Chemoradiation for advanced primary vulval cancer

Abstract

Background

Vulval cancer is a rare gynaecological cancer. There is no standard approach for treating locally advanced primary vulval cancer (FIGO stage III and IV). Combined treatment modalities have been developed using radiotherapy, chemotherapy and surgery. The advantages and disadvantages of such treatment is not well evaluated.

Objectives

To evaluate the effectiveness and safety of neoadjuvant and primary chemoradiation for women with locally advanced primary vulval cancer compared to other primary modalities of treatment such as primary surgery or primary radiation.

Search methods

We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2009, Issue 3), Cochrane Gynaecological Cancer Group Trials Register, MEDLINE and EMBASE (to July 2009). 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) or non‐randomised studies that included multivariate analyses of chemoradiation in women with locally advanced, primary squamous cell carcinoma of the vulva.

Data collection and analysis

Two review authors independently abstracted data and assessed risk of bias. An adjusted hazard ratio (HR) for overall survival was calculated for one non‐randomised study and risk ratios (RRs) were used in an RCT to compare five‐year death rates and adverse events in women who received neoadjuvant, primary chemoradiation or primary surgery. Adverse events were also reported more extensively in a further non‐randomised study. All results were displayed in single study analyses.

Main results

One RCT and two non‐randomised studies that allowed for multivariate analyses met the inclusion criteria and included a total of 141 women.

One RCT found that neoadjuvant chemoradiation did not appear to offer longer survival compared to primary surgery in advanced vulval tumours (RR = 1.29, 95% confidence interval (CI) 0.87 to 1.91). There was also no statistically significant difference in survival between primary chemoradiation and primary surgery in a study that included 63 women (pooled adjusted HR= 1.09, 95% CI 0.37 to 3.17) and in another study that only included 12 eligible women and compared the same interventions (HR was non‐informative when statistical adjustment was made).

Adverse events were extensively reported in only one study, which found no statistically significant difference in risk of adverse events between primary chemoradiation and primary surgery due to the very small numbers in each group. In the RCT there was no observed statistically significant difference between neoadjuvant chemoradiation and primary surgery. Adverse events were not reported in the largest study of 63 women. Quality of life (QoL) was not reported in any of the included studies. All studies were at high risk of bias.

Authors' conclusions

Women with advanced vulval tumours showed no significant difference in overall survival or treatment‐related adverse events when chemoradiation (primary or neoadjuvant) was compared with primary surgery.

The retrospective studies had a high risk of bias as the entry criteria for primary chemoradiation was based on inoperability or tumour requiring exenteration.The radiochemotherapy regimens varied widely. There was no data on QoL.

There is no standard terminology for 'operable and inoperable vulval cancer', and for 'primary and neoadjuvant chemoradiation'. Stratification according to unresectability of the primary tumour and/or lymph nodes is needed, for good quality comparison.

Plain language summary

Chemoradiation in locally advanced vulval cancer

In women with locally advanced vulval cancer (vulval cancer extending to urethra, vagina, perineum, anus, bladder, rectum, fixed to bones and enlarged fixed lymph glands) there was no significant difference in overall survival or treatment‐related adverse events when primary chemoradiation or neoadjuvant chemoradiation (chemoradiation followed by less radical surgery) were compared with primary surgery. Women requiring extensive surgery (urinary and or feacal stoma formation) or with inoperable tumour were predominantly given primary chemoradiation in the two retrospective studies identified, making the available evidence weak (although we only included studies that used statistical adjustment). There was no data on quality of life. There is a great need for good quality studies comparing various primary treatments in locally advanced vulval cancer which are either inoperable at presentation or operable but would require extensive surgery.

Background

Description of the condition

Vulval cancer is predominantly a disease of elderly women, with a mean age at diagnosis of approximately 70 years (Jemal 2006). According to population‐based studies, about 75% of vulval malignancies are squamous cell carcinomas (Platz 95; Velden 1996; Stroup 2008). In advanced stage vulval cancer (FIGO stage III and IV) there can be extension of the vulval tumour to the adjacent genitourinary system and anorectum, and fixity to bones with or without enlarged fixed pelvic or groin lymph nodes. Thirty to forty per cent of squamous carcinoma of the vulva are in advanced stages at presentation. Treatment in these cases is individualised.

Description of the intervention

In women presenting with locally advanced tumour, treatment ranges from radical vulvectomy and bilateral inguinofemoral lymphadenectomy with or without partial resection of urethra, vagina or anus to exenteration. This is followed by adjuvant radiotherapy or chemoradiotherapy depending on the residual disease or risk of recurrence. Plastic reconstruction procedures are considered following excision of large vulval tumours (see Types of interventions for detailed description of surgical procedures).

For women presenting with locally advanced inoperable tumours, chemoradiation followed by no surgery or less radical surgery is generally advocated (see Types of interventions for description of types of chemoradiation). In the 1980s, both Boronow 1982 and Hacker 1984 presented the results on neoadjuvant radiation therapy in vulval cancer. The results were promising as pelvic exenteration did not appear to be necessary and survival was excellent. In the same time period chemoradiation was developed for anal cancer (Cummings 1984). In view of the promising results, various treatment modalities such as chemoradiation alone, neoadjuvant chemoradiation followed by less extensive surgery or surgery followed by adjuvant postoperative radiation or chemoradiation have been developed in this group of women (Gaffney 2009; Landoni 1996).

All types of treatment are associated with high morbidity, treatment‐related deaths and varying but unsatisfactory overall survival rates. In particular, women undergoing exenterative procedure have higher surgical complication rates, including a mortality of 2% to10% (Maggioni A 2009; Moore 1998). Such radical surgery is often inappropriate for the elderly due to severe psychological and physical morbidity (Andersen 1983; Moore 1998; Maggioni A 2009). Even though the incidence of vulval cancer is lower in the younger age group, such surgery is also inappropriate for young women as it causes severe psychosexual problems (Gadducci 2006). Chemoradiation is often associated with extensive desquamation of vulval skin leading to treatment breaks, and is also associated with long term side effects of chemoradiation. There is mortality associated with chemoradiation as well.

There are few studies on the effectiveness of neoadjuvant chemotherapy followed by surgery in this group of women (Benedetti‐Panici 1993; Geisler 2006; Wagenaar 2001) and they have varying results.

Why it is important to do this review

Traditionally, primary vulval cancers have been managed by radical surgery followed by adjuvant radiation or chemoradiation (Ansink 1999). Inoperable tumours at initial presentation are treated with chemoradiation. Inoperability in advanced vulval cancer is determined based on the extent of local tumour and or the extent and fixity of nodal disease. The combination of clinical presentations makes comparison between surgery and radiation or chemoradiation in locally advanced vulval disease difficult. The decision to move away from standard management (e.g. primary surgery where possible) in advanced vulval disease is driven by the need to reduce the mortality and morbidity associated with extensive surgery, especially in elderly patients. Extensive surgery also affects the quality of life for younger patients, in terms of body image and psychosexual morbidity. The use of neoadjuvant chemoradiation in vulval cancer stems from the positive influence of this modality of treatment in anal cancer. On the contrary, in locally advanced cervical cancer combined treatment (surgery and chemoradiation) is generally not advised as it causes more adverse effects than single treatment. However the management of advanced vulval cancer is heterogenous and individualised.

The efficacy and safety of alternative treatment in advanced vulval cancer is mostly based on good quality feasibility studies, case series and case reports with no comparisons. Chemoradiation is also associated with treatment‐related morbidity and mortality. The indications and optimal regime for this treatment have not been completely evaluated. A recent survey from the Gynecologic Cancer Intergroup study on patterns of care for radiation and chemotherapy in vulval cancer confirms the fact that there is a difference in the indications for treatment, treatment fields and use of chemotherapy among various members of the Gynecologic Cancer Intergroup, even though the doses of radiation were similar among the members (Gaffney 2009). Hence we aimed to search for good quality comparative studies in this review.

Objectives

To evaluate the effectiveness and safety of neoadjuvant and primary chemoradiation for women with locally advanced primary squamous vulval cancer compared to other primary modalities of treatment such as primary surgery or primary radiation. Locally advanced primary disease is defined as encompassing women who have FIGO stage III or IVa squamous vulval cancer.

Methods

Criteria for considering studies for this review

Types of studies

Studies regarding patients with histologically proven, locally advanced primary squamous cell carcinoma of the vulva were considered for this review. It was anticipated that only a very small number, if any, randomised controlled trials (RCTs) would have been conducted on chemoradiation treatment in vulval cancer. We therefore also considered non‐randomised studies with concurrent comparison groups:

• quasi‐randomised trials, non‐randomised trials, prospective and retrospective comparative cohort studies, and case series of 10 or more patients that allowed concurrent comparisons of chemoradiation with different treatments.

Case‐control studies, uncontrolled observational studies and case series of fewer than 10 patients were excluded.

In order to minimise selection bias, we decided to include only studies that used statistical adjustment for baseline case mix using multivariable analyses (for example age, performance status, grade) if any constraints were placed on treatment allocation (for example women with poor performance status would not be given chemoradiation or surgery, women who needed exenterative surgery would be allocated to primary chemoradiation treatment (CRT) rather than primary surgery), or treatment was based on clinician preference.

