Treatment of invasive cervical cancer

Squamous cell carcinoma is the most common histological type of invasive cervical cancer in Ireland. Between 1994 and 2012, it accounted for over 76% of invasive cervical cancers while adenocarcinoma accounted for just over 15%. Invasive cervical cancer is staged clinically according to the FIGO classification system (see Appendix 2). The stage of cervical cancer depends upon the size of the tumour, invasion of surrounding tissues, lymph node status and metastases. Risk assessment of a tumour incorporates the size of the tumour and depth of its invasion,

histological genotype, stage, lymph node status and lymphovascular space

involvement.⁽¹²²⁾ Primary treatment is stage dependent and may consist of surgery, radiotherapy or a combination of chemotherapy and radiotherapy.⁽¹²²⁾ Management and treatment are recommended by a multidisciplinary team based on the stage, age and general health of the individual woman.

Early stage disease (FIGO stage IA1) may be managed conservatively with cone biopsy. Treatment options for women with FIGO stage IA2 to IVA include surgery, radiotherapy or the combination of chemotherapy and radiotherapy

(chemoradiotherapy). Surgical treatment options for women with stage IA2 include radical hysterectomy and pelvic lymphadenectomy, large cone biopsy or radical trachalectomy and pelvic lymphadenectomy. Surgical treatment options for women with stage IB1, IB2 and IIA include radical hysterectomy and pelvic

lympadenectomy. Surgery is the preferred treatment option in young women with stage IA2 and IB1 because it confers the benefit of conserving ovarian function, thus avoiding early menopause.⁽⁸³⁾ Radical trachelectomy is an alternative to radical hysterectomy for women with stage IB1 who wish to preserve fertility. Radical trachelectomy involves vaginal resection of the cervix, the upper vagina and the medial portions of the cardinal and uterosacral ligaments and prophylactic cervical cerclage. Radical hysterectomy involves the en-bloc removal of the uterus, cervix,

58 parametrial tissues and upper vagina. This is usually combined with pelvic

lymphadenectomy.

Women with stages IB2, IIA2 to IVA are generally treated with chemoradiotherapy.

(83, 98) Surgery is not offered first-line to women with stage IB2, IIA2 to IVA because of the risk of positive margins and positive lymph nodes, however it may be offered as adjuvant therapy where there is evidence of residual disease.^{(108, 123)}

Radiotherapy to the cervix is given by external beam radiotherapy or brachytherapy.

Brachytherapy involves delivering short wave radiotherapy into the uterus via the vagina. Women who present with metastatic or recurrent cervical cancer are

commonly symptomatic.⁽¹²²⁾ They are generally offered palliative chemotherapy with or without immunotherapy and or individualised radiotherapy to relieve symptoms and to improve their quality of life.⁽¹²²⁾ Depending on previous care and the presence of central versus noncentral disease, treatment may include exenteration with or without intraoperative radiotherapy, radical hysterectomy in carefully selected patients or brachytherapy. Complications associated with advanced cervical cancer include pain, lymphoedema, fistulae, thrombosis, haemorrhage and renal failure.⁽¹⁰⁸⁾ Renal failure due to bilateral ureteric obstruction may require nephrostomy or ureteric stent placement.

The types and numbers of treatments performed for precancerous abnormalities and invasive cervical cancer by CervicalCheck between September 2008 and August 2015 are presented in Table 3.4. LLETZ was the most commonly performed treatment each year accounting for over 84% of procedures per annum.

