Horizon Scanning Centre - May 2014 Bevacizumab (Avastin) for recurrent or persistent stage IVB cervical cancer - in combination with
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Horizon Scanning Centre
May 2014
Bevacizumab (Avastin) for recurrent
or persistent stage IVB cervical
cancer – in combination with
chemotherapy
SUMMARY NIHR HSC ID: 8857
Bevacizumab (Avastin) is intended for the treatment of stage IVB recurrent or
This briefing is persistent cervical cancer, in combination with paclitaxel and cisplatin or
based on paclitaxel and topotecan. If licensed, it will offer an additional treatment
information
option for patients with this disease, who currently have few effective
available at the time
therapies available. Bevacizumab is a humanised anti-vascular endothelial
growth factor (VEGF) monoclonal antibody that inhibits VEGF-induced
of research and a
signalling and VEGF driven angiogenesis, thereby reducing the
limited literature
vascularisation of tumours and subsequent tumour growth. Bevacizumab is
search. It is not
already licensed in the EU for a number of cancers at different sites.
intended to be a
definitive statement
Cervical cancer is a malignant neoplasm arising from the cells of the cervix
on the safety, uteri, and is the 12th most common cancer among women in the UK,
efficacy or accounting for around 2% of all new cases of cancer in females. The annual
effectiveness of the incidence of persistent, recurrent and stage IVB cervical cancer is estimated
health technology at 1,200 in the UK and about 1,000 in England. Of these, 895 (89%) have
covered and should recurrent cancer and 111 (11%) have persistent cancer.
not be used for
commercial Currently, the main option for the prevention of cervical cancer is through
purposes or regular cervical smear testing and treatment of any pre-cancerous lesions.
commissioning Depending on the stage, primary treatment for cervical cancer consists of
without additional surgery, radiotherapy, a combination of radiotherapy and either concomitant
information. chemotherapy, and sometimes neoadjuvant chemotherapy in large primary
cancers with bulky nodal disease. Bevacizumab is currently in one phase III
clinical trial comparing its effect on overall survival of adding it to standard
chemotherapy (paclitaxel plus either cisplatin or topotecan). This trial is
expected to complete in March 2015.
This briefing presents independent research funded by the National Institute
for Health Research (NIHR). The views expressed are those of the author
and not necessarily those of the NHS, the NIHR or the Department of Health.
NIHR Horizon Scanning Centre, University of Birmingham
Email: nihrhsc@contacts.bham.ac.uk
Web: http://www.hsc.nihr.ac.ukNIHR Horizon Scanning Centre
TARGET GROUP
• Cervical cancer: stage IVB; recurrent or persistent ̶ in combination with paclitaxel and
cisplatin or paclitaxel and topotecan.
TECHNOLOGY
DESCRIPTION
Bevacizumab (Avastin; rhuMAb-VEGF) is a humanised anti-vascular endothelial growth
factor (VEGF) monoclonal antibody that inhibits VEGF induced signalling and VEGF driven
angiogenesis, thereby reducing the vascularisation of tumours and subsequent tumour
growth. Decreased VEGF expression is associated with a reduction in ovarian cancer
tumour vascularisation and with prolonged survival 1. It is intended for the treatment of stage
IVB recurrent or persistent cervical cancer, in combination with paclitaxel and cisplatin or
paclitaxel and topotecan. Bevacizumab is administered via intravenous (IV) infusion at
15mg/kg every 21 days in combination with chemotherapy, until disease progression.
Bevacizumab is licensed in the EU for cancers of the colon and rectum (metastatic, in
combination with chemotherapy); breast (metastatic, in combination with chemotherapy);
lung (metastatic or recurrent, in combination with chemotherapy); kidney (metastatic or
advanced, in combination with interferon alfa); and ovary, fallopian tube and peritoneum
(both advanced and recurrent platinum-sensitive, in combination with chemotherapy) 2.