Types of participants

Staging of vulval cancer has changed over the years, from a clinical staging procedure in 1969 to a surgical staging from 1988 onwards (Shepherd 1989). The latter was revised in 2000 and more recently in 2009 (Benedet 2000; FIGO 2009). Staging methods are summarised in tables (Table 1; Table 2). In our review we incorporated patients with biopsy proven, primary locally advanced squamous cell carcinoma of the vulva (stage III/IV). Table 3 summarises the criteria with reference to the FIGO and TNM staging.

1. FIGO staging of the vulva.

stage	FIGO staging 1969	FIGO staging 1988	FIGO staging 2000
	Clinical staging	Surgical staging	Surgical staging
0	Carcinoma in situ	Carcinoma in situ	carcinoma in situ
I	Tumour confined to vulva, 2cm or less in largest diameter, and no suspicious groin nodes	Tumour confined to vulva or perineum, < 2cm in greatest dimension, nodes are negative	Ia: Tumour confined to vulva or vulva and perineum, 2cm or less in greatest dimension and with stroma invasion no greater than 1.0mm. Nodes are negative. Ib: Tumour confined to vulva or vulva and perineum, 2 cm or less in greatest dimension and with tsromal invasion greater than 1.0 mm. Nodes are negative.
II	Tumour confined to vulva, more than 2 cm in diameter, and no suspicious groin nodes	Tumour confined to vulva or perineum, > 2cm in greatest dimension, nodes are negative	Tumour confined to vulva or vulva and perineum, more than 2 cm in greatest dimension. Nodes are negative.
III	Tumour of any size with: (1) Adjacent spread to the urethra and/or vagina, perineum, and anus, and/or (2) Clinically suspicious lymph nodes in either groin.	Tumour of any size with: (1) Adjacent spread to the lower urethra or anus, and/or (2) Unilateral regional lymph nodes metastases.	(1) Tumour invades any of the following: lower urethra, vagina, anus. (2) Unilateral regional lymph nodes metastases.
IVa	IV: Tumour of any size : (1) infiltrating the bladder mucosa, or the rectal mucosa, or both, including the upper part of the urethral mucosa, and/or (2) fixed to the bone, and/or (3) other distant metastases.
IVb		Any distant metastasis, including pelvic lymph nodes	Any distant metastasis, including pelvic lymph nodes

2. TNM classification of carcinoma of the vulva.

Stage	TNM 1969	TNM 1988	TNM 2000
	Clinical staging	Surgical staging	Surgical staging
Tx		Primary tumour cannot be assessed	Primary tumour cannot be assessed
T0		No evidence of primary tumour	No evidence of primary tumour
Tis		Carcinoma in situ	Carcinoma in situ
T1	Tumour confined to the vulva, 2 cm in largest diameter	Tumour confined to the vulva and/or perineum, 2 cm or less in greatest dimension	T1a: Tumour confined to the vulva and/or perineum, 2 cm or less in greatest dimension and with stromal invasion no greater than 1.0 mm. T1b: Tumour confined to the vulva and/or perineum, 2 cm or less in greatest dimension and with stromal invasion greater than 1.0 mm.
T2	Tumour confined to the vulva, 2 cm in largest diameter	Tumour confined to the vulva and/or perineum, more than 2 cm in greatest dimension	Tumour confined to the vulva and/or perineum, more than 2 cm in greatest dimension
T3	Tumour of any size with adjacent spread to the urethra, and/or vagina, and/or perineum, and/or anus.	Tumour involves any of the following: the lower urethra, vagina, anus.	Tumour invades any of the following: the lower urethra, vagina, anus.
T4	Tumour of any size infiltrating the bladder mucosa,and/or the rectal mucosa, or including the upper part of the urethral mucosa, and/or fixed to the bone.	Tumour involves any of the following: bladder mucosa, rectal mucosa, upper urethra, pelvic bone.	Tumour invades any of the following: bladder mucosa, rectal mucosa, upper urethral mucosa, or is fixed to bone.
Nx		Regional (i.e. femoral and inguinal) lymph nodes cannot be assessed	Regional (i.e. femoral and inguinal) lymph nodes cannot be assessed
N0	No nodes palpable	No lymph node metastases	No lymph node metastases
N1	Nodes palpable in either groin, not enlarged, mobile (not clinically suspicious for neoplasm)	Unilateral regional lymph node metastases	Unilateral regional lymph node metastases
N2	Nodes palpable in either groin, enlarged, firm and mobile (clinically suspicious for neoplasm)	Bilateral regional lymph node metastases	Bilateral regional lymph node metastases
N3	Fixed or ulcerated nodes
Mx		Distant metastases cannot be assessed	Distant metastases cannot be assessed
M0	No clinical metastases	No distant metastases	No distant metastases
M1	M1a Palpable deep pelvic lymph nodes. M1b: Other distant metastases	Distant metastases, including pelvic lymph node metastases	Distant metastases, including pelvic lymph node metastases

3. Patient selection for Cochrane review with reference to FIGO and TNM staging.

Criteria	FIGO 1969	FIGO 1988 and 2000	TNM 1969	TNM 1988 and 2000
Fixed to bone	IV	IVa	T4	T4
Spread to lower urethra	III	III	T3	T3
Spread to upper urethra or bladder mucosa	IVa	IVa	T4	T4
Spread to anus	III	III	T3	T3
Spread to rectal mucosa	IV	IVa	T4	T4
Fixed or ulcerated nodes	not classified	not classified	Any T, N3, M0	not classified

Types of interventions

Intervention

• Chemoradiation (primary, neoadjuvant)

Comparison

• Primary surgery

• Radiation (primary, neoadjuvant)

• Chemotherapy (neoadjuvant)

Additionally, we considered any direct comparison between neoadjuvant and primary chemoradiation.

Chemoradiation

This is a combination of chemotherapy and radiotherapy.

Neoadjuvant chemoradiation: Pre‐operative radiation and concurrent chemotherapy given to the whole pelvis and nodes followed by less extensive surgery.

Primary chemoradiation: It is similar to neoadjuvant chemoradiation regime, but is followed by a radiation boost to the residual disease.

Radiation: timing of radiation, radiation field (pelvis, vulva, groin), radiation technique, regimen, dose and fraction size, interruption to treatment and side effects were examined.

Chemotherapy: timing; dose and admission of chemical agents, e.g. 5‐fluorouracil, cisplatin, carboplatin, mitomycin‐C, bleomycin either as single agent or in combination; treatment schedule; interruption to chemotherapy and toxicity were investigated.

Surgery

Radical local excision of vulva: excision of the tumour carried down to the fascia lata with a circumferential tumour‐free margin of at least one centimetre.

Vulvectomy (radical, simple, modified, hemi): radical vulvectomy is defined as excision of the complete vulval skin and subcutaneous tissue down to the fascia lata. Simple and modified vulvectomy is similar but with preservation of varying amounts of vulval skin and subcutaneous tissue. Hemivulvectomy is removal of vulval skin and subcutaneous tissue down to the fascia lata on the affected side. The purpose of the modifications is to achieve a tumour‐free margin of at least one centimetre with preservation of some vulval tissue.

Lymphadenectomy (inguinofemoral or deep, inguinal or superficial, ipsilateral, pelvic): inguino femoral lymphadenectomy is defined as removal of all inguinal and femoral lymph nodes. It is achieved by removing lymph nodes bearing fatty tissue between the inguinal ligament, the sartorius muscle and the adductor longus muscle, as well as dissection of the femoral lymph nodes located in the fossa ovalis medial to the femoral vein. Inguinal lymphadenectomy is defined as removal of all lymph node bearing fatty tissue between the inguinal ligament, the sartorius muscle and the adductor longus muscle above the level of the fascia lata. Ipsilateral lymphadenectomy is removal of inguinofemoral lymph nodes on the side of the tumour. Pelvic lymphadenectomy is removal of iliac and obturator lymph nodes in the pelvis.

Exenteration (anterior, posterior, total): total pelvic exenteration is removal of bladder, urethra, rectum, vulva, vagina, and uterus. It might leave the patient with a urinary or feacal conduit. Anterior exenteration is removal of the bladder, vagina and uterus and the development of a bladder conduit. Posterior exenteration involves removal of vagina, uterus and rectum and the development of a faecal stoma.

Reconstructive surgery: the vulval defect is closed with flaps (fascio, myocutaneous etc.).

Types of outcome measures

Primary outcomes

1. Overall survival: survival until death from all causes

Secondary outcomes

1. Progression‐free survival.

2. Quality of life (QoL) measured using a scale that has been validated through reporting of norms in a peer‐reviewed publication.

3. Adverse events classified according to CTCAE 2006

   1. Direct surgical morbidity: death within 30 days, haemorrhage (intraoperative and postoperative), intraoperative organ Injury (bladder, ureter, bowel and vessels etc.), febrile morbidity and postoperative site specific infection (surgical site, pelvic, urinary, bowel), postoperative complications related to the urinary and gastrointestinal tract (obstruction, fistulae, incontinence), unexpected return to theatre, delayed discharge due to complications.

