Public Release: 

New ECCO 13 data emphasise vital importance of cervical cancer detection, treatment and prevention

ECCO-the European CanCer Organisation

Paris, France, Wednesday 2 November 2005 - Despite intensive efforts focused on detection and early treatment, in certain populations cervical cancer rates are rising and medical therapy remains inadequate, according to data presented at the 13th European Cancer Conference (ECCO).

In sub-Saharan Africa, insufficient radiotherapy appears to be hindering the survival prospects for women with cervical cancer, co-infected with HIV. Results from a pattern of care study carried out by the International Atomic Energy Agency in Uganda, Namibia, Tanzania and Zimbabwe show that inadequate radiotherapy proved more significant for patient survival during the first year than HIV status. Of the 147 women with biopsy-confirmed cervical cancer included in the study, 18.4% were found to be HIV-positive, yet this co-infection did not impact on survival rates. At 407 days, the median survival in HIV infected women was actually found to exceed that for HIV-negative patients. CD4 counts were temporarily depressed with radiotherapy but levels recovered after a few months and no detrimental effects were observed from concurrent administration to HIV-positive women.

Instead, what was found to be significant was the teletherapy dose patients received - this was associated with significant inter-country variability. Lowest levels were recorded in Zimbabwe (mean 22.4 Gy) where a machine breakdown actually resulted in 10 registered patients not receiving any radiotherapy whatsoever during the period studied. The highest radiotherapy doses were used in Namibia and Uganda (mean 50 Gy). Overall analysis revealed that patients receiving higher radiotherapy doses had a significantly greater survival advantage. These results imply that resource limitations which restrict the appropriate use of radiotherapy may be responsible the early deaths of women with cervical cancer in certain African nations, regardless of HIV status.

Dr Bhadrasain Vikram from the International Atomic Energy Agency, Austria commented, "There is a widespread perception that if a patient has both cancer and HIV the situation is hopeless. Our study found that this was clearly NOT true for cervix cancer IF the patient received proper radiotherapy for her cancer. If she did not receive proper radiotherapy, then a poor outcome became a self-fulfilling prophecy." In China, an epidemiological study has described a worrying trend in cervical cancer incidence rates among young women. Results from statistical analysis of the 22,224 cases of primary cervical cancer diagnosed at the Tianjin Cancer Registry between 1981 and 2000 were described at ECCO. Overall, there was a considerable decline in cervical cancer incidence rates, both crude and age-adjusted over the 9-year time timeframe assessed. Yet the changes in incidence rates were non consistent across age groups, with the 40+ age bracket showing the most marked contribution to the observed decline. In contrast, incidence rates in those aged 20-39 and younger, increased in the period from 1981 to 2000. A further undesirable finding was the apparent rebound in incidence rates towards the end of the study, with analysis showing a small upward tail in cervical cancer incidence approaching 2000.

These results are of concern for the future as they indicated that Chinese young women are no longer following the traditional lifestyles of their parents; yet they are pursuing modern lifestyles without the necessary health education to protect them against the risks of cervical cancers and other related diseases. The investigators of this study recommended developing targeted education strategies and more efficient screening programmes to help and protect the young population.

In addition to detection and treatment, prevention is an important component of any overall cervical cancer strategy. Particular focus lies with the human papilloma virus (HPV) as infection by oncogenic HPV types is a necessary cause of cervical cancer. GARDASIL is a quadrivalent vaccine against four HPV types, including those implicated in the pathogenesis of cervical cancer, anogenital warts and low-grade cervical lesions, currently undergoing clinical development. Baseline prevalence of Pap smear abnormalities in two pivotal clinical trials of this vaccine were revealed at ECCO. Overall, in this multi-ethnic, geographically diverse study population of 17,926 young women from Europe, Latin and North American and the Asia-Pacific region, with an average age of 20 years, abnormalities were identified in more than 1 in every 10 Pap smears. These findings underscore the potential value of an effective HPV vaccine given the established association of HPV with cervical lesions, especially those of higher grade.