Common recognised adverse effects of bevacizumab (≥10%) include ovarian failure,
anorexia, dysgeusia, headache, dysarthria, eye disorder, increased lacrimation,
hypertension, dyspnoea, epistaxis, rhinitis, constipation, stomatitis, rectal haemorrhage,
diarrhoea, exfoliative dermatitis, dry skin, skin discolouration, arthralgia, proteinuria, pyrexia,
asthenia, pain, mucosal inflammation2.
Bevacizumab is also in phase III clinical trials for:
• Breast cancer (combination, adjuvant and neoadjuvant therapies).
• Carcinoid tumours.
• Diffuse large B-cell lymphoma.
• Gastric cancer (combination therapy).
• Glioblastoma multiforme (combination therapy).
• Head and neck cancer (combination therapy).
• Non-small cell lung cancer (combination and adjuvant therapies).
• Ovarian cancer, platinum-sensitive (combination therapy).
• Colorectal cancer (combination therapies).
and in phase II clinical trials for:
• Cervical cancer (combination and neoadjuvant therapies).
• Brain metastases (resulting from non-small cell lung cancer).
• Chronic lymphocytic leukaemia.
• Haemangiosarcoma.
• Liver cancer (combination therapy).
• Malignant melanoma.
• Multiple myeloma (combination therapy).
• Neuroblastoma.
• Neuroendocrine tumours (combination therapy).
2NIHR Horizon Scanning Centre
• Non-Hodgkin’s lymphoma.
• Non-small cell lung cancer (combination therapy, first line in the elderly).
• Rectal cancer (combination and neoadjuvant therapies).
• Clear cell renal cell carcinoma (combination therapy).
• Sarcoma (combination therapies; first line in adolescents and children).
• Mesothelioma (combination therapy).
INNOVATION and/or ADVANTAGES
If licensed, bevacizumab in combination with chemotherapy will offer an additional treatment
option for patients with recurrent or persistent, stage IVB cervical cancer, who currently have
few effective therapies available.
DEVELOPER
Roche Products Ltd.
AVAILABILITY, LAUNCH OR MARKETING
In phase III clinical trials.
PATIENT GROUP
BACKGROUND
Cervical cancer is a malignant neoplasm arising from the cells of the cervix uteri, and is the
third most common cancer in women 3. The World Health Organization (WHO) recognizes
three categories of epithelial tumours of the cervix: squamous, glandular (adenocarcinoma),
and other epithelial tumours, including neuroendocrine tumours and undifferentiated
carcinoma. Squamous cell carcinomas account for around 70–80% of cervical cancers and
adenocarcinomas for 10–15%3.
Cancer of the cervix usually takes many years to develop, and it is often preceded by
changes to the cells in the cervix known as cervical intraepithelial neoplasia (CIN) or, less
commonly, cervical glandular intraepithelial neoplasia (CGIN). CIN and CGIN are pre-
cancerous conditions that do not pose an immediate threat to an individual’s health, but they
can potentially develop into cancer in the future 4. Cervical cytology aims to detect these
precancerous changes and it has been estimated that the cervical screening programme in
the UK saves approximately 5,000 lives per year 5.
The most important cause of cervical cancer is persistent papillomavirus infection. The
human papillomavirus (HPV) is detected in 99% of cervical tumours, in particular the
oncogenic subtypes HPV 16 and 18, which cause around 7 in every 10 cervical cancers3,4.
HPV is typically spread during sexual intercourse and is very common. An estimated one in
three women will develop a HPV infection within two years of starting to have regular sex,
and about four in every five women will develop the infection at some point in their lives4.
Other risk factors include smoking, and socioeconomic status5.
The symptoms associated with cervical cancer are non-specific and are mostly associated
with later stage disease, although studies have shown that 16-32% of women with early
stage disease have symptoms at presentation. Symptoms include: inter-menstrual bleeding,
3NIHR Horizon Scanning Centre
post-coital bleeding, post-menopausal bleeding, abnormal appearance of the cervix,
abnormal vaginal discharge (blood stained), and pelvic pain5. Cervical cancer is clinically
staged using the International Federation of Gynaecology and Obstetrics (FIGO) criteria.