   2. Surgical‐related systemic morbidity: vascular and thromboembolic (thrombosis, embolism, coagulopathy), pulmonary (infection, atelectesis etc.), lymphatics (lymphaedema, lymphocele), metabolic (diabetic complications, renal failure etc.), cardiac events (cardiac ischemia, failure), hepatobiliary, cerebrovascular accidents, sexual dysfunction, chronic pain and psychological morbidity.

   3. Radiotherapy toxicity.

   4. Chemotherapy toxicity.

Grades of toxicity relating to radiotherapy and chemotherapy were extracted and grouped as:

• 1. hematological (leucopenia, anaemia, thrombocytopenia, neutropenia, hemorrhage);

  2. gastrointestinal (nausea, vomiting, anorexia, diarrhoea, liver, proctitis);

  3. genitourinary (cystitis, incontinence);

  4. skin (stomatitis, mucositis, alopecia, allergy);

  5. neurological (peripheral and central);

  6. pulmonary;

  7. lymphatics (lymphocele, lymphedema);

  8. psychosexual;

  9. others.

Search methods for identification of studies

Papers were sought in all languages and translations carried out when necessary.

Electronic searches

See: Cochrane Gynaecological Cancer Group methods used in reviews.
 The following electronic databases were searched.

• Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2009, Issue 3)

• Cochrane Gynaecological Cancer Collaborative Review Group Trial Register

• MEDLINE to July 2009

• EMBASE to July 2009

The MEDLINE, EMBASE and CENTRAL search strategies aimed at identifying studies that compared neoadjuvant, primary or adjuvant chemoradiation, primary surgery or radiation therapy are presented in Appendix 1, Appendix 2 and Appendix 3 respectively.

Databases were searched from 1966 until July 2009.

All the 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

Metaregister, Physicians Data Query, www.controlled‐trials.com/rct, www.clinicaltrials.gov and www.cancer.gov/clinicaltrials were searched for ongoing trials. The main investigators of the relevant ongoing trials were contacted for further information, as were the major co‐operative trials groups active in this area (MRC).

Handsearching

The citation list of relevant publications, abstracts of scientific meetings and list of included studies were checked through handsearching and experts in the field were contacted to identify further trial reports. Reports of conferences were handsearched in the following sources:

• British Journal of Cancer;

• British Cancer Research Meeting;

• British Journal of Obstetrics and Gynaecology;

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

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

• International Journal of Gynecological Cancer.

• Journal of Gynecological Oncology

• Society of Gynaecological Oncologists meetings and proceedings

• International Society of Gynecological Oncologists meetings and proceedings

Reference lists

The reference lists of all eligible trials, key textbooks, and previous systematic reviews were searched for additional studies. 

Data collection and analysis

Selection of studies

All titles and abstracts retrieved by electronic searching were downloaded to the reference management database Endnote. Duplicates were removed and the remaining references were independently examined by two review authors (AB, TS). Those studies which clearly did not meet the inclusion criteria were excluded and copies of the full text of potentially relevant references were obtained. The eligibility of retrieved papers was assessed independently by two review authors (AB, TS). Disagreements were resolved by discussion between the two review authors. Reasons for exclusion are documented. 

Data extraction and management

For included studies, data were extracted as recommended in Chapter 7 of the Cochrane Handbook 2008. This included data on the following.

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

• Country

• Setting

• Inclusion and exclusion criteria

• Study design, methodology

• Study population

  • total number enrolled

  • patient characteristics

  • age

  • co‐morbidities

  • smoking status

• Vulval cancer details at diagnosis

  • FIGO stage (III/IV)

  • TNM stage

  • histological cell type

  • grade

• Intervention details

  • chemoradiation details

    • dose, cycles, timing (concurrent, sequential) and combination of chemotherapeutic agents

    • dose, fraction size, field (pelvis, groin) , type of radiotherapy (teletherapy, brachytherapy) and timing (concurrent, sequential)

    • timing and type of surgery (if applicable)

• Comparison details

  • type of intervention

  • surgery details

  • radiation: timing, dose, fraction size, field and type

  • chemotherapy: timing, dose, cycles, single or combination of chemotherapeutic agents

• Risk of bias in study (see below)

• Duration of follow up

• Outcomes

Data on all primary and secondary outcomes that were reported were extracted as follows.

• • For time to event (overall survival) data, we extracted the log of the hazard ratio (log(HR)) and its standard error from trial reports; if these were not reported, we attempted to estimate them from other reported statistics using the methods of Parmar 1998. 

  • For dichotomous outcomes (e.g. adverse events, or deaths if it was not possible to use a HR), we extracted the number of patients 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).

For non‐randomised studies, adjusted statistics were collected and the variables used in adjustment were recorded. Unadjusted and adjusted results, where reported, were collected for RCTs.

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

The time points at which outcomes were collected and reported were noted.

Data were abstracted independently by two review authors (AB, TS) onto a data abstraction form specially designed for the review. Differences between review authors were resolved by discussion.

Assessment of risk of bias in included studies

The risk of bias in included RCTs was assessed using the following questions and criteria (Cochrane Handbook 2008).

Sequence generation

Was the allocation sequence adequately generated?

• Yes: e.g. a computer‐generated random sequence or a table of random numbers

• No: e.g. date of birth, clinic id‐number or surname

• Unclear: e.g. not reported

Allocation concealment

Was allocation adequately concealed?

• Yes: e.g. where the allocation sequence could not be foretold

• No: e.g. allocation sequence could be foretold by patients, investigators or treatment providers

• Unclear: e.g. not reported

Blinding

Blinding was in terms of participants, healthcare providers and outcome assessors.

Was knowledge of the allocated interventions adequately prevented during the study?

• Yes

• No

• Unclear

Incomplete reporting of outcome data

We recorded the proportion of participants whose outcomes were not reported at the end of the study.

Were incomplete outcome data adequately addressed?

• Yes, if fewer than 20% of patients were lost to follow up and reasons for loss to follow up were similar in both treatment arms

• No, if more than 20% of patients were lost to follow up or reasons for loss to follow up differed between treatment arms

• Unclear if loss to follow up was not reported

Selective reporting of outcomes

Are reports of the study free of suggestion of selective outcome reporting?

• Yes: e.g. if review reports all outcomes specified in the protocol

• No

• Unclear

Other potential threats to validity

Was the study apparently free of other problems that could put it at a high risk of bias?

• Yes

• No

• Unclear

The risk of bias in non‐randomised studies was assessed in accordance with four additional criteria.

Cohort selection

1. Were relevant details of criteria for assignment of patients to treatments provided?

   1. Yes

   2. No

   3. Unclear

2. Was the group of women who received the experimental intervention (chemoradiation for advanced primary vulval cancer) representative?

   1. Yes: if they were representative of women with advanced vulval cancer

   2. No: if group of patients was selected

   3. Unclear: if selection of group was not described

3. Was the group of women who received the comparison intervention (surgery or another medical intervention other than intervention group) representative?

   1. Yes: if drawn from the same population as the experimental cohort

   2. No: if drawn from a different source

   3. Unclear: if selection of group not described

Comparability of treatment groups

1. Were there any differences between the two groups, or differences controlled for, in particular with reference to age, FIGO stage, tumour size and lymph node status, grade, smoking status?

   1. Yes: if at least two of these characteristics were reported and any reported differences were controlled for

   2. No: if the two groups differed and differences were not controlled for

   3. Unclear: if fewer than two of these characteristics were reported, even if there were no other differences between the groups, and other characteristics had been controlled for

The risk of bias tool was applied independently by two review authors (AB, TS) and differences resolved by discussion or by appeal to a third review author. Results are presented in both a risk of bias graph and a risk of bias summary. Results of all analyses were interpreted in light of the findings with respect to risk of bias.

Measures of treatment effect

We used the following measures of the effect of treatment.

• For time to event data, we used the hazard ratio where possible.

• For dichotomous outcomes, we used the risk ratio.

Dealing with missing data

We did not impute missing outcome data for any outcomes.

Data synthesis

We were unable to pool the results of the included studies in meta‐analyses as the studies either compared different interventions or there were insufficient numbers of women to pool adjusted results. Therefore it was not relevant to assess heterogeneity between results of trials. We were unable to assess reporting biases using funnel plots or conduct any subgroup or sensitivity analyses.

Results

Description of studies

Results of the search

The title and abstract screening of references using the original search strategy identified 21 studies as potentially eligible for this review. The updated search strategy identified 78 references in MEDLINE, 201 in EMBASE, none in CENTRAL and three in the Specialised Register. When the search results were merged into Endnote and the duplicates removed there were 229 unique references. The title and abstract screening of these references identified 39 references as potentially eligible for the review. Overall, the full text screening of these 39 references excluded 36 for the reasons described in the table Characteristics of excluded studies. The remaining three studies met our inclusion criteria and are described in the table Characteristics of included studies.

Following the above mentioned search strategy, searches of the grey literature and various international trial websites identified two ongoing studies (GOG 0205; EORTC Phase II study). The recruitment was complete but the trials were still ongoing.