Table 3.4 Treatments offered through CervicalCheck, 2008 to 2015 Treatment

2008-2009 2009-

2010 2010-

2011

2011-2012

2012-2013 2013-

2014 2014-2015

LLETZ 4,326 6,591 6,190 7,236 5,702 5,674 5,269

Ablation 353 893 661 758 910 927 1,224

Cone biopsy 27 32 29 40 42 36 16

Hysterectomy - 30 52 74 64 80 51

Trachelectomy - - - 1 1 8 -

Total 4,706 7,546 6,932 8,109 6,719 6,725 6,560

Data acquired from CervicalCheck annual reports(56, 109, 110, 112-115) Key: LLETZ - large loop excision of the transformation zone

According to NCRI data, since the year 2000 the proportion of women receiving different forms of treatment for invasive cervical cancer has been relatively stable (Table 3.5). Between 2000 and 2012, 63.3% received tumour-directed surgery, 39.8% received for chemotherapy or immunotherapy and 55.1% received

radiotherapy. Of interest are the combinations of therapy used for individual women

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59 with invasive cervical cancer. In the five years from 2008 and 2012, 39.7% of

women had surgery alone, 20.2% had chemoradiotherapy and 15.9% had all three therapies.

Table 3.5 Treatment of invasive cervical cancer, 2000 to 2012 Year Tumour-directed

surgery*^$ Chemo or

immunotherapy* Radiotherapy*

2000 116 77 103

2001 107 78 106

2002 128 94 117

2003 127 78 128

2004 127 82 101

2005 155 119 152

2006 135 94 130

2007 192 119 155

2008 163 115 150

2009 240 136 182

2010 208 126 183

2011 232 106 170

2012 181 105 161

*Within a year of diagnosis

$ Surgeries for invasive cervical cancer include procedures such as LLETZ and cone biopsies as well as more extensive procedures such as hysterectomies.

Data courtesy of NCRI

According to Hospital Inpatient Enquiry (HIPE) data, between 2005 and 2014 there were 9,658 inpatient admissions and daycases where invasive cervical cancer was the principal diagnosis. This equated to an average of 966 admissions per year. Just over half were for women in the 35 to 55 year age group. St Luke’s Hospital and St James’s Hospital (and specifically, St Luke’s Radiation Oncology Unit in St James’s Hospital since 2010) accounted for the largest number, together accounting for over 40% of all admissions and daycases.

Complications of treatment for invasive cervical cancer depend on the treatment modality used. Broadly speaking, complications impacting on quality of life can be categorised as: lymphoedema; bladder dysfunction and other urologic complications;

bowel dysfunction and other gastrointestinal problems; sexual dysfunction; and psychosocial problems.⁽¹²⁴⁾ Treatment of advanced cervical cancer can lead to bladder dysfunction, detrusor overactivity, fistula, and hydronephrosis.⁽¹²⁵⁾

Chemotherapy can result in toxicity-related adverse reactions although these may be short-term. Radiation therapy is associated with haemorrhagic cystitis, ureteric stenosis, low-compliance bladder, and fistula.⁽¹²⁵⁾ When multiple treatment

60 approaches are used in combination, there may be a higher risk of long-term

complications.⁽¹²⁴⁾

3.4 Mortality

The estimated annual age standardised mortality rate from invasive cervical cancer in 2012 was 4.3 per 100,000 in Ireland.⁽⁹⁵⁾ This was higher than the average annual rate for the 27 European Union member states (EU-27) which was 3.7 per 100,000 in 2012. The estimated age-standardised mortality rate from invasive cervical cancer in 40 European countries ranged from 14.2 per 100,000 (Romania) to 0.7 per

100,000 (Iceland) in 2012.⁽⁹⁵⁾ Ireland was ranked eighteenth.⁽⁹⁵⁾

According to data from the Central Statistics Office (CSO), between 2007 and 2014, there were 707 deaths in Ireland from invasive cervical cancer, an average of 88 deaths per year. The median age at death from invasive cervical cancer in Ireland is 56 years.⁽¹²⁶⁾ The annual number of deaths in women aged less than 50 years ranged from 21 to 35. This represents between 25% and 38% of all deaths from invasive cervical cancer.

Mortality rates for invasive cervical cancer, standardised to the European Standard population (ESP 1976) are shown in Figure 3.16. Although there has been year-on-year fluctuation, there has been no significant change in mortality between 2007 and 2014. Based on data from 2012 to 2014, the cumulative lifetime risk of death due to cervical cancer (to age 74) was 1 in 333 women.

