|Home | About | Journals | Submit | Contact Us | Français|
Worldwide, cervical cancer is the second most common cancer in women. The peak prevalence of infection is 20-30% in women aged 20-30 years, but in 80% of cases the infection resolves within 12-18 months. In the UK, incidence fell after introduction of the cervical-screening programme, to the current level of approximately 3200 cases and 1000 deaths a year. Survival ranges from almost 100% 5-year disease-free survival for treated stage Ia disease to 5-15% in stage IV disease. Survival is also influenced by tumour bulk, age, and comorbid conditions.
We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of interventions to manage early-stage cervical cancer? What are the effects of interventions to manage bulky early-stage cervical cancer? We searched: Medline, Embase, The Cochrane Library and other important databases up to November 2006 (BMJ Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
We found 19 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.
In this systematic review we present information relating to the effectiveness and safety of the following interventions: HPV vaccine for preventing cervical cancer and conisation of the cervix for microinvasive carcinoma (stage Ia1), neoadjuvant chemotherapy, radiotherapy, chemoradiotherapy, or different types of surgery for treating early stage and bulky early stage cervical cancer.
Worldwide, cervical cancer is the second most common cancer in women.
Vaccination against HPV is effective in preventing certain types of HPV infection, and at reducing rates of cervical intraepithelial neoplasia, but there has been insufficient long-term follow-up to assess effects on cervical cancer rates.
Conisation with adequate excision margins is considered effective for microinvasive carcinoma, and can preserve fertility; however, it is associated with an increased risk of preterm delivery and low birthweight.
Radical trachelectomy plus lymphadenectomy can lead to similar long-term survival rates as radical hysterectomy, but with preserved fertility.
Limited evidence shows that radiotherapy is as effective as surgery in early-stage disease.
Chemoradiotherapy improves survival compared with radiotherapy in women with bulky early-stage cervical cancer.
The benefits of neoadjuvant chemotherapy plus surgery compared with radiotherapy alone are unknown.
Cervical cancer is a malignant neoplasm arising from the uterine cervix. About 80% of cervical cancers are of the squamous type; the remainder are adenocarcinomas, adenosquamous carcinomas, and other rare types. Staging of cervical cancer is based on clinical evaluation (FIGO classification; see table 1 ). Management is determined by tumour bulk and stage. Population: This review deals with treatments for early-stage cancer (defined as FIGO stage Ia1, Ia2, Ib1, and small IIa tumours) and bulky early-stage disease (defined as FIGO stage Ib2 and larger IIa tumours).
Cervical cancer is the second most common cancer in women, with about 450,000 new cases diagnosed worldwide each year. Most (80%) cases occur in resource-poor countries that have no effective screening programmes. The incidence of cervical cancer in the UK and Europe has greatly reduced since the introduction of a screening programme for detecting precancerous cervical intraepithelial neoplasia. Cervical cancer incidence fell by 42% between 1988 and 1997 in England and Wales. This fall has been reported to be related to the cervical screening programme. In England and Wales, cervical cancer has an annual incidence of 3200 women, and causes about 1000 deaths each year.
Risk factors for cervical cancer include sexual intercourse at an early age, multiple sexual partners, tobacco smoking, long-term oral contraceptive use, low socioeconomic status, immunosuppressive therapy, and micronutrient deficiency. Persistent infection by oncogenic, high-risk strains of HPV is strongly associated with the development of cervical cancer. HPV strains 16 and 18 cause about 70% of cervical cancer and high-grade cervical intraepithelial neoplasia. The virus is acquired mainly by sexual intercourse, and has a peak prevalence of 20-30% in women aged 20-30 years, although in 80% of cases the infection is transient and resolves within 12-18 months.
Overall, 5-year disease-free survival is 50-70% for stages Ib2 and IIb, 30-50% for stage III, and 5-15% for stage IV. In women who receive treatment, 5-year survival in stage Ia approaches 100%, falling to 70-85% for stage Ib1 and smaller IIa tumours. Survival in women with more locally advanced tumours is influenced by tumour bulk, the person's age, and coexistent medical conditions. Untreated mortality in locally advanced disease is high.