Included studies

The three included studies (Landrum 2008; Maneo 2003; Mulayim 2004) analysed a total of 141 women. All of them had advanced stage primary vulval cancer. Women with recurrent disease or early stage cancer were excluded in this review. In the Landrum 2008 study, four women had stage 4b disease but this only accounted for less than 3% (4/141) of the total number of women analysed in the review so the study was included.

Study design

Two of the studies were retrospective and one was an RCT, but only the abstract of the RCT was available. The authors of the RCT kindly provided additional information on request.

In terms of the intervention, the two retrospective studies (Landrum 2008; Mulayim 2004) looked at primary chemoradiation versus primary surgery and Maneo 2003, which was an RCT, looked at neoadjuvant chemoradiation versus primary surgery.

In Landrum 2008 43% had adjuvant radiation, 20% had adjuvant chemoradiation after primary surgery. In Mulayim 2004 all six women had adjuvant chemoradiation after primary surgery. In Maneo 2003 15 women (15/27) had adjuvant radiotherapy after primary surgery.

In Landrum 2008 the median follow up was 31 months, in Mulayim 2004 the median follow up was 20 months. The mean and median follow up was 42 months and 40 months respectively in the RCT by Maneo 2003.

Participant characteristics

Both retrospective studies subgrouped the patients into stage III and stage IV, Mulayim 2004 also reported the TNM classification of malignant tumours whereas for the RCT of Maneo 2003 the data on TNM staging was provided by the authors.

In the two non‐randomised studies, the number of women with stage III and stage IV was 57 and 19 respectively. Four of them had stage IVb disease and were included in the analysis as the overall percentage was less than 2.5% of the total number of women included. One study quoted the grade of the cancer (Mulayim 2004). The median age at diagnosis was 64 and 73 years in Landrum 2008 and Mulayim 2004 respectively. The mean age in the RCT (Maneo 2003) was 74 years at the time of diagnosis in both the arms.

In Landrum 2008 all patients that had a primary tumour that was inoperable or would require exenterative procedure underwent primary chemoradiation. Similarly in Mulayim 2004, patients with locally advanced disease that required extensive resection received primary chemoradiation. So in both retrospective studies, the decision to administer primary chemoradiation was largely based on prevention of exenterative surgery.However, in Landrum 2008 the clinical practice was to perform inguinofemoral lymphadenectomy to evaluate the node status and debulk the enlarged nodes prior to primary chemoradiation.

In the RCT by Maneo 2003, all operable cases were randomised. The number of cases needing extensive resection before randomisation was eight in the neoadjuvant chemoradiation arm and five in the surgery arm.

With regards to adjuvant treatment following primary treatment, in Landrum 2008 eight (24%) patients underwent adjuvant surgery following primary chemoradiation and 19 patients (63%) underwent either adjuvant radiation or adjuvant chemoradiation following primary surgery. In Mulayim 2004 one patient in the primary chemoradiation group underwent adjuvant surgery and all the patients who underwent primary surgery underwent adjuvant chemoradiation.

In Maneo 2003, in the primary surgery arm, 15 (15/37) patients underwent adjuvant radiation. Surgery was feasible in 24 out of 28 patients in the neoadjuvant arm.

In Landrum 2008 there were a total of 12 recurrences, five in the primary chemoradiation group and seven in the primary surgery group. In Mulayim 2004 there were four recurrences, one in the primary chemoradiation group and three in the primary surgery group.

In Maneo 2003 there were 30 recurrences, 13 in the neoadjuvant chemoradiation arm and 17 in the primary surgery arm.

Outcomes

Overall survival (OS) was discussed in all the papers. The authors of Landrum 2008 provided us with an adjusted hazard ratio for overall survival, and individual patient data were presented in the Mulayim 2004 study so it was possible to attempt our own adjusted hazard ratio estimate. Landrum 2008 adjusted the hazard ratio for overall survival for important prognostic factors which included age, FIGO stage, size of tumour and nodal status. The RCT of Maneo 2003 reported 5‐year survival rates in each treatment arm so it was possible to estimate a risk ratio for risk of death. Progression‐free survival was reported in the Landrum 2008 study, but this was not examined as an outcome in any multivariate analyses. The Mulayim 2004 study reported recurrence‐free survival times for each patient, so it was possible to attempt our own adjusted hazard ratio estimate. Quality of life data were not reported in any of the trials and the reporting of adverse events was incomplete. The Landrum 2008 study did not report adverse events, Maneo 2003 and Mulayim 2004 reported an extensive range of adverse events for all their patients.

Excluded studies

The full text was obtained for 39 references, but 36 were excluded from the review for the following reasons.

• Twenty‐four references reported results of non‐comparative studies. Many of the studies looked at concomitant chemoradiotherapy with or without tailored surgery (Aki A 2000; Berek 1991; Beriwal 2008; Cunningham 1997; Eifel 1995; Gerszten 2005; Iversen 1982; Jolicoeur 2004; Koh WJ 1993; Landoni 1996; Landrum 2007; Levin W 1986; Lupi G 1996; Montana 2000; Moore 1998; Russell 1992; Scheistroen 1993; Sebag‐Montefiore 1994; Stehman 2006; Stroup 2008; Thomas 1989). The methodological quality of some of these studies was very good, but they were excluded as there was no comparison group. Some were prospective feasibility studies. Three studies looked at neoadjuvant chemotherapy for locally advanced vulval cancer but there was no comparison group (Benedetti‐Panici 1993; Geisler 2006; Wagenaar 2001).

• Three references were systematic reviews (de Hullu 2006; Gadducci 2006; Moore 2009).

• Nine studies were excluded because either a multivariate analysis was not carried or because the numbers were too small in the comparison groups (Beller 2006; Beriwal 2006; Carson 1990; Han 2000(a); Han 2000(b); Makinen 1987; Roberts 1989; Roberts 1991; Wahlen 1995).

For further details of all the excluded studies see the table Characteristics of excluded studies.

Risk of bias in included studies

Both non‐randomised studies were at high risk of bias as they only satisfied one of the six core criteria (see Figure 1; Figure 2) and the RCT of Maneo 2003 was at moderate risk of bias as it satisfied three of the criteria. The trial of Maneo 2003 was an abstract of an RCT, but the authors kindly provided additional information so we were able to fully assess each risk of bias item.

1.

Methodological quality graph: review authors' judgements about each methodological quality item presented as percentages across all included studies.

2.

Methodological quality summary: review authors' judgements about each methodological quality item for each included study.

An adequate sequence had been generated to assign women to treatment groups and the allocation was adequately concealed in the trial of Maneo 2003. These criteria were not relevant to the two non‐randomised studies (Landrum 2008; Mulayim 2004) so these studies were at high risk of bias for these individual quality items. Blinding of the outcome assessor was not carried out in the trial of Maneo 2003 and was not reported in any of the other studies. There was insufficient information to make judgement on whether any additional risk factor for bias existed or whether there had been selective reporting of outcomes, in all three studies. The Landrum 2008 study did not analyse progression‐free survival in a multivariate analysis, but the main outcome was overall survival. This was reported and was not statistically significant so it seems unlikely progression‐free survival was not reported in a multivariate analysis because it was not significant. All of the studies assessed an adequate proportion of their recruited women, as at least 94% of eligible women were assessed at the endpoint for all outcomes.

Both non‐randomised studies fully reported details of the assignment of women to the two methods of treatment, but the two groups were not representative of the wider population of women with locally advanced vulval cancer as interventions were decided depending on particular disease characteristics. The data were too sparse in the Mulayim 2004 study to assess comparability of treatment groups as there were only 12 women who met the inclusion criteria. Women in the Landrum 2008 study appeared to be comparable as the only predictor of overall survival was found to be age in a multivariate Cox model and age was not significantly different between the two groups at baseline (P = 0.09).

Effects of interventions

See Table 4 for summary of outcomes for comparisons of interventions in included studies.

4. Summary of trial comparisons, outcomes and follow up.

Trial ID, design and comparison	Deaths	Adverse events	Duration of follow up
Landrum 2008 Retrospective study Primary chemoradiation versus primary surgery	9/30 (31%) versus 8/33 (24%) Adjusted HR=1.09 (95% CI 0.37 to 3.17) For list of adjusted variables ‐see Effects of interventions	Not reported	Median follow up was 31 months (range from 3–161 months)
Maneo 2003 RCT Neoadjuvant chemoradiation versus primary surgery	Death at 5 years: 20/28 (70%) versus 19/37 (51%)	Overall surgical morbidity: 13/24 (54%) versus 17/37 (46%)	Mean follow up was 42 months
Mulayim 2004 Retrospective study Primary chemo‐radiation versus primary surgery	3/6 (50%) versus 6/6 (100%) Adjusted HR was non‐ informative due to sparse data	Acute toxicity Severe hematologic toxicity: 3/6 (50%) versus 4/6 (67%) Severe gastrointestinal toxicity: 1/6 (17%) versus 3/6 (50%) Severe skin toxicity: 2/6 (34%) versus 4/6 (67%) Severe pain: 2/6 (34%) versus 0/6 (0%) Other severe acute toxicity: 1/6 (17%) versus 0/6 (0%) Late toxicity Severe gastrointestinal toxicity: 0/6 (0%) versus 1/6 (17%) Severe genitourinary toxicity: 0/6 (0%) versus 1/6 (17%) Other severe late toxicity: 4/6 (67%) versus 3/6 (50%)	Median follow up was 20 months (range 5–74 months)

For dichotomous outcomes, we were unable to estimate a risk ratio (RR) for comparisons of treatments if one or both treatment groups experienced no events.