Following on from Dr Paavonen's epidemiology study, results from clinical trials with GARDASIL showed significant protection from the human papilloma virus infection. Using CIN 2/3 and AIS obligate precursor lesions for cervical squamous cell and adeno-carcinoma respectively, prophylactic use of quadrivalent human papillomavirus (HPV) (Types 6,11,16,18) L1 virus-like particle (VLP) vaccine (GARDASIL) was found to reduce the incidence of these precursor lesions.

Four clinical trials were established to assess the effectiveness of GARDASIL against cervical cancer and CIN 1-3 and genital warts. 20,541 women were recruited from Americas, Europe and Asia. In one trial, subjects were randomised to either a monovalent HPV 16 L1 VLP vaccine or placebo and in the other three trials, subjects were randomised to either quadrivalent HPV (Types 6,11,16,18)L1 VLP vaccine or placebo. For all trials, vaccinations occurred at day 1 and months 2 and 6. Genital tract specimens for Pap and HPV DNA tests were obtained at day 1 and at 6-12 month intervals for a maximum of 48 months.

Results offered virtually 100% efficacy with prophylactic quadrivalent HPV vaccination (only 16 cases were included in the HPV 16 vaccine trial) in the prevention of HPV 16/18-related CIN 2/3 and AIS precursor lesions and consequent risk of cervical cancer.

Dr Kevin Ault from the Emory University Hospital, USA reported, "Cervical cancer is a unique cancer because nearly all cases are caused by a prior infection with human papilloma virus (HPV). Studies have shown that a potential vaccine for HPV may prevent cervical infection with HPV. Our study shows that these vaccines may prevent precancerous disease of the cervix. In the developing world, this vaccine has the potential of greatly reducing deaths due to this common cancer. Vaccines have been a very successful tool to prevent infectious disease, hopefully cervical cancer will join the list of diseases that can be prevented by vaccination."

About Cervical Cancer

Cervical cancer develops in the lining of the cervix. This condition can develop over time when normal cervical cells undergo changes to become precancerous and then cancerous. Cervical intraepithelial neoplasia (CIN) is the term used to describe these abnormal changes. CIN may progress to squamous intraepithelial lesion (SIL) a condition that precedes cervical cancer or to carcinoma in situ which can over time progress to invasive cancers. Other less common types of cervical cancer result from changes in the glandular surface cells (ademocarcinomas). Adenocarcinoma in situ (AIS) is a precursor of invasive cervical adenocarcinomas.1

In Europe the incidence of cervical cancer has decreased since the introduction of screening programmes around 9.84 deaths per 100,000 population (Northern Europe) and 10.18 per 100,000 population (Southern Europe) compared to sub-Sahara Africa with 25.08 to 44.32 deaths per 100,000 population.3

Infection with two types of human papilloma virus (HPV) which is transmitted sexually is strongly associated with the risk cervical cancer. HIV infection also reduces the immune system's ability to fight HPV infection. Sexual activity that increases risk for infection with HPV and HIV and for cervical cancer can include: having multiple sexual partners or a promiscuous partner, history of sexually transmitted disease, sexual intercourse at a young age and women who smoke, oral contraceptive use and giving birth to many children. It is commonly found in middle aged women and of women from poor socioeconomic status groups.1, 2

There are very few specific new treatments for cervical cancer which follows the traditional route of surgery, radiotherapy and chemotherapy. However if the cancer is caught early it is treated successfully. New treatments currently investigated include the tyrosine kinase inhibitors. 1

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1 www.oncologychannel.com
2 www.clinicalevidence.com
3 International Agency for Research on Cancer (IARC), Globalscan 2000.