To reduce morbidity and mortality; to improve quality of life with minimal adverse effects.
Prevention: Seroconversion rates, rates of HPV, rates of cervical intraepithelial neoplasia, rates of cervical cancer. Treatment: Overall survival; progression-free survival; local recurrence; distant recurrence; quality of life; and adverse effects of treatment. Some treatments — including "fertility-preserving treatments" — may affect fertility. We therefore examined the effects of treatment on pregnancy rates and live-birth rate. Adverse effects of chemotherapy are usually graded according to severity, using scales such as the Chassagne morbidity scale (grades 0-3), National Cancer Institute Common Toxicity scale (grades 0-4), and the Southwest Oncology Group scale (grades 0-5); unless otherwise stated, grade 0 refers to no adverse effects, and higher scores indicate a greater severity of adverse effects.
Clinical Evidence search and appraisal November 2006.The following databases were used to identify studies for this systematic review: Medline 1966 to November 2006, Embase 1980 to November 2006, and The Cochrane Database of Systematic Reviews and Cochrane Central Register of Controlled Clinical Trials 2006, Issue 4. Additional searches were carried out using these websites: NHS Centre for Reviews and Dissemination (CRD) — for Database of Abstracts of Reviews of Effects (DARE) and Health Technology Assessment (HTA), Turning Research into Practice (TRIP), and NICE. Abstracts of the studies retrieved from the initial search were assessed by an information specialist. Selected studies were then sent to the author for additional assessment, using pre-determined criteria to identify relevant studies. Study-design criteria for inclusion in this review were: published systematic reviews and RCTs in any language, including open studies — as comparisons between radiotherapy and chemotherapy would be difficult to blind for — and containing more than 20 individuals of whom more than 80% were followed up. There was no minimum length of follow-up required to include studies. In addition, we use a regular surveillance protocol to capture harms alerts from organisations such as the FDA and the UK Medicines and Healthcare products Regulatory Agency (MHRA), which are added to the reviews as required. For the bulky early-stage disease question, we included RCTs, which included solely women with stage Ib2 and IIa tumours, as well as studies that comprised women with stage Ib2 and IIa tumours in addition to women with less-extensive (lower-stage) tumours. We excluded studies that included women with tumours of stage IIb and above, unless they performed prespecified subgroup analyses in women with bulky early-stage disease (stage Ib2 or IIa tumours). We have performed a GRADE evaluation of the quality of evidence for interventions included in this review (see table ).
The information contained in this publication is intended for medical professionals. Categories presented in Clinical Evidence indicate a judgement about the strength of the evidence available to our contributors prior to publication and the relevant importance of benefit and harms. We rely on our contributors to confirm the accuracy of the information presented and to adhere to describe accepted practices. Readers should be aware that professionals in the field may have different opinions. Because of this and regular advances in medical research we strongly recommend that readers' independently verify specified treatments and drugs including manufacturers' guidance. Also, the categories do not indicate whether a particular treatment is generally appropriate or whether it is suitable for a particular individual. Ultimately it is the readers' responsibility to make their own professional judgements, so to appropriately advise and treat their patients.To the fullest extent permitted by law, BMJ Publishing Group Limited and its editors are not responsible for any losses, injury or damage caused to any person or property (including under contract, by negligence, products liability or otherwise) whether they be direct or indirect, special, incidental or consequential, resulting from the application of the information in this publication.
Dr Sudha Sudesh Sundar, Pan Birmingham Gynaecological Cancer Centre, City Hopsital and Division of cancer studies, University of Birmingham, Birmingham, United Kingdom.
Professor Amanda Horne, Churchill Hospital, Oxford, United Kingdom.
Prof Sean Kehoe, Nuffield Department of Obstetrics and Gynaecology, John Radcliffe Hospital Headington, Oxford, UK.