Primary chemoradiation versus primary surgery

Adverse event outcomes were reported by treatment arm in Mulayim 2004 so analyses were based on only six patients in each group.

Overall and recurrence‐free survival

In the Mulayim 2004 study, the number of cases of tumour recurrence and deaths were too small to compute an adjusted hazard ratio (HR). The confidence interval (CI) was non‐informative for all combinations of covariate adjustment, so there is no evidence as to whether primary chemoradiation or surgery is the most effective treatment from this study. However, the Landrum 2008 study found no statistically significant difference in the risk of death in women with locally advanced primary vulval cancer between women who received primary chemoradiation and those who received primary surgery, after adjustment for important prognostic factors which included age, FIGO stage, size of tumour and nodal status (HR 1.09, 95% CI 0.37 to 3.17). Recurrence or progression‐free survival was not reported in a multivariate analysis in this study.

No statistical adjustment was made for any of the following adverse events as the data were too sparse. While it is essential to adjust estimates in studies prone to selection bias for survival outcomes, it appears reasonable to report unadjusted results for the toxicity outcomes below, particularly as most are acute.

Severe acute toxicity

Hematologic toxicity

There was no significant difference in the risk of severe acute hematologic toxicity between primary chemoradiation and surgery (RR 0.75, 95% CI 0.28 to 2.00).

Gastrointestinal toxicity

There was no significant difference in the risk of severe acute gastrointestinal toxicity between primary chemoradiation and surgery (RR 0.33, 95% CI 0.05 to 2.37).

Skin toxicity

There was no significant difference in the risk of severe acute skin toxicity between primary chemoradiation and surgery (RR 0.50, 95% CI 0.14 to 1.77).

Pain

There was no significant difference in the risk of severe acute pain between primary chemoradiation and surgery. The study reported only two cases of severe pain, which were in women who received primary chemoradiation.

Other toxicity

There was no significant difference in the risk of other severe acute toxicities between primary chemoradiation and surgery. The study reported only one additional case of a severe toxicity, which was in a women who received primary chemoradiation.

Severe late toxicity

Gastrointestinal toxicity

There was no significant difference in the risk of other severe late gastrointestinal toxicity between primary chemoradiation and surgery. The study reported only one case of severe gastrointestinal toxicity, which was in a women who received adjuvant chemoradiation.

Genitourinary toxicity

There was no significant difference in the risk of other severe late genitourinary toxicity between primary chemoradiation and surgery. The study reported only one case of severe genitourinary toxicity, which was in a women who received primary surgery.

Other late toxicity

There was no significant difference in the risk of other severe late toxicities between primary chemoradiation and surgery (RR 1.33, 95% CI 0.50 to 3.55).

Neoadjuvant chemoradiation versus primary surgery

Only the RCT of Maneo 2003 reported data on neoadjuvant chemoradiation versus primary surgery.

Death at five years

The trial found no statistically significant difference in the risk of death at five years in women with locally advanced primary vulval cancer who received neoadjuvant chemoradiation and those who received primary surgery (RR 1.39, 95% CI 0.94 to 2.06).

Overall morbidity

The trial found no statistically significant difference in the risk of overall treatment related morbidity in women with locally advanced primary vulval cancer who received neoadjuvant chemoradiation and those who received primary surgery (RR 1.18, 95% CI 0.71 to 1.96).

Discussion

Summary of main results

We found one RCT and two retrospective studies that met our inclusion criteria. These studies assessed the effectiveness and safety of primary chemoradiation, neoadjuvant chemoradiation and primary surgery in women with locally advanced primary vulval cancer.

All comparisons were restricted to single study analyses, where we found no evidence that any form of chemoradiation prolonged the survival of women or was associated with greater safety in terms of adverse events in women with locally advanced primary vulval cancer when compared to primary surgery. There were also insufficient data or no reporting of recurrence‐free survival in the three studies. This review was based on only 141 women and meta‐analyses were not possible, so it was not adequately powered to detect differences in survival.

Despite the fact that vulval cancer is predominantly a disease of elderly women (Jemal 2006), the RCT and two retrospective studies all had a relatively short follow‐up period. The RCT had a mean follow up of 42 months and the studies of Landrum 2008 and Mulayim 2004 had median follow ups of 31 and 20 months respectively. Adverse effects of treatment were reported in the two retrospective studies and there was no statistically significant difference in adverse events between the different treatments.

Quality of life (QoL) was not reported in any of the studies. QoL may be of additional importance to both elderly and young women who may be psychologically scarred as well as having obvious physical limitations to their life after developing the disease and receiving treatment. We did not find any studies that directly compared primary versus neoadjuvant chemoradiation or any form of chemoradiation with primary or neoadjuvant radiation.

Overall completeness and applicability of evidence

From this review, the evidence that chemoradiation(primary or neoadjuvant) and primary surgery are useful modalities of treatment for locally advanced vulval cancer is relevant. This can be applied to women with locally advanced vulval cancer. Whether one treatment modality is better or worse than the other in terms of overall survival is not completely conclusive as the numbers of women included in the review are small. Although individual patient data were presented in the two retrospective studies, the criteria for assignment of patients to treatment was selective so statistical adjustment was necessary to minimise bias. Unfortunately the data were too sparse to offer any satisfactory conclusions in the multivariate analyses that were performed.

The studies were incomplete in terms of comparing all available primary modalities of treatment for locally advanced vulval cancer, for example there were no studies comparing primary chemoradiation versus neoadjuvant chemoradiation or neoadjuvant chemotherapy.

Two studies in the review addressed the adverse effects of various treatments, but again the numbers were small and no meta‐analyses were possible to make definite conclusions.

The data on QoL was incomplete, hence conclusions cannot be drawn on QoL for the various treatments.

Overall the evidence, though weak, does not favour one primary treatment over the other.

Quality of the evidence

The two retrospective studies have a higher degree of bias due to the methodology (retrospective) and the entry criteria for the various treatments. The exact reasons for preferring one treatment over the other were not well documented.The RCT did not report a hazard ratio, which is the best statistic to summarise the difference in risk between two treatment groups over the duration of a trial when there is 'censoring', that is the time to death (or disease progression) is unknown for some women as they were still alive (or disease free) at the end of the trial. It instead reported 5‐year survival rates in each group. Adjustments for type of surgery were not very obvious in all the studies. The details of extensive surgery, which was prevented or could have been prevented, was not well documented. A meta‐analysis could not be carried out as the numbers in the studies were small and for overall survival an adjusted estimate could not be obtained in either of the clinically similar studies. The reporting of the methodological quality of the studies showed that two studies (Landrum 2008; Mulayim 2004) were at high risk of bias as they only satisfied two of the criteria used to assess risk of bias, while the trial of Maneo 2003 was at moderate risk of bias as it only satisfied three of the six core criteria used to assess risk of bias in RCTs. Hence the evidence is weak and incomplete and does not allow for a robust conclusion based on the objectives.

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 independently by two review authors. We were not restrictive in our inclusion criteria with regards to types of studies as we included non‐randomised studies with concurrent comparisons groups that used multivariate analyses, as we suspected that we would not find any relevant RCTs. Therefore we attempted to ensure that we did not overlook any relevant evidence and searched a wide range of reasonable quality non‐randomised study designs (case‐control studies and case series of fewer than 10 patients were excluded).

The greatest threat to the validity of the review is likely to be publication bias; that is studies that did not find the treatment to be effective may not have been published. We were unable to assess this possibility as we did not find an adequate number of studies that met the inclusion criteria.

Agreements and disagreements with other studies or reviews

There were many prospective phase II studies which had good methodological quality but were excluded as there were no comparison groups (Landoni 1996; Montana 2000; Moore 1998). The review article by Moore 1998 concluded that on the basis of many good phase II studies, chemoradiation therapy is now inherent to the clinical management of vulval cancer and international collaboration is needed to conduct prospective RCTs due to the rarity of the disease. The review article by Gadducci 2006 also proposed chemoradiation followed by tailored surgery as an attractive option based on available evidence. Even though this seems to be a logical conclusion, as chemoradiation reduces the need for extensive surgery,clearly there is a lack of evidence as to which type of chemoradiotherapy (primary versus neoadjuvant) is best suited. The stratification of disease based on inoperability due to lymphnodes or local tumour is not very clear in many excluded studies, and the available evidence for primary surgery and neoadjuvant chemoradiation is not strong enough to recommend any one primary treatment over combined treatments, or vice versa.

Authors' conclusions

Implications for practice.

There was no evidence of a survival advantage when chemoradiation (primary or neoadjuvant) was compared to primary surgery for women with locally advanced vulval cancer. There was no statistically significant difference in treatment‐related adverse effects with the above mentioned methods of treatment. Due to sparse data and the relatively high risk of bias in the included studies, we are unable to reach definite conclusions about the relative benefits and harms of the different forms of treatment, and we are unable to identify subgroups of women who are likely to benefit from one form of treatment to the other.

Implications for research.

The evidence is weak. There is a great need for an RCT or, at the very least, comparative non‐RCTs that include multivariate analysis or statistical adjustments. There is a need to find a suitable radiosensitising chemotherapeutic agent or agents for this tumour type. Finding the right radiotherapeutic dose,regime and type to minimise the adverse effects is also essential. The quality of life issues with extensive surgery versus various chemoradiation therapeutic treatments should be addressed. International collaboration is needed to evaluate the efficacy and safety of various treatments due to the rarity of the tumour.

What's new

Date	Event	Description
21 September 2016	Amended	Contact details updated.

History

Protocol first published: Issue 3, 2002
 Review first published: Issue 3, 2006

Date	Event	Description
27 March 2014	Amended	Contact details updated.
1 March 2011	New search has been performed	Review taken over by new author team. Extensive changes to text and searches updated to July 2009.
1 March 2011	New citation required and conclusions have changed	New author team, review substantially amended. New inclusion criteria incorporated. Conclusions changed.
4 May 2006	New search has been performed	Substantive amendment

Appendices

Appendix 1. MEDLINE search strategy

Updated Medline Ovid 2005 to July week 3 2009

1. exp Vulvar Neoplasms/

2. (vulva* adj5 (cancer* or carcinom* or tumor* or tumour* or malignan* or neoplasm*)).mp.

3. 1 or 2

4. (chemoradi* or radiochemo*).mp.

5. exp Radiotherapy/

6. radiotherap*.mp.

7. radiotherapy.fs.

8. radiation.mp.

9. 5 or 6 or 7 or 8

10. chemotherap*.mp.

11. exp Chemotherapy, Adjuvant/

12. drug therapy.fs.

13. exp Antineoplastic Agents/

14. exp Antineoplastic Combined Chemotherapy Protocols/

15. 10 or 11 or 12 or 13 or 14

16. 9 and 15

17. 4 or 16

18. 3 and 17

19. limit 18 to yr= "2005 ‐ 2009"

key:

mp=title, original title, abstract, name of substance word, subject heading word

fs=floating subheading

Appendix 2. EMBASE search strategy

Updated EMBASE 2005 to 2009 week 30

1. exp vulva tumor/

2. (vulva* adj5 (cancer* or carcinom* or tumor* or tumour* or malignan* or neoplasm*)).mp.

3. 1 or 2

4. (chemoradi* or radiochemo*).mp.

5. exp radiotherapy/

6. exp cancer radiotherapy/

7. adjuvant therapy/

8. radiotherap*.mp.

9. rt.fs.

10. radiation.mp.

11. 5 or 6 or 7 or 8 or 9 or 10

12. chemotherap*.mp.

13. dt.fs.

14. exp chemotherapy/

15. exp antineoplastic agent/

16. 12 or 13 or 14 or 15

17. 11 and 16

18. 4 or 17

19. 3 and 18

20. limit 19 to yr ="2005 ‐ 2009"

key:

mp= mp=title, abstract, subject headings, heading word, drug trade name, original title, device manufacturer, drug manufacturer name

dt=drug therapy

Appendix 3. CENTRAL search strategy

CENTRAL, The Cochrane Library Issue 3, 2009

1. MeSH descriptor Vulvar Neoplasms explode all trees

2. vulva* adj5 (cancer* or carcinom* or tumor* or tumour* or malignan* or neoplasm*)

3. (#1 OR #2)

4. chemoradi* or radiochemo*

5. MeSH descriptor Radiotherapy explode all trees

6. radiotherap*

7. Any MeSH descriptor with qualifier: RT

8. radiation

9. (#5 OR #6 OR #7 OR #8)

10. chemotherap*

11. MeSH descriptor Chemotherapy, Adjuvant explode all trees

12. Any MeSH descriptor with qualifier: DT

13. MeSH descriptor Antineoplastic Agents explode all trees

14. MeSH descriptor Antineoplastic Combined Chemotherapy Protocolsexplode all trees

15. (#10 OR #11 OR #12 OR #13 OR #14)

16. (#9 AND #15)

17. (#4 OR #16)

18. (#3 AND #17)

19. (#18), from 2005 to 2009

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Landrum 2008.

Methods	Retrospective study at a single institution
Participants	Period of study: 1990‐2006 All patients diagnosed with stage III and stage IV primary squamous cell carcinoma of the vulva (FIGO 1988). 63 patients were identified, 46 (73%) with stage III and 17 (27%) with stage IV, out of which 3 (5%) women had IVb disease. The median age at diagnosis was 64 years (range 27‐88). 39 (62%) women had a history of tobacco use.
Interventions	Primary chemoradiation therapy (PCRT): 33 patients who otherwise would have required exenterative surgery to obtain adequate tumour free surgical margin were treated with PCRT. Concurrent chemoradiation(platinum and 5‐ flurouracil) with a variety of radiation techniques and doses to suit the disease characteristics and individual needs of the patient were administered. 25 patients underwent lymphadenectomy prior to PCRT, 6 patients who had gross nodes underwent lymphadenectomy after PCRT, 2 patients did not have suspicious nodes so did not undergo lymphadenectomy at any point. 8 patients underwent surgical excision of residual disease following PCRT out of whom 2 required posterior exenteration. Primary surgery (PS): 30 patients were treated with primary surgery (radical/modified radical vulvectomy). This group underwent radical or modified vulvectomy. 19 of 25 patients who had positive lymph nodes following primary surgery completed adjuvant radiation or chemoradiation.
Outcomes	Median follow up was 31 months (range 3‐161 months) Overall survival: 69% for PS and 76% for PCRTgroup (NS)
Notes	For the 63 patients with primary disease, by treatment arm The median age at study entry was 61 years (range 27‐87) in the PCRT group and 72 years (range 36‐88) in the PS group (P=0.09). 19 (58%) women were diagnosed with FIGO stage III and 14 (42%) with stage IV in the PCRT group, and 27 (90%) women were diagnosed with FIGO stage III and three (10%) with stage IV in the PS group (P=0.004). 26 (62%) women had a history of tobacco use in the PCRT group compared to 13 in the PS group (P=0.004). Significant improvements in OS (P=0.002) and PFS (P=0.03) were noted in younger patients compared to older patients. No difference in OS and PFS groups with other prognostic factors like lesions size, nodal metastasis, stage, treatment group. Dr Landrum kindly presented us with an estimate of the adjusted HR for OS from the Cox model, corresponding to the following text, "When clinical size of lesion, stage, treatment group and number of positive lymph nodes were accounted for in a multivariate analysis, the only predictor of OS was age. In a separate model in which size, stage, treatment group and number of positive lymph nodes were accounted for, there were no significant predictors for OS".
Risk of bias
Bias	Authors' judgement	Support for judgement
Adequate sequence generation?	High risk	Study was not randomised
Allocation concealment?	High risk	Concealment of allocation was not applicable to this study design
Blinding? All outcomes	Unclear risk	Not reported
Incomplete outcome data addressed? All outcomes	Low risk	63/63 (100%)
Free of selective reporting?	Unclear risk	The adjusted HR for OS from the Cox model was not reported, but the study authors provided us with the estimates. They did not carry out multivariate analyses for PFS, but this was not likely to be due to selective reporting and appears it was not of primary interest to the authors.
Free of other bias?	Unclear risk	Insufficient information to assess whether an important risk of bias exists
Details of assignment of patients reported?	Low risk	Patients who could be treated with a radical/modified radical vulvectomy with adequate margins without resorting to exenterative procedures were treated with primary surgery. Patients underwent inguinofemoral lymphadenectomy prior to administration of PCRT to debulk the nodes and to evaluate the node status. Patients who had residual disease after PCRT underwent surgery.
Representative intervention group?	High risk	The intervention was decided depending on particular disease characteristics (enlarged nodes, tumour requiring exenteration).
Representative comparison group?	High risk	The comparison was decided depending on particular disease characteristics (enlarged nodes, tumour requiring exenteration).
Comparability of treatment groups?	Unclear risk	"when clinical size of lesion, stage, treatment group and number of positive lymph nodes were accounted for in a multivariate analysis, the only predictor of OS was age." The authors also provided us with adjusted hazard ratio for OS which included a number of prognostic factors.

Maneo 2003.