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Abstract: 552
2010 Epidemiology
Cervical cancer in sub-Saharan Africa: a patterns of care study by the international atomic energy agency

E. Rosenblatt1, V. Levin1, B. Jeremic1, T. Ngoma2, D. Kronke3, G. Ihorst4, L. Kasumba5, B. Vikram1,
1International Atomic Energy Agency, Applied Radiation Biology and Radiotherapy, Vienna, Austria
2Ocean Road Cancer Institute, Radiotherapy Department, Dar es Salaam, Tanzania
3Windhoek Central Hospital, Radiotherapy Department, Windhoek, Namibia
4University Hospital Freiburg, Biometry and Data Management, Freiburg, Germany
5Mulago Hospital, Dept. of Radiation Oncology, Kampala, Uganda
Introduction:
Cervical cancer and HIV/AIDS are both very common in sub-Saharan African countries. In order to assess the prevalence of HIV infection in cervical cancer patients treated with radiotherapy and its impact on treatment outcome, the IAEA conducted a study (CRP E 3-30-20) in Uganda, Namibia, Tanzania and Zimbabwe. The main objectives of the study were: 1) to examine the prevalence of HIV infection among patients with invasive cervical cancer and 2) to assess the effects of pelvicirradiation on their survival.
Patients and Methods:
Between 3/2000 and 12/2001, one hundred and forty-seven unselected patients with biopsy-proven squamous-cell carcinoma of the uterine cervix that were referred for radiotherapy were tested for HIV using the ELISA test. Haemoglobin levels and CD4 counts were also determined. Teletherapy and brachytherapy were delivered according to the local protocols. No concomitant chemotherapy or anti-retroviral therapy were administered. There were 43 patients from Uganda, 40 from Zimbabwe, 40 from Tanzania and 24 from Namibia. The distribution by FIGO stages was: IB/IIA 2%, IIB 27%, IIIA 7%, IIIB 64%. Survival analysis was performed by log-rank test. Multivariate analysis was performed by Cox proportional hazards regression model considering age, dose of radiation and ELISA test results, stratified by country.
Results:
Twenty seven of the 147 patients (18.4%) tested positive for HIV. The median age of the HIV negative patients was 50 years (range 28-80) and it was 39 years (range 25-57) for the HIV positive patients. The mean pre-treatment haemoglobin level was 10.8 g/dL (range: 2.6-16.1), 10.9 g/dL for HIV negative and 10.4 g/dL for HIV positive patients (p=0.23).

The mean baseline CD4 count for all 147 patients was 772 cells/mm3 (range: 48-2356). It was 884 (48-2356) for HIV negative and 280 (58-484) for HIV positive patients. A decrease in CD4 counts was noted 6 weeks after the start of radiotherapy ("mean decrease" for the HIV negative = minus 485, mean decrease for the HIV positive =minus 118).

Three months later, the CD4 counts had partially recovered ("mean decrease" for HIV negative = minus 317, "mean decrease" for the HIV positive = plus 6). One-hundred and twenty of the 147 patients (82%) received radiotherapy as planned, while in the rest either the teletherapy or the brachytherapy component was not done. Seventeen patients (11.6%) did not receive a boost dose following EBRT to the whole pelvis. Among the 130 patients receiving a boost, it was delivered either by brachytherapy (75%) or a small volume external beam field (25%).

The total teletherapy dose was significantly different among the four countries, being the lowest in Zimbabwe (mean 22.4 Gy, range 0-50) and highest in Namibia and Uganda (mean 50 Gy, range 50-50) p=0.0001. A machine breakdown in Zimbabwe resulted in 10 registered patients not receiving any radiotherapy whatsoever (4 HIV positive and 6 HIV negative) while 11 received only brachytherapy. Thus, 21/40 Zimbabwean patients had major protocol violations.