RATES OF SEROCONVERSION Compared with placebo: Vaccination against HPV is more effective at increasing HPV antibodies at 7–48 months ( moderate-quality evidence ). RATES OF HPV INFECTION Compared with placebo: Vaccination against HPV is more effective at reducing the incidence of persistent HPV infections at 6–30 months ( high-quality evidence ). RATES OF CERVICAL INTRAEPITHELIAL NEOPLASIA Compared with placebo: Vaccination is more effective at reducing the rates of cervical intraepithelial neoplasia at 12–48 months (moderate-quality evidence). NOTE We found no direct information about the effects of vaccination against HPV in reducing rates of cervical cancer.
We found no systematic review but found four RCTs, one published in two papers. The first RCT (2392 women aged 16 to 23 years) compared three doses of HPV-16 virus-like particle vaccine 40 microgram versus placebo.At 3 months, women receiving vaccine had substantially higher levels of HPV-16 antibodies than women receiving placebo (1510 mMU per mL with vaccine v 6 mMU per mL with placebo; significance not reported). Analysis of 1533/2392 (64%) of participants found that HPV-16 vaccine significantly reduced HPV-16 infection after 17.4 months (incidence of persistent HPV-16 infection: 0/768 [0%] with vaccine v 41/765 [5%] with placebo; P less than 0.001). Of the women who had HPV-16 infection, 9/41 (22%) had cervical intraepithelial neoplasia (CIN); the RCT did not directly compare rates of CIN in women receiving vaccine or placebo. Most women excluded from the analysis had HPV infection at enrollment in the trial. The second RCT (1113 women aged 15 to 25 years) compared three doses of bivalent HPV-16/18 L1 virus-like particle vaccine versus placebo. At 7 months, women receiving vaccine had substantially higher levels of HPV antibodies than women receiving placebo (HPV-16: 3892 mMU per mL with vaccine v 37 mMU per mL with placebo; HPV-18: 801 mMU per mL with vaccine v 12 mMU per mL with placebo; significance not reported). The RCT also found that vaccination significantly reduced incident and persistent HPV infection compared with placebo (incident infection: 2/366 [0.5%] with vaccine v 23/355 [6.5%] with placebo; P less than 0.0001; persistent infection: 0/366 [0%] with vaccine v 7/355 [2%] with placebo; P = 0.007). Follow-up of this RCT found that efficacy was maintained at 6 and 12 months (incident infection with bivalent HPV-16/18 L1 virus-like particle vaccine: 97% efficacy, 95% CI 82 to 100, P less than 0.0001; persistent infection at 6 months: 94% efficacy, 95% CI 63 to 100, P less than 0.0001; persistent infection at 12 months: 100% efficacy, 95% CI 33 to 100, P = 0.0062). It found that vaccination significantly reduced the proportion of women with cytological abnormalities associated with HPV-16/18 after 18 months compared with placebo (2/560 [0.4%] with vaccine v 33/553 [6.0%] with placebo; P less than 0.0001). Pooling data from the initial and extended follow-up studies, the RCT found that vaccine significantly reduced rates of CIN at 12 months compared with placebo (proportion of women with CIN: 0/481 [0%] with vaccine v 8/470 [2%] with placebo; P = 0.003). The third RCT (1106 women, mean age 20 years) compared three different formulations of prophylactic quadrivalent (types 6/11/16/18) HPV vaccine (administered at day 1, month 2, month 6) versus placebo for 36 months. It found that vaccine significantly reduced rates of persistent infection or disease with HPV 6, 11, 16, or 18 over 30 months compared with placebo (incidence per 100 woman–years at risk 0.8 with vaccine v 7.2 with placebo; P less than 0.0001). A follow-up analysis of the RCT assessed seroconversion. It found that at 2 months (after dose 1), vaccine-induced anti-HPV responses were approximately 12 to 26 times higher than those in women receiving placebo (HPV16: mean 147 mMU/mL with vaccine v 6.4 mMU/mL with placebo; HPV-18: mean 14m MU/mL with vaccine v 4.5 mMU/mL with placebo; significance not assessed). The study reported that the anti-HPV response initially decreased, then plateaued and remained stable over 3 