The stage and the presence of lymph nodes metastases or other distant sites of disease are
important indicators of prognosis and for determining treatment5. FIGO stage IV disease has
extended beyond the true pelvis or has clinically involved the mucosa of the bladder or
rectum (IVA), with stage IVB indicating spread to distant organs 6,7. PET CT scanning is
usually used to stage these patients a.
NHS or GOVERNMENT PRIORITY AREA
This topic is relevant to:
• Improving Outcomes: A Strategy for Cancer (2011).
• NHS England. 2013/14 NHS Standard Contract for Cancer: Chemotherapy (Adult).
B15/S/a.
• NHS England. 2013/14 NHS Standard Contract for Cancer: Radiotherapy (All Ages).
B01/S/a.
• NHS England. 2013/14 NHS Standard Contract for Complex Gynaecology – Specialist
Gynaecological Cancers. E10/S/f.
CLINICAL NEED and BURDEN OF DISEASE
Cervical cancer is the 12th most common cancer among women in the UK, accounting for
around 2% of all new cases of cancer in females 8. In 2010, there were 2,851 new cases of
cervical cancer in the UK. In England, the crude incidence rate of cervical cancer was 10.4
per 100,000 population in 2011 9. Cervical cancer incidence is related to age, with two peaks
observed: the first in women aged 30-34 (at 21 per 100,000 women) and the second in
women aged 80-84 (at 13 per 100,000 women). The earlier peak is thought to be related to
many women becoming sexually active in their late teens/early 20s, giving rise to an
increase in HPV infections. The second smaller peak is due to increasing cancer incidence
with age and persisting uncleared HPV infectionsa. In the UK between 2008 and 2010, an
average 20% of cervical cancer cases were diagnosed in women aged 65 years and over.
Over three-quarters (78%) of cervical cancer cases occur in 25-64 year olds8. The annual
incidence of persistent, recurrent and stage IVB cervical cancer is estimated at 1,200 in the
UK and about 1,000 in England. Of these, 895 (89%) have recurrent cancer and 111 (11%)
have persistent cancer 10.
Among women in the UK, cervical cancer is the 17th most common cause of cancer death,
accounting for 1% of all female cancer deaths 11. In the UK between 2009-2011, an average
31% of cervical cancer deaths were in women aged 75 years and over, and almost three-
quarters (73%) were in women aged 50 and over11. In England, 83.6% of women are
expected to survive their disease for at least one year, falling to 66.6% surviving five years or
more 12. Only 10% of patients with recurrent disease respond to therapy and are alive at 5
years 13. In 2012/13 there were 8,785 admissions for malignant neoplasm of the cervix uteri
(ICD-10 C53) in England, resulting in 16,491 bed-days and 9,215 finished consultant
episodes 14. Seven hundred and eighty six deaths were registered in England and Wales
during 2012 15.
Expert personal communication.
a
4NIHR Horizon Scanning Centre
PATIENT PATHWAY
RELEVANT GUIDANCE
NICE Guidance
• NICE technology appraisal. Guidance on the use of liquid-based cytology for cervical
screening (TA69). October 2013.
• NICE technology appraisal. Topotecan for the treatment of recurrent and stage IVB
cervical cancer (TA183). October 2009.
Other Guidance
• NHS Clinical Knowledge Summary. Cervical cancer and HPV. 2010 16.
• Scottish Intercollegiate Guidelines Network. Management of cervical cancer (SIGN 99).
20085.
• European Society for Medical Oncology. Cervical cancer: ESMO clinical practice
guidelines for diagnosis, treatment and follow-up. 20123.
• American Cancer Society, American Society for Colposcopy and Cervical Pathology, and
American Society for Clinical Pathology Screening Guidelines for the Prevention and
Early Detection of Cervical Cancer. 2012 17.
• International Federation of Gynaecology & Obstetrics. Global guidance for cervical
cancer prevention and control. 2009 18.
• World Health Organization. Comprehensive Cervical Cancer Control, a guide to essential
practice. 2006 19.