The median follow-up for all patients was 71 days (range: 2-609). Median survival was 407 days for HIV positive patients and exceeds this for the HIV negative. The 20 HIV positive patients receiving full course radiotherapy had a median survival of 489 days while the 7 HIV positive patients who did not receive a full course had a median survival of 92 days. On univariate analysis there was a significant survival advantage for patients receiving higher teletherapy doses (0-22 Gy versus 22-48 Gy versus = 50 Gy, p<0.001). The FIGO stage did not influence survival (p=0.40). On univariate analysis, HIV negative patients survived longer than HIV positive (p=0.011) but multivariate analysis showed that only the total teletherapy dose was significant for survival (p<0.001).

Conclusions:
The data from these four countries with limited resources showed that adequate radiotherapy was more significant for the patient's survival during the first year than her HIV status. No detrimental effect was observed from administering radiotherapy to HIV positive patients, notwithstanding the temporary depression of CD4 counts that recovered after a few months.

Abstract: 553
601 Epidemiology, prevention, public health
Increasing incidence trends of cervical cancer in young women in Tianjin, China 1981-2000
P.P. Wang1, B.C. Sun2, J.H. Zhao3, K.X. Chen2, X.S. Hao2
1Memorial University of Newfoundland, Community Health, St. John's, Canada
2Tianjin Medical University, Tianjin Cancer Hospital, Tianjin, China
3University of Toronto, Public Health Sciences, Toronto
Bacground:
To describe trends in the incidence rates of primary cervical cancer in a geographically defined Chinese population. To compare incidence trends of cervical cancer in young with older women.
Methods:
Primary cervical cancer cases (N=2,2224) were diagnosed between 1981 and 2000 and identified by the Tianjin Cancer Registry. Age-adjusted and age-specific incidence rates were examined. Poisson regression was employed to assess the incidence rate trends. All statistical analyses were conducted using SAS 8.0.
Results:
Crude and age-adjusted incidence rates in the study period were: 6.4/100,000 and 3.8/100,000, respectively. There were remarkable declining trends in incidence rates. The crude and age-adjusted incidence rates declined from 13.8/100,00 and 10.3/100.000 in 1981 to 3.3/100,000 and 2.0/100,000 in 2000. However, the changes in incidence rates were not consistent across age groups. In general, those aged 40 and older had contributed the most observed incidence decline. Contrary to the incidence patterns in people aged 40 and older, incidence rates in those aged 20-39 years and younger increased during the study period. While the results from Poisson regression analyses suggest overall significant trends of declining incidence rates in cervical cancer, there seemed to be a small upward tail toward the end of the study period.
Conclusion:
The findings also indicated two worrisome aspects. First, the incidence rates seemed to increase in younger women; second, there seemed to be a rebound in incidence rates toward the end of the study period. The findings highlight the importance of targeted education toward high-risk population and shed light toward setting up more efficient screening strategies.

Abstract: 551
2010 Epidemiology
Prevalence of abnormal Pap smears among young adult women participating in human papillomavirus (HPV) L1 virus-like particle (VLP)-vaccine clinical trials

J. Paavonen
University of Helsinki, Obstetrics and Gynecology, Helsinki, Finland
Background:
HPV infection by oncogenic types is a necessary cause of cervical cancer and infection by non-oncogenic types causes anogenital warts and some low-grade cervical lesions. A quadrivalent vaccine against HPV types 6, 11, 16, and 18 (GARDASILTM) is currently in development. The baseline characteristics of this large Phase III study population are described here.
Methods:
Two parallel pivotal clinical trials of GARDASILTM enrolled women from Europe (50.6%), Latin America (30.6%), North America (14.7%) and the Asia-Pacific region (4.2%). Participants were to be either using or seeking contraception and were to have no more than 4 lifetime sexual partners. The baseline prevalence of Pap smear abnormalities was evaluated.
Results:
17926 women, ages 15 to 26 years (median 20 years), were randomized to participate in the trials. 69.5% (n=12463) were white, 13% (n=2538) Hispanic, 3.9% (n=706) black, and 3.5% (n=629) Asian. 4825 (26.9%) were current smokers and 1347 (7.5%) were former smokers. Six percent (803) were virgins; among non-virgins the median number of previous partners was 2 and most (n=11779, 69.9%) had no new partners in the 6 months prior to study baseline. Chlamydia trachomatis infection was found at baseline examination in 746 women (4.2%); Neisseria gonorrheae infection in 58 (0.3%). Only 74 (0.4%) reported a prior HPV infection. A total of 17404 satisfactory Pap smears were obtained at baseline, the results of which are shown in the table. All Pap smears were read at a central laboratory.