Methods	RCT of neoadjuvant chemoradiation (FUMIR) versus primary surgery (PS)
Participants	68 with operable advanced vulval cancer TNM status was as follows: T1 N + 1 (3%) versus 0 (0%) T2 N ‐ 2 (7%) versus 10 (26%) T2 N + 15 (50%) versus 19 (50%) T3 N ‐ 4 (13%) versus 4 (11%) T3 N + 8 (27%) versus 5 (13%) The mean age at diagnosis was 74 years (range 31‐85) in the FUMIR group and 74 years (range 57‐87) in the PS group. Mean tumour size (mm) was 50 mm (20‐100) and 45 mm (25 ‐100) in the FUMIR and PS groups respectively. Number of women with tumour size ≥4 cm was 23 (77%) and 29 (76%) in the FUMIR and PS groups respectively. Number of women with positive nodes was 24 (80%) in the FUMIR group and 24 (63%) in the PS group.
Interventions	Intervention: neoadjuvant chemoradiation Comparison: primary surgery Mean follow up of women alive in the trial was 42 months
Outcomes	5‐year survival, overall treatment related morbidity
Notes	The median length of follow‐up in the trial was 40 months (range 8‐88 months). The number of the cases needing extensive resection before randomisation were 8 in the FUMIR arm and 5 in the PS arm. Surgery was feasible in 24/28 women in the FUMIR arm (5‐ FU, mitomycin C and radiotherapy). 15/37 patients in the PS arm received adjuvant radiotherapy. One woman received FUMIR due to progressive disease. Of the 24 patients in the FUMIR arm who received surgery 13 (54%) women experienced treatment‐related morbidity. Of the 37 women who received PS, 17 (46%) women experienced surgical morbidity.
Risk of bias
Bias	Authors' judgement	Support for judgement
Adequate sequence generation?	Low risk	The treatment was assigned by block randomisation (clusters of 10 cases) from a computer‐generated table created before starting the trial
Allocation concealment?	Low risk	The assignation of treatments was blind to the investigators and was decoded after informed consent of the patient
Blinding? All outcomes	High risk	The outcome assessor was not blinded
Incomplete outcome data addressed? All outcomes	Low risk	% analysed: 61/65 (94%) for overall surgical morbidity and 65/65 (100%) for 5‐year overall survival
Free of selective reporting?	Unclear risk	Insufficient information to permit judgement
Free of other bias?	Unclear risk	Insufficient information to assess whether an important risk of bias exists
Details of assignment of patients reported?	Low risk	Not applicable
Representative intervention group?	Low risk	Not applicable
Representative comparison group?	Low risk	Not applicable
Comparability of treatment groups?	Low risk	Not applicable

Mulayim 2004.

Methods	Retrospective study at a single institution
Participants	Period of study: 1991‐2002 All patients diagnosed with stage III and stage IV primary squamous cell carcinoma of the vulva (FIGO 1994). 12 patients with primary disease were identified, 11 ( 85 %) with stage III and 2 (15%) with stage IV, out of which 1 woman had IVb disease. four patients with recurrent disease were excluded. The tumour grade was grade 1 in one (8%) woman, grade 2 in five (38%) and grade 3 in the remaining seven (54%) women. The mean age at study entry was 69.9 years (range 52‐79). 39 (62%) women had a history of tobacco use.
Interventions	Primary chemoradiation therapy (PCRT): offered to women if they had disease requiring extensive resection. Seven patients received PCRT, but we excluded one due to them having stage IVb disease. One patient underwent bilateral inguinofemoral lymph node dissection (IFLND) prior to PCRT. Concurrent chemoradiation was administered using 5‐FU and mitomycin C. Radiation therapy was administered to the vulva, pelvis and groin depending on the individual disease characteristics. Primary surgery followed by adjuvant chemoradiotherapy (aCRT): 6 patients underwent primary surgery, four underwent radical vulvectomy and bilateral IFLND, one underwent radical vulvectomy and ipsilateral IFLND, and one underwent wide local excision of the primary tumour and ipsilateral IFLND. All 6 patients received adjuvant chemoradiotherapy (5‐FU and mitomycin) for histologically proven lymph node metastases.
Outcomes	Overall survival and treatment related toxicity
Notes	For the 13 patients with primary disease by treatment arm Six (86%) women were diagnosed with FIGO stage III and one (14%) with stage IV in the PCRT group, and five (83%) women were diagnosed with FIGO stage III and one (17%) with stage IV in the primary surgery followed by adjuvant chemoradiation (aCRT) group. The mean age at study entry was 66.14 years (range 52‐74) in the PCRT group and 74.33 years (range 67‐79) in the aCRT group. In the PCRT group there were no women with tumour grade grade 1, 1. (14%) with grade 2 and 6 (86%) with grade 3; in the aCRT group 1 (16.5%) woman had grade 1 disease, 4 (67%) had grade 2 and 1 (16.5%) woman had grade 3 disease. All but three patients had grade 3 and grade 4 hematologic or non‐hematologic toxicity. Three patients had life‐threatening neutropenia and 2 patients died of treatment related complications. Median follow up was 20 months (range: 5‐74 months). The median overall survival was 31 months in the PCRT group (range 13‐74 months), 10 months in the aCRT group (5‐21 months). In the PCRT group, 4 patients were alive without evidence of disease, 2 died of disease and 2 died of other causes. There were no survivors in the aCRT group. In the PCRTgroup, 86% had complete response. 6 out of 7 responded to treatment, one had progressive disease. In the aCRT group, 2 out of 6 responded to treatment, 2 died secondary to complication of CRT, 2 had progressive disease. In the PCRT group, 5 of 6 patients has no recurrence at median follow up of 31 months (range 13‐74), In the aCRT group, 2 of 2 developed recurrence. Overall, there were no survivors in this group.
Risk of bias
Bias	Authors' judgement	Support for judgement
Adequate sequence generation?	High risk	Study was not randomised
Allocation concealment?	High risk	Concealment of allocation was not applicable to this study design
Blinding? All outcomes	Unclear risk	Not reported
Incomplete outcome data addressed? All outcomes	Low risk	12/12 (100%)
Free of selective reporting?	Unclear risk	Insufficient information to permit judgement
Free of other bias?	Unclear risk	Insufficient information to assess whether an important risk of bias exists
Details of assignment of patients reported?	Low risk	Patients were offered primary CRT if they had locally advanced disease that required extensive resection. Patients undergoing primary surgery were offered adjuvant CRT (aCRT) for histological proven lymph node metastases. Three of them had clinically enlarged and three radiologically enlarged inguinal lymph nodes prior to surgery.
Representative intervention group?	High risk	Patients receiving PCRT were not representative of the wider population as these women were offered PCRT if they had disease requiring extensive resection. Adjuvant chemoradiation (aCRT) therapy was offered following surgery for histologically proven lymph node metastases. These patients were offered aCRT for being at high risk for recurrent disease.
Representative comparison group?	High risk	Similarly, women who did not have disease requiring extensive resection were given aCRT.
Comparability of treatment groups?	Unclear risk	The data were too sparse to include multivariate analysis for overall and recurrence‐free survival. The adjusted HR estimate was uninformative. Although age and FIGO stage were not significantly different at baseline, it is still unclear whether the groups are comparable as there were only 12 women who met the inclusion criteria.

PS: primary surgery, IFLND: inguinofemoral lymph node dissection

PCRT: primary chemoradiotherapy, aCRT: adjuvant chemoradiotherapy, 5‐FU: 5‐fluorouracil, MMC: mitomycin c

OS: overall survival, PFS: progression free survival

Characteristics of excluded studies [ordered by study ID]

Study	Reason for exclusion
Aki A 2000	No comparison group. Twelve patients were given concomitant chemotherapy and radiotherapy followed by vulval biopsies and groin lymph node dissection 4‐6 weeks after treatment.
Beller 2006	Report of volume 26 of the FIGO Annual report. Comparison of chemoradiation and surgery alone was possible. However, in a multivariate analysis that adjusted for important prognostic factors and stratified by stage, chemoradiation was not compared to surgery alone (grouped in 'other treatment' category). Multivariate analysis that did include a comparison of chemoradiation and surgery included women of all stages, so it was not possible to distinguish between early and late stage disease.
Benedetti‐Panici 1993	No comparison group. All 21 patients with stage IV vulval cancer were treated with neoadjuvant chemotherapy. Nineteen patients were operated on after chemotherapy.
Berek 1991	No comparison group. All the patients were given chemoradiotherapy as primary treatment. In 4 patients salvage surgery followed.
Beriwal 2006	Only 1/15 woman had advanced vulval cancer. Most patients (13/15) had stage II diease and one woman had stage I disease.
Beriwal 2008	No comparison group. All patients received preoperative intensity‐modulated radiotherapy and chemotherapy for locally advanced vulval carcinoma.
Carson 1990	In this study the treatment given to patients with advanced primary (n = 6) or recurrent (n = 2) vulval carcinoma was not uniform; five of eight patients underwent lymph node dissection prior to treatment with chemoradiation, whereas the other three were operated on after chemoradiation.
Cunningham 1997	No comparison group. Chemotherapy in combination of radiotherapy was used in 14 patients with advanced vulval disease. Surgical excision was performed in patients with clinical residual disease.
de Hullu 2006	Systematic review in which no further possible included studies were identified.
Eifel 1995	Study of prolonged continuous infusion cisplatin and 5‐fluorouracil with radiation for locally advanced carcinoma of the vulva, but it did not include a comparison group.
Gadducci 2006	Systematic review in which no further possible included studies were identified.
Geisler 2006	Study looked at neoadjuvant chemotherapy in vulval cancer, but there was no comparison group.
Gerszten 2005	Study of preoperative chemoradiation for locally advanced carcinoma of the vulva cancer, but it did not include a comparison group.
Han 2000(a)	Comparison of primary versus adjuvant chemoradiation and individual patient data available, however survival times are not reported for each individual patient so a multivariate analysis was not possible.
Han 2000(b)	No information about assignment of women to treatment groups was provided.
Iversen 1982	Fifteen patients with inoperable squamous cell carcinoma of the vulva were treated with bleomycin and irradiation. Only 2 patients were also treated with vulvectomy and bilateral lymphadenectomy 2 weeks later. No comparison was possible.
Jolicoeur 2004	No comparison group. This study assigned chemoradiotherapy as the sole treatment for advanced cancers. Treatment regiments were diverse with respect to agents and radiotherapy regimens.
Koh WJ 1993	No comparison group. Study looked at combined radiotherapy and chemotherapy in the management of local‐regionally advanced vulval cancer. 20 patients were included in the study, the disease‐specific survival rate was 49%.
Landoni 1996	Forty‐one patients with locally advanced primary vulval cancer received neoadjuvant chemoradiation followed by limited surgery. No comparison group.
Landrum 2007	No comparison group. All the patients included in the study had primary surgery with or without adjuvant treatment.
Levin W 1986	No comparison group. Five patients underwent primary chemoradiotherapy, out of which 4 underwent surgery.
Lupi G 1996	No comparison group. 24 patients with primary locally advanced vulval cancer underwent primary chemoradiotherapy followed by radical surgery in responsive patients.
Makinen 1987	Report of a single institution experience with all stages of vulval cancer.
Montana 2000	GOG study of preoperative chemoradiation for carcinoma of the vulva with N2/N3 nodes, but it did not include a comparison group.
Moore 1998	Phase II GOG study of preoperative chemoradiation for advanced vulval cancer, but it did not include a comparison group.
Moore 2009	Systematic review which identified the study of Mulayim 2004 as being potentially relevant to this review.
Roberts 1989	This study does not meet our criteria since it describes the results in women with diverse advanced gynaecological malignancies. Only one out of 23 patients suffered from advanced vulval cancer. Management varied markedly.
Roberts 1991	This study adds another 44 patients to the Roberts 1989 study. The study looked at primary chemoradiotherapy for advanced lower genital tract malignancy. No comparison group.
Russell 1992	No comparison group. eighteen patients with locally advanced vulval cancer were treated with primary chemoradiotherapy.
Scheistroen 1993	All the patients had primary chemoradiotherapy, so no comparison group.
Sebag‐Montefiore 1994	No comparison group. Thirty‐two patients with advanced disease were treated with chemotherapy and radiation either as split course or continuous course.
Stehman 2006	Commentary of Rouzier 2002 study which was dismissed during the title and abstract sift as it does not include chemoradiation as a treatment.
Stroup 2008	No comparison of chemoradiation with any other treatment was made, multivariate analysis did not include treatment as a covariate.
Thomas 1989	No comparison group. Chemotherapy combined with radiotherapy was used in the primary setting. Women with residual or recurrent disease underwent surgery.
Wagenaar 2001	Phase II EORTC trial using neoadjuvant chemotherapy (modified BMC regimen). No comparison group.
Wahlen 1995	Comparision between primary RT and primary CRT was possible, but there were only two patients in the primary RT arm.

Characteristics of ongoing studies [ordered by study ID]

EORTC Phase II study.

Trial name or title	Paclitaxel in Treating patients with Locally Advanced, Metastatic, or Recurrent Cancer of the vulva
Methods	EORTC phase II intervention study
Participants	Patients with locally advanced, metastatic, recurrent vulval cancer
Interventions	Patients receive paclitaxel IV over 3 hours on day 1. Treatment repeats every 21 days for a maximum of 10 courses in the absence of disease progression or unacceptable toxicity
Outcomes	Effectiveness of paclitaxel in treating the above group of patients
Starting date	February 2001
Contact information	Department of Medical Oncology, University Medical Centre, Utrecht, P.P witteveen@umcutrecht.nl
Notes	Study still ongoing, not recruiting. Annals of Oncology 2009 Sep;20 (9):1511‐6

GOG 0205.

Trial name or title	Phase II study of radiotherapy and cisplatin followed by resection of residual disease in patients with locally advanced squamous cell carcinoma of the vulva that is not amendable to standard radical vulvectomy
Methods	Phase II intervention trial
Participants	T3 or T4 vulva tumours not amenable to radical vulvectomy (N0‐3, M0)
Interventions	Pretreatment groin node dissection (unless nodes are unresectable), weekly cisplatin chemotherapy and external beam radiation to the primary tumour, inguinal‐femoral and lower pelvic lymph nodes. Followed after 6‐8 weeks by surgical excision of any residual vulval and/or inguinal tumour (incisional biopsy of the primary tumor site if complete clinical response)
Outcomes	Feasibility. Acute and late toxicity. Response (clinical and pathological), survival, recurrences, metastases
Starting date	January 2005
Contact information	David H Moore, M.D., Indiana Cancer Pavilion, 535 Barnhill drive, RT 433, Indianapolis, IN 46202, email: dhmoore@iupui.edu http://www.cancer.gov/search/ViewClinicalTrials.aspx?cdrid=322259&version=patient&protocolsearchid=2094462
Notes	Trial still ongoing, but not recruiting participants

Differences between protocol and review

Quality of life

Quality of life was not reported in any of the trials so the following sections in the protocol which discussed the handling of data for continuous outcomes were removed as they were unnecessary.

Data extraction and management

• For continuous outcomes (e.g. QoL measures), we will extract the final value and standard deviation of the outcome of interest and the number of patients assessed at endpoint in each treatment arm at the end of follow‐up, in order to estimate the mean difference (if trials measured outcomes on the same scale) or standardised mean differences (if trials measured outcomes on different scales) between treatment arms and its standard error.

Measures of treatment effect

• For continuous outcomes, we will use the mean difference between treatment arms if all trials measured the outcome on the same scale, otherwise standardised mean differences will be used."

Dealing with missing data

In the protocol, we stated:
 "If data were missing or only imputed data were reported we contacted trial authors to request data on the outcomes only among participants who were assessed". This was not done, as none of the studies imputed missing data.

We were unable to assess reporting biases using funnel plots or conduct subgroup and sensitivity analyses as there were only two meta analyses in the review, with the largest only including four trials. The following sections of the protocol were therefore removed.

Data synthesis

We were unable to pool the results of the included trials in meta‐analyses as they all compared different interventions. Therefore it was not relevant to assess heterogeneity between results of trials and we were unable to assess reporting biases using funnel plots or conduct any subgroup analyses or sensitivity analyses. The following sections of the protocol were therefore removed:

Assessment of heterogeneity  

Heterogeneity between studies will be assessed by visual inspection of forest plots, by estimation of the percentage heterogeneity between trials which cannot be ascribed to sampling variation (Higgins 2003), by a formal statistical test of the significance of the heterogeneity (Deeks 2001) and, where possible, by subgroup analyses (see below). If there was evidence of substantial heterogeneity, the possible reasons for this were investigated and reported.

Assessment of reporting biases  

Funnel plots corresponding to meta‐analysis of the primary outcome were examined to assess the potential for small study effects such as publication bias. If these plots suggested that treatment effects may not be sampled from a symmetric distribution, as assumed by the random effects model, further meta‐analyses were performed using fixed effects models.

Data synthesis

Where sufficient clinically similar studies were available, their results will be pooled in meta‐analyses. Adjusted summary statistics will be used for non‐randomised studies and unadjusted and adjusted results, if reported, will be used in RCTs.

• For time‐to‐event data, HRs will be pooled using the generic inverse variance facility of RevMan 5.For any dichotomous outcomes, the RR will be calculated for each study and these were then pooled

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

If any trials had multiple treatment groups, the ‘shared’ comparison group will be divided into the number of treatment groups and comparisons between each treatment group and the split comparison group will be treated as independent comparisons.Random effects models with inverse variance weighting will be used for all meta‐analyses (DerSimonian 1986).

If possible, studies making different comparisons will be synthesised using the methods of Bucher 1997.

Subgroup analysis and investigation of heterogeneity  

Subgroup analyses will be performed, grouping the trials by:

• Tumour size

• Nodal status

Factors such as age, stage, grade, length of follow‐up, were considered in interpretation of any heterogeneity.

Sensitivity analysis  

Sensitivity analyses were performed (i) excluding non‐randomised studies if RCTs had been included (ii) excluding studies at high risk of bias".

Contributions of authors

In the original review HCvD formulated the question, prepared the initial text. AA advised on methodological content and edited text. LS searched for background material with special emphasis on the radiotherapeutic area. MV‐L searched for background material with special emphasis on chemotherapy, and edited text.

In the updated version of the review, TS drafted the clinical sections of the review; AB drafted the methodological sections of the review. AB and TS sifted the studies and abstracted data, assessed risk of bias and wrote up the review. All authors agreed on the final version.

Sources of support

Internal sources

• No sources of support supplied

External sources

• Department of Health, UK.

  NHS Cochrane Collaboration programme Grant Scheme CPG‐506

Declarations of interest

None

Edited (no change to conclusions)