CURRENT TREATMENT OPTIONS
Currently, the main option for the prevention of cervical cancer is through regular cervical
smear testing and treatment of pre-cancerous lesions. The HPV vaccine, Gardasil, currently
recommended by the Department of Health for all girls aged 11-12 years, has a protective
effect against 4 oncogenic subtypes of HPV, and hence may prevent the development of
cervical cancer as well as other HPV related cancers such as vulval, anal, penile and
oropharyngeal cancers 20,b.
Depending on the stage, primary treatment for cervical cancer consists of surgery,
radiotherapy, or a combination of radiotherapy and either concomitant chemotherapy and/or
sometimes neoadjuvant chemotherapy in large primary cancers with bulky nodal diseasec.
Definitive radiation therapy should consist of pelvic external beam radiation with high-energy
photons and intracavitary brachytherapy, and must be administered at high doses (>75-85
Gy) and in a short time (NIHR Horizon Scanning Centre
EFFICACY and SAFETY
Trial NCT00803062, NCI-2009-01084, NCT00548418, 06-1098, 201110266,
CDR0000628746, GOG-0240, GSK 107278; bevacizumab with
U10CA027469; bevacizumab with or cisplatin and topotecan; phase II.
without paclitaxel and cisplatin or
topotecan; phase III.
Sponsor National Cancer Institute. Washington University School of
Medicine.
Status Published. Published.
21 22 13 23
Source of Publication , trial registry . Publication , trial registry .
information
Location USA and Spain. USA.
Design Randomised, active-controlled. Non-randomised.
Participants n=455; aged 18 years and older; female; n=27; aged 18 years and older; female;
carcinoma of the cervix; primary stage IVB; carcinoma of the cervix; recurrent or
recurrent, or persistent disease not persistent; disease not amenable to
amenable to curative treatment with surgery curative treatment with surgery and/or
and/or radiotherapy. radiotherapy; no prior therapy for
recurrence or persistence.
Schedule Randomised to Participants receive bevacizumab
2 2
Arm 1: Paclitaxel 135mg/m IV as a 24 hour 15mg/kg IV, and cisplatin 50mg/m IV,
2
infusion on day 1 and cisplatin 50mg/m IV both on day 1, and both in combination
2 2
on day 2; or paclitaxel 175mg/m IV as a 3 with topotecan 0.75mg/m IV on days 1,
hour infusion on day 1 and cisplatin 2, and 3. All given as part of a 21 day
2
50mg/m IV on day 1 or 2. cycles.
Arm 2: Paclitaxel 175mg IV as a 3 hour
2
infusion on day 1 and cisplatin 50mg/m IV
on day 2; in combination with bevacizumab
15mg/kg IV as a 90 minutes infusion
administered on same day as cisplatin.
2
Arm 3: Paclitaxel 175mg/m IV as a 3 hour
2
infusion on day 1 and topotecan 0.75mg/m
IV as a 30 minute infusion on days 1-3.
2
Arm 4: Paclitaxel 175mg/m IV as a 3 hour
2
infusion on day 1 and topotecan 0.75mg/m
IV as a 30 minute infusion on days 1-3; in
combination with bevacizumab 15mg/kg IV
as a 90 minute infusion on day 1.
All given as part of 21 day cycles.
Follow-up Active treatment period until disease Active treatment period until disease
progression or unacceptable toxicities or progression.
complete response; follow-up every 3
months for 2 years, then every 6 months for
3 years.
Primary Overall survival (OS), safety. PFS.
outcome/s
Secondary Progression free survival (PFS), quality of OS, frequency of response,
c
outcome/s life (QoL) . pharmacogenomics (including hypoxia
inducible factor 1 and hypoxia induced
gene expression), role of FDG-PET
imaging as early indicator of response.
Health related quality of life as assessed by FACT-Cx TOI; neuropathy symptoms as assessed by FACT/GOG-Ntx4
c
subscale; and pain as assessed by the Brief Pain Inventory.
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Key results For chemotherapy alone (arms 1 and 3) vs PFS at 6 months, 59% (80% CI, 46-
chemotherapy plus bevacizumab (arms 2 70%); median PFS, 7.1 months (80%
and 4), respectively: median OS, 13.3 CI, 7.7-10.1 months); OS, 13.2 months
months vs 17.0 months (hazard ratio [HR], (80% CI, 8.0-15.4 months); overall
0.71, 98% CI, 0.54-0.95); PFS, 5.9 months response rate, 35% (80% CI, 22-49%);
vs 8.2 months (HR, 0.67, 95% CI, 0.54- complete response, 4% (80% CI, 0.4-
0.82); response rate, 36% vs 48% (relative 14%); partial response, 31% (80% CI,
probability of response 1.35, 95% CI, 1.08- 19-45%).
1.68, p=0.008).
As compared with cisplatin-paclitaxel (arm
1 and 2), topotecan-paclitaxel (arm 3 and 4)
was associated with a higher risk of
progression, HR, 1.39 (95% CI, 1.09-1.77),
but this did not affect OS, HR, 1.20 (99%
CI, 0.82-1.76).
Cisplatin-paclitaxel-bevacizumab vs
cisplatin-paclitaxel alone was associated
with a reduced risk for death (HR, 0.68
[95% CI, 0.48-0.97]) and response rate of
50% vs 45% respectively.
Topotecan-paclitaxel-bevacizumab vs
topotecan-paclitaxel was associated with a
reduced risk for death (HR, 0.74 [95% CI,
0.53-1.05]) and response rate of 47% vs
27% respectively.
Adverse AEs for chemotherapy alone (arms 1 and 3) Sixteen patients (59%) had at least one
effects (AEs) vs chemotherapy plus bevacizumab (arms cycle delayed due to toxicity; 21
2 and 4), respectively: gastrointestinal patients (78%) required at least one
events, excluding fistulas, 96 (44%) vs 114 unanticipated hospital admission for
(52%); hypertension, 4 (2%) vs 54 (25%); supportive therapy and/or management
pain, 62 (28%) vs 71 (32%); neutropenia, of toxicities due to protocol treatment.
57 (26%) vs 78 (35%); febrile neutropenia, Common AEs include: leukopenia,
12 (5%) vs 12 (5%); thromboembolism, 3 neutropenia, thrombocytopenia,
(1%) vs 18 (8%). anaemia, allergy, auditory,
cardiovascular, coagulation,
constitutional, dermatologic, endocrine,
gastrointestinal, genitourinary/renal,
haemorrhage, infection, lymphatic,
metabolic, musculoskeletal, neurologic,
visual, pain, pulmonary.
ESTIMATED COST and IMPACT
COST
Bevacizumab is marketed in the UK for a number of existing licensed indications; six cycles
of bevacizumab at a dose of 15mg/kg every 3 weeks, costs approximately £16,640 24.
IMPACT - SPECULATIVE
Impact on Patients and Carers
Reduced mortality/increased length of survival Reduced symptoms or disability
Other: No impact identified
7NIHR Horizon Scanning Centre
Impact on Health and Social Care Services
Increased use of existing services: additional Decreased use of existing services
IV treatment.
Re-organisation of existing services Need for new services
Other: None identified
Impact on Costs and Other Resource Use
Increased drug treatment costs: additional IV Reduced drug treatment costs
treatment.
Other increase in costs: Other reduction in costs:
Other: None identified
Other Issues
Clinical uncertainty or other research question None identified
identified:
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May 2014.
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http://www.ons.gov.uk
8NIHR Horizon Scanning Centre
16 NICE Clinical Knowledge Summary. Cervical Cancer and HPV. December 2010.
http://cks.nice.org.uk/cervical-cancer-and-hpv#!topicsummary Accessed 22 May 2014.
17 Saslow D, Solomon D, Lawson HW et al. American Cancer Society, American Society for
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Pathology 2012;137(4):516-542.
18 International Federation of Gynecology and Obstetrics. Global guideline for cervical cancer
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