Day 1 Pap smear results N (%)
Negative for SIL 15433 (88.7)
SIL present 1971 (11.3)
LSIL 1012 (5.8)
HSIL 108 (0.6)
ASC-US 789 (4.5)
ASC-H 54 (0.3)
Atypical glandular cells 8 (0.04)
Conclusions:
In this multi-ethnic, geographically diverse population of young adult women, abnormalities were identified in more than one in ten Pap smears. These findings underscore the potential value of an effective HPV vaccine, given the established association of HPV with cervical lesions, especially of higher grade.

Abstract: Presidential symposium
Prophylactic Use of Quadrivalent Human Papillomavirus (HPV) (Types 6, 11, 16, 18) L1 Virus-Like Particle (VLP) Vaccine Reduces Cervical Intraepithelial Neoplasia (CIN) 2/3 and Adenocarcinoma in situ (AIS) Risk

Kevin Ault MD, Emory University School of Medicine, on behalf of the GARDASILTM Phase III Steering Committee
Background:
CIN 2/3 and AIS are the obligate precursor lesions for cervical squamous cell- and adeno-carcinoma, respectively. Thus, if prophylactic HPV vaccines are demonstrated to reduce the incidence of these precursor lesions, it can be inferred that the vaccines reduce risk of development of cervical cancer. A clinical program consisting of 4 randomized clinical trials was developed to evaluate the impact of a prophylactic HPV vaccine on the rates of these diseases. It is part of a program to assess the vaccine's impact on cervical cancer, CIN 1-3, and genital warts.
Methods:
20,541 women (16-26 yrs) from the Americas, Europe and Asia were enrolled in one of four trials. In one trial, subjects were randomized to either a monovalent HPV 16 L1 VLP vaccine or placebo. In 3 trials, subjects were randomized to either quadrivalent HPV (Types 6/11/16/18) L1 VLP vaccine or placebo. For all trials, vaccination occurred at day 1, and months 2 and 6. Genital tract specimens for Pap and HPV DNA tests were obtained at day 1 and at 6-12 months intervals thereafter for a maximum of 48 months. Colposcopy referral was algorithm-based. Biopsies were HPV-typed. Cytology, histology, and HPV detection were conducted centrally. A combined analysis of the 4 studies was prespecified in 2001. The primary endpoint was the combined incidence of HPV 16/18-related CIN 2/3, AIS, or cancer as read by a blinded pathology panel. In the HPV 16 vaccine study, only HPV 16-related cases were considered. Analyses were done in a per protocol (PP) population (subjects received 3 doses, had no major protocol violations, were HPV 16/18 seronegative at Day 1 and HPV 16/18 DNA negative Day 1 through month 7) and in a modified intention to treat (MITT) population (subjects received ≥1 dose and were HPV 16/18 negative at day 1). Endpoint counts began at Month 7 and Day 30 in the PP and MITT analyses, respectively.
Results:
The below table displays results. Vaccination was generally well tolerated.

PP (n = 8487)
Vaccine Placebo Efficacy (%) 95% Conf. Int. Cases† Rate‡ Cases† Rate‡
CIN 2/3+ 0 0 53 0.4 100 93-100§
CIN 2 0 0 36 0.3 100 89-100
CIN 3/AIS 0 0 32 0.2 100 88-100

MITT (n = 9342)
Vaccine Placebo Efficacy (%) 95% Conf. Int. Cases† