up;
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outcomes – response to treatment, recurrence on long‐term follow up, progression to vulval cancer, symptom assessment, QoL, pain, itching, soreness, superficial dyspareunia and adverse events;
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for each outcome: outcome definition (with diagnostic criteria if relevant);
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unit of measurement (if relevant);
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for scales: upper and lower limits, and whether high or low score is good
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results: number of participants allocated to each intervention group;
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for each outcome of interest: sample size; missing participants.
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We extracted data on outcomes as below.
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For dichotomous outcomes (e.g. adverse events, response to treatment, pain due to disease, pruritis due to disease), we extracted the number of women in each treatment arm who experienced the outcome of interest and the number of patients assessed at endpoint, in order to estimate a risk ratio (RR).
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Where possible, we extracted data relevant to an intention‐to‐treat analysis.
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We noted the time points at which outcomes were collected and reported.
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Two review authors (LP, SK) independently extracted data onto a data extraction form specially designed for the review. Differences between review authors were resolved by discussion or by appeal to a third review author (AB) when necessary.
Assessment of risk of bias in included studies
We assessed the risk of bias in included RCTs using the Cochrane Collaboration's tool and the criteria specified in chapter 8 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011b). This included assessment of:
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sequence generation;
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allocation concealment;
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blinding (of participants, healthcare providers and outcome assessors);
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incomplete outcome data;
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selective reporting of outcomes;
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other possible sources of bias
The 'Risk of bias' tool was applied independently by two review authors (LP, SK for the original review, and LP and TL for the update) and differences resolved by discussion or by appeal to a third review author (AB). Results are presented in both a 'Risk of bias' graph and a 'Risk of bias' summary. Results of meta‐analyses were interpreted in light of the findings with respect to risk of bias.
Measures of treatment effect
For dichotomous outcomes, we used RR.
Dealing with missing data
We did not impute missing outcome data for any outcomes.
Assessment of heterogeneity
We assessed heterogeneity between trials by visual inspection of forest plots, by estimation of the percentage heterogeneity between trials which cannot be ascribed to sampling variation (Higgins 2003), and by a formal statistical test of the significance of the heterogeneity (Deeks 2001). If there was evidence of substantial heterogeneity, we investigated and reported the possible reasons.
Assessment of reporting biases
We did not produce a funnel plot to assess the potential for small study effects, since there were only three trials in the primary meta‐analysis.
Data synthesis
We considered the trials of Mathiesen 2007, Sterling 2005 and Van Seters 2008 to be clinically similar enough to pool their results in meta‐analyses, where possible. We used random effects models with inverse variance weighting for all meta‐analyses (DerSimonian 1986).
Results
Description of studies
Results of the search
The search strategy conducted for the original review identified 2584 unique references, from which we identified 12 potentially eligible articles, retrieving the full texts and translating them into English where appropriate. Of these 12 references, we included four (Mathiesen 2007; Naik 2006; Sterling 2005; Van Seters 2008) and excluded seven with reasons. One reference related to an ongoing trial (RT3VINa), the details of which we recorded in the 'Characteristics of ongoing studies' section of the original review.
For the update, electronic database searches identified 1035 references. From these, we identified three potentially eligible studies. In addition, we identified five records of ongoing trials on clinical trial registries. Therefore, in total, we identified eight records as potentially eligible and obtained full texts of these references. Following examination of the full texts, we classified the articles as included (Tristram 2014), excluded (Frega 2013; Stier 2013) and ongoing (EUCTR2008‐008251‐42‐NL; EUCTR2011‐003134‐13‐NL; ISRCTN98495886; NCT01861535; NTR1526) (See Figure 1). Details of these ongoing trials can be found in the Characteristics of ongoing studies section.
Study flow diagram for the 2015 update.
Included studies
Design of studies
Five trials met our inclusion criteria: Mathiesen 2007 (31 participants), Sterling 2005 (21 participants) and Van Seters 2008 (52 participants) evaluated topical imiquimod versus placebo; Tristram 2014 (180 participants) evaluated topical cidofovir versus imiquimod, and Naik 2006 (13 participants) evaluated different doses of the natural compound I3C. These five trials included 297 women in total. Mathiesen 2007, Sterling 2005 and Van Seters 2008 were conducted in Denmark, the United Kingdom (UK) and the Netherlands, respectively, and were prospective, randomised, double‐blinded, placebo‐controlled trials. The Sterling 2005 trial was published as an abstract only, with scant information. We contacted the authors in October 2010, however, did not receive any further details. Tristram 2014 was an open‐label multi‐centre, phase 2 trial conducted in 32 centres in the UK. Naik 2006 was a randomised, open‐label trial conducted in a single centre in Gateshead, UK, in which participants were randomised to receive one of two different dosage regimens of I3C without a placebo control.
Patient characteristics
All five trials randomised women with histologically proven VIN. The investigators of all studies used the older histological definitions, namely VIN 2 or 3 (Mathiesen 2008; Tristram 2014; Van Seters 2008) or high‐grade VIN (Sterling 2005; Naik 2006). None of the studies used the term uVIN or HSIL. The proportion of women with HPV DNA detected were reported for Mathiesen 2007, Tristram 2014, and Van Seters 2008 as 58%, 84% and 96% , respectively, with test results missing for a few women in Mathiesen 2007 and Tristram 2014. One HPV DNA positive woman in the imiquimod arm of Van Seters 2008 had co‐existing lichen sclerosis and one had a histological diagnosis of VIN 1. Sterling 2005 reported that "HPV was detected in almost all women...with the majority shown to harbour HPV 16". HPV DNA status was not reported in Naik 2006.
Women in most studies had a mean or median age of between 45 and 50 years old, except for Van Seters 2008, in which the median age of enrolled women was between 39 and 44 years. In Mathiesen 2007, Naik 2006, Tristram 2014 and Van Seters 2008, active smokers accounted for approximately 80%, 75%, 60% and 88% of the samples, respectively. The proportion of active smokers was not reported in Sterling 2005.