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61 Figure 3.16 Age-standardised mortality rates of invasive cervical cancer

per 100,000 population by year of death in Ireland (2007 to 2014)

Data acquired from CSO, standardised to the European Standard Population (1976)

In Ireland, mortality rates from invasive cervical cancer increased in the late 1960s and the early 1970s.⁽⁹³⁾ Rates subsequently declined somewhat, however average mortality rates for invasive cervical cancer in the last five years are approximately 60% higher than in the early 1950s.⁽⁹³⁾ Relatively little change in the mortality rate from invasive cervical cancer has been seen in recent years.⁽⁹³⁾ When stratified by age at time of death, mortality rates are higher in women aged 50 years and over compared with younger women (Figure 3.16).

3.5 Survival

Based on data from the EUROCARE-5 study, the five-year relative survival for European women diagnosed with invasive cervical cancer between 2000 and 2007 was 62%.⁽¹²⁷⁾ Survival was lowest in Eastern Europe (57%), particularly in Bulgaria and Latvia (51%) and highest in Northern Europe (67%). Norway had the highest five-year relative survival at 71%. Ireland ranked 21^st out of 28 countries with a five-year survival of 58.9%.⁽¹²⁷⁾ Across Europe, the study reported improvements in the age-standardised five-year relative survival from 61% (in 1999 to 2001) to 65% (in 2005 to 2007), although it noted that exceptions to this trend were observed in Scotland and Ireland where a statistically significant reduction in five-year survival

62 was observed.⁽¹²⁷⁾ In Ireland, five-year relative survival for these two periods were reported as 64% and 55%, respectively.⁽¹²⁷⁾

The NCRI have estimated five-year survival using a cohort method (1994–1998, 1999–2003, 2004–2008) and a hybrid method (2009–2013). While relating to different time periods, in contrast with the EUROCARE-5 study data, five-year

survival was estimated to have improved over time in Ireland from 56.3% in 1994 to 1998 to 61.0% in 2009 to 2013 (Figure 3.17).⁽¹²⁸⁾ The estimated trends in survival are clearly sensitive to the methodology used which may indicate that net five-year survival has remained largely static over the last 20 years.

Figure 3.17 Age-standardised net five-year survival for invasive cervical cancer in Ireland (1994 to 2013)

Figures acquired from NCRI , age-standardised

Age-standardised five-year relative survival in European women diagnosed with invasive cervical cancer between 2000 and 2007 reduced with advancing age.⁽¹²⁹⁾ Five-year relative survival in 15 to 44 year olds was 81%, but fell to 34% in those women aged 75 years and over at the time of diagnosis.⁽¹²⁹⁾

This pattern was also observed in NCRI-calculated age-specific five-year relative survival for the time period 2008 to 2012 (Figure 3.18).⁽¹²⁸⁾ Those in the 15 to 44 year age group had a net five-year survival of 83.5%, whereas those aged 75 years and older at the time of diagnosis had a net five-year survival of 30.7%.

56.3 62.1

58.3 61.0

0 10 20 30 40 50 60 70 80 90 100

1994-1998 1999-2003 2004-2008 2009-2013

Percent

Net five year survival

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63 Figure 3.18 Net five-year survival for invasive cervical cancer by age, 2008

to 2012

Figures acquired from NCRI

The reduction in survival rates with increasing stage is well recognised.⁽²⁵⁾ NCRI age-standardised relative five-year survival calculations for the time period 2008 to 2012 are shown in Figure 3.19.⁽¹²⁸⁾ Net five-year survival for those diagnosed at stage II, III and IV disease were 63.6%, 47.8% and 21.6%, respectively. Note

age-standardised survival is unavailable for stage I as there were insufficient deaths in some age groups to allow age-standardisation calculations to be made. The five year (un-standardised) survival for stage I disease was 93.9%.

64 Figure 3.19 Net five-year survival for invasive cervical cancer by stage,

2008 to 2012

Figures acquired from NCRI

~Data are age-standardised, with the exception of Stage I which is not age-standardised due to insufficient cases in some age groups

Im Dokument Health technology assessment of human papillomavirus testing as the primary screening method for prevention of cervical cancer (Seite 99-106)