years' follow-up. The fourth RCT (2391 women aged 16–23) compared HPV-16 L1 VLP vaccine (administered at day 1, month 2, and month 6) versus placebo over 48 months. It found that HPV-16 antibodies were higher at 48 months in women receiving vaccine compared with placebo (data presented graphically, significance not assessed). A per-protocol analysis of 1505/2391 (63%) of participants found that the vaccine significantly reduced the proportion of women who developed HPV-16 infection compared with placebo (0/755 [0%] with vaccine v 12/750 with placebo; vaccine efficacy 100%, 95% CI 65 to 100%). This analysis also found that the vaccine significantly reduced the incidence of persistent HPV-16 infection (7/755 (1%) with vaccine v 111/750 [15%] with placebo; vaccine efficacy 94%, 95% CI 88 to 98%).The RCT also found that fewer women receiving vaccine than placebo developed HPV-16-related CIN over 48 months (intention-to-treat analysis: 7/1017 [1%] with vaccine v 41/1050 [4%] with placebo; significance not assessed).
The first RCT found that a similar proportion of women receiving vaccine and placebo had adverse effects (proportion with one or more adverse effect: 1052/1194 [93%] with vaccine v 1054/1198 [92%] with placebo; P value not reported). The most frequent adverse effect was pain at the injection site. The second RCT found that significantly more women receiving vaccine than placebo had pain, swelling, or redness at the injection site (overall injection site symptoms: 499/531 [94%] with vaccine v 472/538 [88%] with placebo; P = 0.0004). In the follow-up study to this RCT assessing 744/1113 [67%] of participants, more women who had received placebo than vaccine had adverse effects and new onset of chronic diseases, but the study did not asses the significance of the difference between groups (adverse effects: 81/371 [22%] with placebo v 54/373 [24%] with vaccine; new-onset diseases: 18/371 [5%] v 10/373 [3%]; P value not reported).In the third RCT, adverse effects at the injection site (particularly pain) were slightly more common in women receiving vaccine than placebo, but the RCT did not assess the signficance of the difference between groups (250/272 [92%] with vaccine v 242/274 [88%] with placebo). A modest increase (from 3% to 6%) in injection-site adverse effects was recorded with higher doses of vaccine. The fourth RCT gave no information on adverse effects.
HPV infection does not necessarily result in cervical intraepithelial neoplasia (CIN). Most HPV infection is transient; persistent HPV infection may result in CIN. A proportion of women will go on to have high-grade CIN leading to cervical cancer. Complete seroconversion rate for type-specific HPV infection, therefore, should translate to a reduction in type-specific CIN, but data about length of immunity are lacking. Both vaccines (targeting HPV-16 and -18 or targeting HPV-16, -18, -6, and -11) have been evaluated in industry-funded trials and, as of November 2006, when the search for this review was completed, include follow-up of 4.5 years. We found no RCTs that had sufficient sample size and length of follow-up to assess the effects of the vaccine in reducing rates of CIN.
HPV vaccine for the prevention of cervical cancer New option for which we identified four RCTs. Vaccines, increased seroconversion rates, and reduced rates of HPV infection and cervical intraepithelial neoplasia. Categorised as Unknown effectiveness for reducing rates of cervical cancer.
FERTILITY Compared with control: Cold-knife conisation or large-loop excision of the transformation zone may lead to higher rates of preterm delivery and infants with low birthweight compared with untreated controls ( very low-quality evidence ). NOTE We found no clinically important results about conisation of the cervix compared with simple hysterectomy for microinvasive carcinoma (stage Ia1). There is consensus that conisation of the cervix is effective for microinvasive carcinoma (stage Ia1), provided that excision margins are clear of cancer or intraepithelial neoplasia. Conisation of the cervix can, unlike hysterectomy, preserve fertility.