Nine women (three in the cidofovir arm and six in the imiquimod arm) were 'immunocompromised' in Tristram 2014, and two women in Van Seters 2008 had received corticosteroid cream prior to enrolment in the study. Immune deficiency or immunosuppressive treatment were exclusion criteria for Van Seters 2008 and Mathiesen 2007, respectively. Participants in Sterling 2005 were described as immunocompetent. Naik 2006 similarly noted that women were immunocompetent and there was no significant difference in menopausal status between women randomised to the two study arms.
The proportion of women with recurrent VIN lesions was 46% and 71% in Tristram 2014 and Van Seters 2008, respectively, and multifocal lesions were present in 51%, and 100% of participants in these studies, respectively. In addition, 40% and 62% of women in Tristram 2014 and Van Seters 2008 had previous anogenital neoplasia. In Mathiesen 2007, 29% of participants had multifocal lesions (five of 21 in the imiquimod group and four of 10 in the control group). These pre‐treatment characteristics were not reported in the other two studies.
There were no significant differences in baseline characteristics between the study groups for most baseline data; however, significantly more women reported vulval pain at baseline in the imiquimod group compared with the placebo group of Van Seters 2008. Similarly, more women reported vulval pain at baseline in the cidofovir group of the Tristram 2014 trial, compared with the imiquimod group.
Interventions
Mathiesen 2007, Sterling 2005 and Van Seters 2008 randomised participants to receive either topical imiquimod 5% cream or placebo. In Mathiesen 2007, 21 women received imiquimod and 10 received placebo. All participants applied topical treatment for 16 weeks. The regimen involved application once a week for two weeks, twice a week during the following two weeks and, if tolerated, three times a week for the last 12 weeks. The end‐point of the study was two months after the end of treatment.
In Van Seters 2008, 26 women received imiquimod and 26 received placebo. The women applied the treatment overnight twice a week for a period of 16 weeks. They were advised to use topical sulphur precipitate 5% in zinc oxide the day after treatment application to avoid superinfection. In both these trials, women were reviewed every fourth week and a post‐treatment biopsy was taken after six months (24 weeks from randomisation).
In Van Seters 2008, further assessments were performed at seven months and 12 months following treatment, after which the randomisation code was revealed. In Sterling 2005, 15 women received imiquimod and six received placebo. It was not possible to ascertain the frequency of application, however active treatment continued for 16 weeks. Histological assessment was carried out eight weeks after the start of treatment and four weeks after the completion of treatment (20 weeks from randomisation).
Tristram 2014 randomised women to receive either 1% cidofovir gel or topical 5% imiquimod cream self‐applied overnight three times a week for a maximum of 24 weeks. Women were assessed at 6, 12, 18, and 24 weeks during treatment. Post‐treatment assessment was either six weeks after the end of treatment or six weeks after a complete response or disease progression. Two biopsy specimens were taken to assess histological response and test for HPV DNA. Women with a complete response were followed up every 6 months (6, 12, 18, 24 months) to the end of the study; however, at the time of writing, only the six week follow‐up results were available.
In Naik 2006, of the women completing the trial (three women dropped out, one could not access the medication and two did not attend the six month follow‐up), six were randomised to receive I3C 200 mg/day and seven received 400 mg/day. Vitamin C was also administered at the discretion of the treating clinician and five patients were prescribed this. Participants were reviewed at six weeks, three months and six months. Histological assessment was performed at six months (24 weeks).
Outcomes
Response to treatment was the primary outcome in all five trials. Histological response was determined by a repeat biopsy either from the lesion or lesions, if still present, or from the area where a lesion had been at initial assessment, when it had regressed entirely. Clinical response was varyingly defined as a reduction of the size of the lesion(s) at vulvoscopic assessment.
Van Seters 2008 classified clinical responses as either a complete response (CR) or partial response (PR). Partial responses were further subdivided into a strong partial response (76% to 99% reduction in lesion size) or a weak partial response (26% to 75% reduction in lesion size), or no response (reduction in lesion size of 25% or less). Histological response was described as change from high grade VIN to a lower grade or complete clearance. Mathiesen 2007 and Sterling 2005 both defined responses as either complete response (CR), which was defined as complete histological and clinical clearance, partial response (> 50% clearance) and no response (< 50% clearance). Tristram 2014 defined response according to adapted RECIST (Response Evaluation Criteria in Solid Tumours) criteria, whereby a partial response was at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters, and progressive disease is at least a 20% increase in the sum of the diameters, or the appearance of one or more new lesions (Eisenhauer 2009). Naik 2006 commented on the size of the lesions and histological assessments without grouping responses further.
The only trial to report progression to invasive cancer 12 months after randomisation was Van Seters 2008, which also described the proportion of initially HPV‐positive patients who cleared the virus at the end of the study period, and measured QoL comprehensively by means of recognised questionnaires administered at baseline, 20 weeks and 12 months. The questionnaires used to assess QoL were: the mental health scale of the Medical Outcomes Study 36‐Item Short‐Form General Health Survey (ranging from 0 to 100, with higher numbers indicating a better health‐related QoL); the overall QoL scale of the European Organisation for Research and Treatment of Cancer (EORTC) QoL questionnaire (QLQ‐C30) used to assess generic and cancer‐specific health‐related QoL; and the EORTC QLQBR23 to assess body image and sexuality.
Participants in Tristram 2014, Mathiesen 2007 and Van Seters 2008 were asked to keep a diary of compliance with treatment and side effects. Adherence was reported as an outcome in Tristram 2014 and was assessed at six weeks and 24 weeks in terms of the median number of applications up to those time‐points. All studies reported side effects, with the exception of Sterling 2005. Tristram 2014 graded adverse effects according to CTCAE 2006 criteria, whereas Van Seters 2008 did not grade most adverse effects, but distinguished erythema and erosion as mild‐to‐moderate or severe. Naik 2006 asked women to report symptoms of pruritus and pain using a visual analogue scale at recruitment and at each subsequent visit.
Excluded studies
Ten references listed were excluded after obtaining the full text (see Characteristics of excluded studies). Spirtos 1990 (also reported in abstract form prior to full publication) was a prospective randomised blinded cross‐over trial using topical α‐IFN with and without 1% nonoxynol‐9. However, only women who did not respond to the initial treatment were crossed over to the other treatment arm, so interpretation of this trial's results was not possible. Todd 2005 was a review; Iavazzo 2008 and Mahto 2010 were systematic reviews; Van de Nieuwenhof 2008 and Mathiesen 2008 were letters replying to comments regarding Mathiesen 2007; Frega 2013 was a non‐randomised study comparing topical imiquimod with surgical excision; Stier 2013 was a prospective cohort study of cidofovir in men and women with anogenital intraepithelial neoplasia; and Melamed 1965 was not an RCT.
Risk of bias in included studies
We judged two trials to be at a low risk of bias overall (Mathiesen 2007; Van Seters 2008), as they satisfied four of the criteria that we used to assess risk of bias. We considered Tristram 2014 to be at a low to moderate risk of bias due to its open‐label methodology, whereas the trials of Naik 2006 and Sterling 2005 were at potentially high risk of bias, as they provided scant methodological details on which to base risk of bias judgements (see Figure 2, Figure 3). Sterling 2005 has only been published in abstract form so we were unable to properly assess its risk of bias. To our knowledge the complete details of this study remain unpublished.
Methodological quality graph: review authors' judgements about each methodological quality item presented as percentages across all included studies.
Methodological quality summary: review authors' judgements about each methodological quality item for each included study.
Three trials (Mathiesen 2007; Tristram 2014; Van Seters 2008) reported the method of generation of the sequence of random numbers used to allocate women to treatment arms, and this allocation was adequately concealed. These trials also had minimal attrition.
Mathiesen 2007 and Van Seters 2008 were both double‐blind trials in which the participants, healthcare professionals and outcome assessors were blinded; Tristram 2014 was an open‐label trial, and blinding was unclear in the remaining three trials. It was not clear whether all trials reported all the outcomes that they assessed and it was unclear whether any other bias may have been present. Intention‐to‐treat data were not reported in full in Tristram 2014.
Effects of interventions
See: Summary of findings for the main comparison Summary of findings for imiquimod versus placebo; Summary of findings 2 Summary of findings for imiquimod versus cidofovir
Topical imiquimod versus placebo
In Analysis 1.1 and Analysis 1.2 complete and partial response data were grouped together for 'overall response'.
Response to treatment at 5 to 6 months after randomisation
Meta‐analysis of three RCTs (Mathiesen 2007; Sterling 2005; Van Seters 2008), assessing 104 participants, found that the proportion of women who responded to treatment at 5 to 6 months was much higher in the group who received topical imiquimod than in the group who received placebo (RR 11.95, 95% CI 3.21 to 44.51). There was no statistical heterogeneity. There were 18/62 and 1/42 partial responses and 36/62 and 0/42 complete responses in the topical imiquimod and placebo groups respectively (Analysis 1.1; high‐quality evidence).
Response to treatment at 12 months after randomisation
One study (Van Seters 2008) reported 12 month data, which found that the proportion of women who responded to treatment at 12 months was much higher in the group who received topical imiquimod than in the placebo group (RR 9.10, 95% CI 2.38 to 34.77; Analysis 1.2; moderate‐quality evidence). There were 10/24 and 2/23 partial responses and 9/24 and 0/23 complete responses in the topical imiquimod and placebo groups respectively. The response status was unknown for two women in the imiquimod group and three women in the placebo group, as they were lost to follow‐up.
Progression to vulval cancer at 12 months after randomisation
Only one trial reported this outcome. The trial of Van Seters 2008 did not find a difference in progression to vulval cancer at 12 months between women who received imiquimod and those who received placebo (1/24 versus 2/23 events, respectively; RR 0.50, 95% CI 0.05 to 5.18; Analysis 1.3; low‐quality evidence).
Adverse events
Only one study (Van Seters 2008) reported adverse effect data for fatigue, headache, erythema, erosion, oedema, pain and pruritis. Mathiesen 2007 reported 'local side effects' (Analysis 1.11), and Sterling 2005 did not report adverse event data.
Fatigue
There was no difference in fatigue between women who received imiquimod compared with those who received placebo (one study, 52 participants (RR 2.00, 95% CI 0.69 to 5.83 Analysis 1.4; moderate‐quality evidence).
Headache
There was no difference in this outcome between women who received imiquimod compared with those who received placebo (one study, 52 participants: RR 1.41, 95% CI 0.51 to 3.85, Analysis 1.5; moderate‐quality evidence).
Erythema (redness)
Women who received imiquimod were more likely to experience local erythema of any grade than those who received placebo (one study, 52 participants: RR 10.00, 95% CI 2.60 to 38.50,Analysis 1.6; moderate‐quality evidence).
Erosion/ulceration
Women who received imiquimod had more than three times the risk of vulval erosion compared with women who received placebo (one study, 52 participants: RR 3.40, 95% CI 1.47 to 7.84, Analysis 1.7, moderate‐quality evidence).
Oedema
Women who received imiquimod were more likely to experience vulval oedema than those who received placebo (one study, 52 participants: RR 23.00, 95% CI 1.43 to 371.00, Analysis 1.8; moderate‐quality evidence).
Pain or pruritis (itchiness)
Women who received imiquimod were more likely to experience vulval pain or pruritus during treatment than those who received placebo (one study, 52 participants: RR 3.43, 95% CI 1.80 to 6.52, Analysis 1.10 and Analysis 1.9, moderate‐quality evidence).
Local side effects
One study (Mathiesen 2007) reported 'local side effects' and found that women who received imiquimod were over six times more likely to suffer local side effects than those who received placebo (one study, 31 participants: RR 6.67, 95% CI 1.01 to 43.86; Analysis 1.11, low‐quality evidence).
No side effects
One study (Van Seters 2008) reported the number of women experiencing no side‐effects and these data favoured the control group (one study, 52 participants: RR 0.08, 95% CI 0.01 to 0.55, Analysis 1.12; moderate‐quality evidence).
Dose reductions
Women who received imiquimod were more likely to require dose reductions compared with the placebo group (two studies, 83 participants RR 7.77, 95% CI 1.61 to 37.36; I2 = 0%; Analysis 1.13; high‐quality evidence).
Quality of life (QoL)
One study (Van Seters 2008) reported QoL and did not find any statistically significant differences in any of the QoL outcomes including self‐reported health‐related QoL, body image or sexuality scores at baseline, 20 weeks, and at 12 months between the treatment and the placebo groups. None of the other trials reported on QoL.
Topical imiquimod versus topical cidofovir
One randomised trial (Tristram 2014) with 180 participants evaluated this comparison, comparing topical 5% imiquimod cream with 1% cidofovir gel applied three times per week for 24 weeks, and the results are reported below. We considered most of the resulting evidence to be of a moderate quality, downgrading mainly due to imprecision.
Response to treatment at six months after randomisation
There was no difference in overall response between imiquimod and cidofovir study groups (180 participants: RR 0.92, 95% CI 0.73 to 1.18; Analysis 2.1; moderate‐quality evidence), or for complete and partial response data separately.
Progressive disease
There was no difference between imiquimod and cidofovir study groups in the proportion of women experiencing progressive disease (180 participants RR 1.30, 95% CI 0.55 to 3.11, Analysis 2.2; low‐quality evidence).
Investigators also reported that fewer women in the imiquimod group developed new lesions during treatment compared with the cidofovir group (RR 0.55, 95% CI 0.28 to 1.09; Analysis 2.3, not statistically significant). However, due to flaws in the data collection process they were uncertain whether these lesions occurred at the site of treatment, therefore it was not possible to establish whether these data represented progressive disease.
Adverse effects
Total serious adverse events
There was no difference in total serious adverse event data between imiquimod and cidofovir study groups (RR 1.26, 95% CI 0.88 to 1.81, Analysis 2.4; moderate‐quality evidence).
Pain
There was no difference in vulval pain of any grade between imiquimod and cidofovir study groups (RR 1.08, 95% CI 0.93 to 1.25, Analysis 2.5; moderate‐quality evidence), with similar proportions of women in each group experiencing severe pain (grade 3 and higher).
Pruritis
There was no difference in pruritis of any grade between imiquimod and cidofovir study groups (RR 1.03, 95% CI 0.90 to 1.17; Analysis 2.6; moderate‐quality evidence) with similar proportions of women in each group experiencing severe pruritis (grade 3 and higher).
Erosion
There was no difference in vulval erosion of any grade between imiquimod and cidofovir study groups (RR 0.88, 95% CI 0.63 to 1.22; Analysis 2.7; moderate‐quality evidence) with similar proportions of women in each group experiencing severe erosion (grade 3 and higher).
Fatigue
More women in the imiquimod group experienced fatigue of any grade compared with the cidofovir group (RR 1.25, 95% CI 1.02 to 1.55, Analysis 2.8; moderate‐quality evidence).
Headache
More women in the imiquimod group experienced headache of any grade compared with the cidofovir group (RR 1.49, 95% CI 1.12 to 1.98; Analysis 2.9; moderate‐quality evidence) and the proportion of women experiencing severe headache (grade 3 or higher) favoured cidofovir (borderline statistical significance).
Skin reactions
There was no difference in the number of women experiencing skin reactions of any grade between imiquimod and cidofovir study groups (RR 0.88, 95% CI 0.46 to 1.68; Analysis 2.10; moderate‐quality evidence).
Treatment discontinuation
There was no difference between imiquimod and cidofovir study groups in the proportion of women requiring a dosage reduction or treatment cessation (15/89 versus 11/87, respectively; RR 1.33, 95% CI 0.65 to 2.74; Analysis 2.11; moderate‐quality evidence).
200 versus 400 mg/day of indole‐3‐carbinol (I3C)
The trial of Naik 2006 reported that there were no differences in any of the outcomes between the six women taking 200 mg/day of I3C and the six on 400 mg/day. Both groups reported significant improvement in symptoms of pruritus and pain. However, nine out of ten women followed up for six months still had high grade VIN after biopsy. The authors did not comment regarding to which of the two doses these women had been randomised. The trial reported only one case of mild bowel upset, which was of a woman who received the high dose regimen.
Discussion
Summary of main results
Our analysis showed that, at five to six months from the start of treatment, women with VIN who received imiquimod had a much better response to treatment than those who received placebo, in terms of achieving either complete clearance of lesions, or a reduction in size or histological grade of residual lesions (RR 11.95, 95% CI 3.21 to 44.51). Evidence from one study showed this response to be sustained at 12 months post‐randomisation (RR 9.10, 95% CI 2.38 to 34.77). Imiquimod appeared to be relatively well‐tolerated, although it was associated with significantly more local side effects than placebo. These side effects included localised pain, oedema, erythema and a single case of an erosion. Encouragingly, none of the patients discontinued treatment and these side effects were managed by reducing the number of applications. The total number of patients in these trials was small (n = 104). Only one trial followed participants up for 12 months (Van Seters 2008), in this trial, three women had lesions that progressed to invasive disease, one in the imiquimod arm and two in the placebo arm. The same trial reported increased clearance of HPV infection with imiquimod treatment. QoL was also assessed in this trial and no differences were found between the two groups.
Moderate‐quality evidence from one well‐conducted RCT suggested that cidofovir was as effective as imiquimod with respect to response rates at six months after randomisation, but longer follow‐up data are still to be reported. Adverse effects occurred with similar frequency between the treatment groups, with the exception of fatigue and headache, which were more common with imiquimod.
Although the Naik 2006 trial, which assessed low dose (200 mg/day) versus high dose (400 mg/day) I3C, met our inclusion criteria, it only included 12 participants and the report lacked detail. Participants in both study arms reported significant symptomatic improvement (pruritus and pain); however, nine out of ten participants followed up for six months still had high grade VIN after biopsy. The authors reported that there were no differences between study arms in any of the outcomes recorded and it was not possible for us to draw any conclusions about the effectiveness of this treatment.
Overall completeness and applicability of evidence
Most of the participants in the included studies had high‐grade HPV‐related VIN lesions and this evidence therefore applies to HPV‐related VIN only, and not dVIN, for which the standard treatment is surgical excision due to it's high malignant potential. Currently, the evidence on the use of imiquimod for the treatment of high‐grade VIN is encouraging, but incomplete. We were unable to draw any conclusions about possible differences in the efficacy of treatment according to lesion focality or size. In addition, the absence of sufficient data on QoL, sexual function and adverse events did not allow us to draw any firm conclusions about these outcomes. In most trials of imiquimod it was reported that intolerable local side‐effects were managed by dose reductions which seldom led to discontinuation; however, it remains unclear what the optimal dose regimen for imiquimod use should be for VIN treatment, and how symptoms related to treatment are best relieved.
Although it is probable that VIN treatment needs to be individualised, based on a woman's preference, lesion size, focality, and other factors, no completed RCTs to date have compared medical with surgical interventions for VIN; however, our search identified one ongoing trial assessing this comparison (NCT01861535). Limited data from non‐randomised studies (NRS) have produced conflicting results. Le 2007 compared imiquimod in 30 women with high‐grade VIN to 40 'randomly selected' historical surgical controls and reported that imiquimod treatment was associated with significantly fewer recurrences (20.5% versus 53.5%) than surgery. Whereas Frega 2013 prospectively compared imiquimod with surgical excision and reported that relapse (recurrence plus treatment failure) was higher among women receiving imiquimod compared with surgery (22/32 [68.7%] versus 17/38 [44.7%]; P value = 0.04), and complete response was lower (10/32 [31%] versus 21/38 [55%]). Surgical conversion occurred in 53% (17/32) of women in the imiquimod group, with two women in the imiquimod group and three in the surgery group developing invasive cancer in spite of treatment.
Without more evidence, it remains unclear whether the effect of imiquimod on VIN clearance is sustained, and whether it protects against the development of vulval cancer. Seven‐year follow‐up data from Van Seters 2008 (Terlou 2011) suggests that women who have a complete response to imiquimod treatment have a promising long‐term outlook: only one out of nine complete responders in this trial experienced a recurrence, and none progressed to vulval cancer. However, in Frega 2013, five out of 15 women relapsed after a complete response during a five‐year follow‐up period, reinforcing the fact that long term follow‐up of participants is important to fully understand the benefits and risk of these newer treatment options.
Role for natural compounds, e.g. IC3, SR‐T100 (solanum incanum extract) and sinecatechins (from green tea leaves), if any, in high‐grade VIN is still unknown. An ongoing study ISRCTN98495886 is currently evaluating SR‐T100, a traditional Chinese herbal medicine that has purportedly been used to treat cancer for centuries and has been reported to induce apoptosis in squamous carcinoma cells (Wu 2011) for VIN. Other ongoing trials are evaluating HPV vaccination in combination with imiquimod (EUCTR2008‐008251‐42‐NL; NTR1526), and PDT versus imiquimod (EUCTR2011‐003134‐13‐NL) for women with high‐grade VIN.
Quality of the evidence
The trials that evaluated imiquimod versus placebo were randomised, double‐blinded, placebo‐controlled trials without significant drop out rates, making them largely reliable sources of data, although one (Sterling 2005) was at a potentially high risk of bias. We assessed the quality of the evidence according to GRADE Working Group 2004 criteria, taking into account the fact that VIN is a relatively rare condition, therefore included trials tended to have small sample sizes.
We graded the evidence relating to the effectiveness (overall response) of imiquimod compared with placebo at five to six months as high‐quality, and at 12 months as moderate quality due to imprecision. Evidence related to progression to vulval cancer was graded as low‐quality due to imprecision and sparse data. Women receiving imiquimod were more likely to experience pain during treatment and to require dose reductions compared with placebo (high‐quality evidence). Evidence relating to other adverse events was of a low‐ to moderate‐quality, with only one study reporting these outcomes in detail (Van Seters 2008).
We graded most of the evidence relating to imiquimod versus cidofovir as moderate‐quality evidence, downgrading for imprecision. This evidence pertains to the six‐month follow‐up period only and longer‐term follow‐up data are required to fully understand the relative effects of these topical treatment options. We did not grade the quality of evidence relating to I3C as these data were limited.
Potential biases in the review process
A comprehensive search was performed, including a thorough search of the grey literature and all studies were sifted and data extracted by at least two reviewers independently. We restricted the included studies to RCTs as they provide the strongest level of evidence available. However, as VIN is a relatively rare condition, there is an argument for assessing non‐randomised data, particularly with respect to adverse events and disease progression.
The evolving terminology of VIN poses certain difficulties for reviewers. We did our best to determine whether investigators had recruited similar types of participants with uVIN by recording and comparing baseline characteristics, including HPV status of the lesions, where possible. Whilst our aim was to evaluate the effect of treatments on uVIN, it was not possible to exclude data of women with dVIN, as these data were not clearly identifiable. It is, therefore, possible that participants with dVIN were included. We believe, however, that review results pertain to women with uVIN, and not to dVIN, for which a separate review is required.
We did not include HPV clearance as an outcome, which was reported for the Van Seters 2008 trial and found that participants in the imiquimod group had a significantly higher rate of HPV clearance than the placebo group (15 of 25 imiquimod group versus 2/25 in placebo group; P < 0.001). In future versions of this review, we would like to include this outcome.
The greatest threat to the validity of the review may be the possibility of publication bias i.e. studies that did not find the treatment to have been effective may not have been published. We were unable to assess this possibility as all the treatment comparisons were restricted to either a meta‐analysis of only three trials or single trial analyses.
Agreements and disagreements with other studies or reviews
We are aware of two other reviews of the use of imiquimod for VIN, as well as vaginal intraepithelial neoplasia (VAIN), by Iavazzo 2008 and anogenital intraepithelial neoplasia by Mahto 2010. The latter included Mathiesen 2007 and Van Seters 2008, two of the three RCTs included in our review; we additionally included Sterling 2005. However, Mahto 2010 also collected results from observational cohort studies (case series) and published case reports. Our analysis agreed with the conclusions these reviews presented, namely the favourable evidence for efficacy of imiquimod and the reasonably tolerable side‐effects. None of the study participants were hospitalised or discontinued treatment due to severe side effects in the imiquimod versus placebo studies; however, in Tristram 2014 15 out of 89 participants (17%) discontinued imiquimod treatment. Mathiesen 2007 reported that 14 out of 21 women (67%) had to decrease the frequency of applications due to side effects, and Van Seters 2008 reported that 25 out of 26 women reported side effects, but again these were not sufficient to discontinue treatment. Similarly, in a published case series (Todd 2002), where 13 out of 15 women reported significant side effects resulting in reduction of frequency of applications per week, none of the women discontinued treatment. Wendling 2004 reported on a case series of 12 women where three out of 12 women (43%) discontinued treatment due to side effects. Three women (8%) dropped out of Le 2007 due to imiquimod side‐effects. Todd 2002 concluded that the lack of response to treatment could be attributed to decreased administration of the treatment and suggested that the use of local anaesthetics might improve compliance. The authors of the three RCTs included in the review analyses did not make any reference to the need for local anaesthesia nor to an apparent relationship between the change in frequency of administrations and response to treatment.
One of the draw backs of all the published RCTs is the lack of long term follow‐up of women treated with imiquimod. Only one of the included studies has published long term follow‐up data for 24 out of 26 women treated with imiquimod in their original trial (Van Seters 2008; Terlou 2011). The median follow‐up period of complete responders to imiquimod (nine women) was 7.3 years (range 5.6 to 8.3 years), and eight of the nine had no recurrence of VIN. One woman had a recurrence after four years, which was treated with laser vaporisation. Median follow up in the partial responders was 7.2 years (range 5.7 to 8.3 years) and all but two women required local excision or laser treatment. There were no reported cases of invasive vulval carcinoma. Although they did not report the follow up of the control group, this study has added valuable information concerning the long term safety and efficacy of imiquimod, and suggests that imiquimod treatment has significant benefits for women who have a complete response within six months from the start of treatment.
Cidofovir has been shown to be active in other HPV‐related disease, such as cervical intraepithelial neoplasia (CIN) and perianal intraepithelial neoplasia (PAIN) (Stier 2013). There is now one good quality trial of cidofovir for VIN, which shows that cidofovir probably has a similar efficacy to imiquimod and may be slightly better tolerated. Both may be reasonable alternatives to surgery; however, longer term follow‐up data from this and other trials are needed.
A trial that did not meet our inclusion criteria because it was a phase II trial with no comparison arm, demonstrated the potential efficacy of sequential imiquimod and PDT in treating high grade VIN (Winters 2008). This trial included 20 women and the authors reported that there was evidence of response to imiquimod alone at 10 weeks. Of the participants who tolerated treatment at 26 weeks, four had complete response, eight had partial responses and eight had stable disease. There were no cases of progression to invasive disease over 52 weeks. The authors recognised that completion of the treatment regimen may have resulted in better outcomes. However, delivery of PDT was intolerable for a large proportion of participants making this treatment modality difficult to adopt without effective pain relief. Similarly to Van Seters 2008, Winters 2008 reported that all five complete responders had cleared the HPV virus. There is currently an ongoing trial of PDT versus imiquimod, which should help to clarify the relative effectiveness and safety of these different types of treatments.
A further RCT that did not meet our inclusion criteria, based on the study design and reporting of outcomes, was a double‐blinded cross‐over trial testing α‐IFN with or without nonoxynol‐9, a surfactant used to improve absorption, in women with VIN 3 (Spirtos 1990). In this trial 21 women were randomised initially to one of the two arms. Patients who failed to respond were crossed over to the other treatment arm and data were analysed together, therefore it is not possible to make any valid comparisons of the treatment regimens. The authors concluded that nonoxynol‐9 did not add any benefit to treatment.
Study flow diagram for the 2015 update.
Methodological quality graph: review authors' judgements about each methodological quality item presented as percentages across all included studies.
Methodological quality summary: review authors' judgements about each methodological quality item for each included study.
Comparison 1 Topical imiquimod versus placebo, Outcome 1 Response to treatment at 5‐6 months.
Comparison 1 Topical imiquimod versus placebo, Outcome 2 Response to treatment at 12 months.
Comparison 1 Topical imiquimod versus placebo, Outcome 3 Progression to vulval cancer at 12 months.
Comparison 1 Topical imiquimod versus placebo, Outcome 4 Fatigue.
Comparison 1 Topical imiquimod versus placebo, Outcome 5 Headache.
Comparison 1 Topical imiquimod versus placebo, Outcome 6 Erythema.
Comparison 1 Topical imiquimod versus placebo, Outcome 7 Erosion.
Comparison 1 Topical imiquimod versus placebo, Outcome 8 Oedema.
Comparison 1 Topical imiquimod versus placebo, Outcome 9 Pain.
Comparison 1 Topical imiquimod versus placebo, Outcome 10 Pruritis.
Comparison 1 Topical imiquimod versus placebo, Outcome 11 Local side effects.
Comparison 1 Topical imiquimod versus placebo, Outcome 12 No side‐effects.
Comparison 1 Topical imiquimod versus placebo, Outcome 13 Dose reductions.
Comparison 2 Topical imiquimod versus cidofovir, Outcome 1 Response to treatment at 6 months.
Comparison 2 Topical imiquimod versus cidofovir, Outcome 2 Progressive disease.
Comparison 2 Topical imiquimod versus cidofovir, Outcome 3 New lesions during treatment.
Comparison 2 Topical imiquimod versus cidofovir, Outcome 4 Total serious adverse events.
Comparison 2 Topical imiquimod versus cidofovir, Outcome 5 Pain.
Comparison 2 Topical imiquimod versus cidofovir, Outcome 6 Pruritis.
Comparison 2 Topical imiquimod versus cidofovir, Outcome 7 Erosion.
Comparison 2 Topical imiquimod versus cidofovir, Outcome 8 Fatigue.
Comparison 2 Topical imiquimod versus cidofovir, Outcome 9 Headache.
Comparison 2 Topical imiquimod versus cidofovir, Outcome 10 Skin reactions.
Comparison 2 Topical imiquimod versus cidofovir, Outcome 11 Treatment discontinuation.
| Imiquimod compared with placebo for high‐grade VIN | |||||
| Patient or population: women with high‐grade VIN Settings: outpatient Intervention: imiquimod 5% cream Comparison: placebo | |||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of Participants | Quality of the evidence | |
| Assumed risk (risk in study population) | Corresponding risk | ||||
| Placebo | Imiquimod | ||||
| Response to treatment at 5‐6 months ‐ Overall response | 24 per 1000 | 285 per 1000 | RR 11.95 (3.21 to 44.51) | 104 | ⊕⊕⊕⊕ |
| Response to treatment at 5‐6 months ‐ Complete response | 0 per 1000 | not estimable | RR 14.40 (2.97 to 69.80) | 104 | ⊕⊕⊕⊕ |
| Response to treatment at 12 months ‐ Overall response | 87 per 1000 | 791 per 1000 | RR 9.10 (2.38 to 34.77) | 47 | ⊕⊕⊕⊝ |
| Response to treatment at 12 months ‐ Complete response | 0 per 1000 | not estimable | RR 18.24 (1.12 to 296.41) | 47 | ⊕⊕⊕⊝ |
| Progression to vulval cancer at 12 months | 56 per 1000 | 28 per 1000 | RR 0.48 (0.05 to 4.93) | 47 | ⊕⊕⊝⊝ |
| Pain ‐ Any grade | 269 per 1000 | 922 per 1000 | RR 3.43 (1.80, 6.52) | 52 | ⊕⊕⊕⊕ |
| Dose reductions | 28 per 1000 | 218 per 1000 | RR 7.77 (1.61 to 37.36) | 83 | ⊕⊕⊕⊕ |
| The risk in the cidofovir group is based on the assumed risk on the comparison group and the relative effect of the intervention and its 95% CI. | |||||
| GRADE Working Group grades of evidence | |||||
| 1 Downgraded due to imprecision 2 Downgraded due to sparse data (few events) | |||||
| Imiquimod compared with cidofovir for high‐grade VIN | |||||
| Patient or population: women with high‐grade VIN Settings: outpatient Intervention: imiquimod 5% cream Comparison: 1% cidofovir gel | |||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of Participants | Quality of the evidence | |
| Assumed risk (risk in study population) | Corresponding risk | ||||
| cidofovir | imiquimod | ||||
| Response to treatment at 6 months ‐ Overall response | 618 per 1000 | 569 per 1000 (451 to 729) | RR 0.92 (0.73 to 1.18) | 180 | ⊕⊕⊕⊝ |
| Response to treatment at 6 months ‐ Complete response | 461 per 1000 | 461 per 1000 | RR 1.00 (0.73 to 1.37) | 180 | ⊕⊕⊕⊝ |
| Pain ‐ Any grade | 516 per 1000 | 598 per 1000 | RR 1.16 | 168 | ⊕⊕⊕⊝ |
| Fatigue ‐ Any grade | 607 per 1000 | 759 per 1000 | RR 1.25 (1.02 to 1.55) | 168 (1 study) | ⊕⊕⊕⊝ |
| Headache ‐ Any grade | 440 per 1000 | 656 per 1000 | RR 1.49 (1.12 to 1.98) | 168 (1 study) | ⊕⊕⊕⊝ |
| Total serious adverse events | 369 per 1000 | 465 per 1000 | RR 1.26 (0.88 to 1.81) | 168 (1 study) | ⊕⊕⊕⊝ |
| Treatment discontinuation | 126 per 1000 | 168 per 1000 | RR 1.33 (0.65 to 2.74) | 176 (1 study) | ⊕⊕⊕⊝ |
| *The risk in the cidofovir group is based on the assumed risk on the comparison group and the relative effect of the intervention and its 95% CI. | |||||
| GRADE Working Group grades of evidence | |||||
| 1 Downgraded due to imprecision | |||||
| ISSVD 1986 | ISSVD 2004 | LAST 2012 |
| VIN 1 | Flat condyloma or HPV effect | LSIL |
| VIN 2 | VIN, usual type (uVIN) a. VIN, warty type b. VIN, basaloid type c. VIN, mixed (warty/basaloid) type | HSIL |
| VIN 3 | ||
| Differentiated VIN | VIN, differentiated type (dVIN) | |
| Table derived from ISSVD 2014. Abbreviations: ISSVD ‐ International Society for the Study of Vulvar Disease; LSIL ‐ low‐grade squamous intraepithelial lesions; HSIL ‐ high‐grade squamous intraepithelial lesion | ||
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Response to treatment at 5‐6 months Show forest plot | 3 | Risk Ratio (IV, Random, 95% CI) | Subtotals only | |
| 1.1 Overall response | 3 | 104 | Risk Ratio (IV, Random, 95% CI) | 11.95 [3.21, 44.51] |
| 1.2 Complete response | 3 | 104 | Risk Ratio (IV, Random, 95% CI) | 14.40 [2.97, 69.80] |
| 1.3 Partial response | 3 | 104 | Risk Ratio (IV, Random, 95% CI) | 3.88 [0.75, 19.95] |
| 2 Response to treatment at 12 months Show forest plot | 1 | Risk Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 2.1 Overall response | 1 | Risk Difference (IV, Fixed, 95% CI) | 0.0 [0.0, 0.0] | |
| 2.2 Complete response | 1 | Risk Difference (IV, Fixed, 95% CI) | 0.0 [0.0, 0.0] | |
| 2.3 Partial response | 1 | Risk Difference (IV, Fixed, 95% CI) | 0.0 [0.0, 0.0] | |
| 3 Progression to vulval cancer at 12 months Show forest plot | 1 | Risk Ratio (IV, Random, 95% CI) | Subtotals only | |
| 4 Fatigue Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 5 Headache Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 6 Erythema Show forest plot | 1 | Risk Ratio (IV, Random, 95% CI) | Totals not selected | |
| 6.1 Grade 1‐2 | 1 | Risk Ratio (IV, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 6.2 Grade ≥ 3 | 1 | Risk Ratio (IV, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 6.3 Any grade | 1 | Risk Ratio (IV, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 7 Erosion Show forest plot | 1 | Risk Ratio (IV, Random, 95% CI) | Totals not selected | |
| 7.1 Grades 1‐2 | 1 | Risk Ratio (IV, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 7.2 Grade ≥ 3 | 1 | Risk Ratio (IV, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 7.3 Any grade | 1 | Risk Ratio (IV, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 8 Oedema Show forest plot | 1 | Risk Ratio (IV, Random, 95% CI) | Subtotals only | |
| 9 Pain Show forest plot | 1 | Risk Ratio (IV, Random, 95% CI) | Subtotals only | |
| 10 Pruritis Show forest plot | 1 | Risk Ratio (IV, Random, 95% CI) | Subtotals only | |
| 11 Local side effects Show forest plot | 1 | Risk Ratio (IV, Random, 95% CI) | Subtotals only | |
| 12 No side‐effects Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 13 Dose reductions Show forest plot | 2 | 83 | Risk Ratio (M‐H, Random, 95% CI) | 7.77 [1.61, 37.36] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Response to treatment at 6 months Show forest plot | 1 | Risk Ratio (IV, Random, 95% CI) | Totals not selected | |
| 1.1 Overall response | 1 | Risk Ratio (IV, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 1.2 Complete response | 1 | Risk Ratio (IV, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 1.3 Partial response | 1 | Risk Ratio (IV, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 2 Progressive disease Show forest plot | 1 | Risk Ratio (IV, Random, 95% CI) | Subtotals only | |
| 3 New lesions during treatment Show forest plot | 1 | Risk Ratio (IV, Random, 95% CI) | Subtotals only | |
| 4 Total serious adverse events Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 5 Pain Show forest plot | 1 | Risk Ratio (IV, Random, 95% CI) | Totals not selected | |
| 5.1 Grade 1‐2 | 1 | Risk Ratio (IV, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 5.2 Grade ≥ 3 | 1 | Risk Ratio (IV, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 5.3 Any grade | 1 | Risk Ratio (IV, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 6 Pruritis Show forest plot | 1 | Risk Ratio (IV, Random, 95% CI) | Totals not selected | |
| 6.1 Grade 1‐2 | 1 | Risk Ratio (IV, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 6.2 Grade ≥ 3 | 1 | Risk Ratio (IV, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 6.3 Any grade | 1 | Risk Ratio (IV, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 7 Erosion Show forest plot | 1 | Risk Ratio (IV, Random, 95% CI) | Totals not selected | |
| 7.1 Grade 1‐2 | 1 | Risk Ratio (IV, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 7.2 Grade ≥ 3 | 1 | Risk Ratio (IV, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 7.3 Any grade | 1 | Risk Ratio (IV, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 8 Fatigue Show forest plot | 1 | Risk Ratio (IV, Random, 95% CI) | Totals not selected | |
| 8.1 Grade 1‐2 | 1 | Risk Ratio (IV, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 8.2 Grade ≥ 3 | 1 | Risk Ratio (IV, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 8.3 Any grade | 1 | Risk Ratio (IV, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 9 Headache Show forest plot | 1 | Risk Ratio (IV, Random, 95% CI) | Totals not selected | |
| 9.1 Grade 1‐2 | 1 | Risk Ratio (IV, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 9.2 Grade ≥ 3 | 1 | Risk Ratio (IV, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 9.3 Any grade | 1 | Risk Ratio (IV, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 10 Skin reactions Show forest plot | 1 | Risk Ratio (IV, Random, 95% CI) | Totals not selected | |
| 10.1 Grade 1‐2 | 1 | Risk Ratio (IV, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 10.2 Grade ≥ 3 | 1 | Risk Ratio (IV, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 10.3 Any grade | 1 | Risk Ratio (IV, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 11 Treatment discontinuation Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