We found no RCTs.
There is consensus that conisation is effective for microinvasive carcinoma (stage Ia1), provided that excision margins are clear of cancer or cervical intraepithelial neoplasia, and that there has been an adequate review of histology by a pathologist and multidisciplinary team experienced in dealing with gynaecological cancer. Consensus is based on observational studies, and is consistent with guidelines issued by the NHS cervical screening programme. Conisation of the cervix can, unlike hysterectomy, preserve fertility. One systematic review (search date 2004, 27 retrospective cohort studies) assessed outcomes after conservative treatments for early invasive cervical lesions. It found that, compared with women who had not received treatment, women who had received cold-knife conisation or large-loop excision of the transformation zone (LLETZ) had significantly higher rates of preterm delivery and infants with low birthweight (RR of preterm delivery v untreated controls: cold-knife conisation: RR 2.59, 95% CI 1.80 to 3.72, LLETZ: RR 1.70, 95% CI 1.20 to 2.40; RR of low birthweight v untreated controls: cold-knife conisation: RR 2.53, 95% CI 1.19 to 5.36, LLETZ: RR 1.82, 95% CI 1.09 to 3.06). Preterm delivery was defined as delivery before 37 weeks and low birthweight as under 2500 grams. Analysis by depth of excised tissue found that risks of preterm delivery increased further if the depth was more than 10 mm (RR of preterm delivery v depth less than 10 mm: 2.6, 95% CI 1.3 to 5.3).
No new evidence
RECURRENCE Compared with control: We don’t know whether radical trachelectomy plus lymphadenectomy is more effective at increasing recurrence-free survival at 2 years ( very low-quality evidence ). NOTE We found no clinically important results about radical trachelectomy plus lymphadenectomy compared with radical hysterectomy in women with early-stage cervical cancer. Unlike hysterectomy, radical trachelectomy plus lymphadenectomy can preserve fertility.
We found no systematic review or RCTs.
We found no RCTs.
Fertility can be preserved if surgery is restricted to radical trachelectomy and lymphadenectomy. One retrospective observational study included women with stage Ia2 or Ib tumours of size 2 cm or smaller, and without pelvic lymph node metastasis. Women who had received radical trachelectomy and lymphadenectomy (32 women) were compared with two groups of women who had received radical hysterectomy (1 unmatched control group, 556 women and 1 control group matched for age and tumour characteristics, 30 women). The study found no significant difference in recurrence-free survival between groups at 2 years (95% with radical trachelectomy v 100% for matched radical hysterectomy controls v 97% for unmatched radical hysterectomy controls; P reported as not significant, CI not reported). The conception rate in the radical-trachelectomy group was 37% at 1 year. The study found that there were significantly more intraoperative complications with radical trachelectomy plus lymphadenectomy than with radical hysterectomy in unmatched controls (AR for complications: 25% with radical trachelectomy plus lymphadenectomy v 4% with radical hysterectomy; P less than 0.05). One non-systematic review of 210 women (9 case series, 1 case-control study) presented data from published literature on cure rates, survival, and reproductive outcome of radical vaginal trachelectomy. It found that the proportion of women with recurrence after radical trachelectomy ranged from 0% to 8%. It found that 35/210 (17%) women had live births post-surgery; however, the rates of second-trimester losses and preterm deliveries due to cervical weakness were high.
No new evidence
MORTALITY Radiotherapy compared with radical hysterectomy plus lymphadenectomy: We don’t know whether radiotherapy is more effective than surgery at increasing disease-free or 5-year survival in women with stage Ib–IIa cervical cancer ( low-quality evidence ). RECURRENCE Radiotherapy compared with radical hysterectomy plus lymphadenectomy: We don’t know whether radiotherapy is more effective than surgery (with or without adjuvant radiotherapy) at reducing recurrence in women with stage Ib–IIa cervical cancer (low-quality evidence). ADVERSE EFFECTS Radiotherapy compared with radical hysterectomy plus lymphadenectomy: Surgery is more likely to cause an increased risk of adverse effects compared with radiotherapy in women with stage Ib–IIa cervical cancer ( moderate-quality evidence ). NOTE There is consensus that both surgery and radiotherapy are likely to be beneficial.
We found no systematic review. We found one RCT (343 women stage Ib–IIa) comparing radiotherapy versus radical hysterectomy plus lymphadenectomy (see comment below). It found no significant difference between radiotherapy and surgery in 5-year or disease-free survival rates (results presented graphically; AR for survival: about 83% for both groups; AR for disease-free survival: about 74% for both groups; for both comparisons P value reported as not significant). Recurrence rates were similar in both groups (42/170 [25%] with surgery v 44/167 [26%] with radiotherapy; significance assessment not reported). However, the RCT did not report what proportion of women with stage Ib cancer had stage Ib1 and stage Ib2 disease. The radical-hysterectomy group in the RCT received a class III abdominal hysterectomy and pelvic lymphadenectomy; women with enlarged para-aortic lymph nodes only received sampling and selective procedures. Also, a large number of women in the surgery group (108/170 [64%]) received postoperative pelvic radiotherapy. The decision to provide adjuvant radiotherapy was taken preoperatively, based on the presence of one or more known risk factors, such as UICC surgical stage greater than pT2a (see table 2 ), less than 3 mm of uninvolved cervical stroma, cut-through, or lymph node metastases. The trial excluded women considered medically unfit for surgery.
Surgery significantly increased the risk of severe adverse effects compared with radiotherapy (grade 2–3 on the Chassagne morbidity scale; 28% with surgery v 12% with radiotherapy; P less than 0.0004). Two women in the surgery group died (1 of spontaneous ileal perforation 11 months after adjuvant radiotherapy and 1 of pulmonary embolism). Pelvic radiotherapy will usually result in ablation of ovarian function. Certain surgical procedures can maintain fertility (See harms of conisation of the cervix and harms of radical trachelectomy plus lymphadenectomy).
Consensus regards both surgery and radiotherapy as likely to be beneficial.
No new evidence
MORTALITY Compared with radiotherapy alone: Chemoradiotherapy used either before or after hysterectomy is more effective at increasing progression-free and overall survival at 3–4 years in women with bulky early-stage cervical carcinoma ( high-quality evidence ). NOTE Combined chemoradiotherapy has been associated with more haematological and gastrointestinal adverse effects.
We found one systematic review (search date 2003), which identified two RCTs that compared chemoradiotherapy versus radiotherapy alone in women with bulky early-stage cervical carcinoma. The first RCT identified by the review (374 women with stage Ib2 tumours) compared chemoradiotherapy versus radiotherapy, before hysterectomy, in all participants. It found that chemoradiotherapy significantly increased progression-free survival and overall survival at 3 years compared with radiotherapy (HR for progression 0.51, 95% CI 0.34 to 0.75; HR for mortality 0.54, 95% CI 0.34 to 0.86). The second RCT identified by the review included 268 women who had had radical hysterectomy for stage Ia2, Ib, and IIa tumours (tumour diameter 0.2–5.2 cm; proportion of women with stage Ia2 tumours not reported). The women had histologically confirmed positive lymph nodes, positive parametrial involvement, or a positive surgical margin. The RCT found that chemoradiotherapy significantly improved progression-free survival and overall survival at 4 years compared with radiotherapy (estimated progression-free survival: AR 80% with chemoradiotherapy v 63% with radiotherapy; adjusted HR 2.01, CI not reported, P = 0.003; estimated overall survival, AR: 81% with chemoradiotherapy v 71% with radiotherapy; adjusted HR 1.96, CI not reported, P = 0.007).
The first RCT in women with bulky early-stage cervical carcinoma found that, compared with radiotherapy, chemoradiotherapy increased the proportion of women with moderate or severe adverse effects (grade 3 or 4 toxicity according to National Cancer Institute Common Toxicity Criteria; mainly haematological and gastrointestinal toxicity: 64/183 [35%] with chemoradiotherapy v 25/186 [13%] with radiotherapy; significance assessment not performed). The second RCT also found that, compared with radiotherapy, chemoradiotherapy increased serious adverse effects (grade 4 Southwest Oncology Group criteria; mainly haematological toxicity: 27/122 [17%] with chemoradiotherapy v 4/112 [4%] with radiotherapy; significance assessment not performed). We found one systematic review (search date not reported), which assessed long-term toxicity. When assessing the first RCT,the review suggested that the "same number of women" receiving chemoradiotherapy and radiotherapy had toxicity (mainly bowel toxicity) at long-term follow-up (11–61 months, median 36 months; absolute figures not reported).The review found no data on long-term toxicity from the second RCT.
MORTALITY Compared with local treatment (radiotherapy; surgery; radiotherapy plus surgery) alone: Neoadjuvant chemotherapy (before surgery, radiotherapy, or both) seems to be more effective at increasing overall survival at 2–9 years and disease-free survival at 5 years in women with bulky (stages Ib-IIa) tumours ( low-quality evidence ). RECURRENCE Compared with local treatment (radiotherapy; surgery; radiotherapy plus surgery)alone: Neoadjuvant chemotherapy (before surgery, radiotherapy, or both) may be more effective at reducing local recurrence in women with bulky (stage Ib) tumours (low-quality evidence).
We found one systematic review (search date 2006), one additional, and one subsequent RCT of neoadjuvant chemotherapy in women with cervical cancer.
The review identified 21 RCTs comparing neoadjuvant chemotherapy before surgery, radiotherapy or radiotherapy plus surgery, versus local treatment alone (radiotherapy; surgery; radiotherapy plus surgery) in women with cervical cancer (including stages Ib–IVa). The review also identified a further three RCTs for future inclusion, but did not include these in the analysis as the authors of the review were awaiting individual patient data. Four identified RCTs met Clinical Evidence inclusion criteria as they involved women with bulky early-stage cervical cancer, and were published in full.
The first RCT identified by the review (205 women with stage Ib tumours, 57% with stage Ib2) compared neoadjuvant chemotherapy versus no neoadjuvant chemotherapy before local treatment for unresectable tumours. Local treatment involved surgery plus radiotherapy or radiotherapy alone. Prespecified subgroup analysis found that neoadjuvant chemotherapy significantly improved overall survival at 9 years, and reduced local recurrence in women with bulky (stage Ib2) tumours (117 women, survival: 80% with neoadjuvant chemotherapy v 61% with no neoadjuvant chemotherapy; P less than 0.01; local recurrence: 6% with neoadjuvant chemotherapy v 23% with no neoadjuvant chemotherapy; P less than 0.01, absolute numbers not reported).
The second RCT identified by the review (124 women with Ib–IIa tumours) compared cisplatin-based neoadjuvant chemotherapy (see comment below) plus radical abdominal hysterectomy and pelvic lymphadenectomy versus radiotherapy alone. It found no significant difference between neoadjuvant chemotherapy plus surgery and radiotherapy alone in overall survival at 2 years or in estimated 5-year survival (2-year overall survival: 81% with neoadjuvant chemotherapy plus surgery v 84% with radiotherapy alone; 5-year overall survival: 70% with neoadjuvant chemotherapy plus surgery v 62% with radiotherapy alone; P = 0.77 for both comparisons, absolute numbers not reported).
The third RCT identified by the review (441 women with stage Ib2–III tumours) compared cisplatin-based neoadjuvant chemotherapy plus radical abdominal hysterectomy and pelvic lymphadenectomy versus radiotherapy alone. A subgroup analysis (87 women in each arm) of stage Ib2 and IIa (greater than 4 cm) was prespecified at randomisation. It found that, compared with radiotherapy alone, neoadjuvant chemotherapy plus surgery significantly increased 5-year overall survival (69% with neoadjuvant chemotherapy plus surgery v 51% with radiotherapy alone; P = 0.01) and 5-year progression-free survival (65% with neoadjuvant chemotherapy plus surgery v 51% with radiotherapy alone; P = 0.01, absolute numbers not reported).
The additional RCT (identified by the review for future inclusion, 192 women with stage Ib-IIIb tumours) compared neoadjuvant chemotherapy (cisplatin, vincristine and bleomycin) before surgery or radiotherapy versus surgery or radiotherapy alone. A post-hoc subgroup analysis in women with Ib-IIa tumours, found that neoadjuvant chemotherapy significantly increased disease-free 5-year survival compared with no neoadjuvant chemotherapy but found no significant difference in overall 5-year survival between groups (126 women, disease-free 5-year survival: 77% with neoadjuvant chemotherapy v 64% with no neoadjuvant chemotherapy, P < 0.05; overall 5-year survival: 79% with neoadjuvant chemotherapy v 73% with no neoadjuvant chemotherapy, reported as not significant, P value not reported).
The subsequent RCT (106 women with Ib tumours, 64% with stage Ib2) compared cisplatin-based neoadjuvant chemotherapy before surgery with surgery alone. All women with deep cervical invasion, parametrial extension or positive lymph nodes also received postoperative radiotherapy. A subgroup analysis in women with bulky (stage Ib2) tumours found that neoadjuvant chemotherapy significantly improved overall 5-year survival compared with no neoadjuvant chemotherapy (32/38 [84%] with neoadjuvant chemotherapy v 23/30 [77%] with no neoadjuvant chemotherapy, P = 0.04). The RCT did not report recurrence rates separately for stages Ib1 and Ib2 tumours. It found no significant difference in recurrence rates within 5 years between neoadjuvant chemotherapy and no neoadjuvant chemotherapy, however recurrence was lower with neoadjuvant chemotherapy (10/52 [19%] with neoadjuvant chemotherapy v 19/54 [35%] with no neoadjuvant chemotherapy, P = 0.08).
The first RCT identified by the review reported that, in women receiving neoadjuvant chemotherapy, there were four confirmed cases of peripheral neurotoxicity, one case of renal toxicity with transient tubular failure, and two cases of mild pulmonary toxicity. It did not report on adverse effects in the group that had no neoadjuvant chemotherapy.
The second RCT identified by the review found that rates of acute nausea and vomiting were higher in women receiving neoadjuvant chemotherapy plus surgery than in women receiving radiotherapy alone (59/68 [87%] with neoadjuvant chemotherapy plus surgery v 29/50 [58%] with radiotherapy alone). Rates of intestinal obstruction and lymphoedema were also higher (intestinal obstruction: 23/68 [34%] with neoadjuvant chemotherapy plus surgery v 12/50 [24%] with radiotherapy alone; lymphoedema: 8/68 [26%] with neoadjuvant chemotherapy plus surgery v 14/50 [28%] with radiotherapy alone; significance assessment not performed for any of the comparisons). However, radiotherapy increased the proportion of women with diarrhoea (13/68 [19%] with neoadjuvant chemotherapy plus surgery v 46/50 [92%] with radiotherapy alone), and late radiation cystitis and late radiation proctitis (22/68 [32%] with neoadjuvant chemotherapy plus surgery v 41/50 [82%] with radiotherapy alone; significance assessment not performed for any of the comparisons) compared with neoadjuvant chemotherapy plus surgery. There were no treatment-related deaths. These results must be interpreted with caution, since several women in these groups would have received adjuvant chemotherapy and adjuvant radiotherapy in addition to their primary treatment, and this will influence toxicity.
The review suggested that the scheduling and dose intensity of cisplatin (i.e. short cycle length and dose greater than 25 mg/m2 ) was an important factor in determining benefit from neoadjuvant chemotherapy. However, further trials are required to confirm this. The systematic review did not identify that stage of disease was a factor in influencing response to neoadjuvant chemotherapy.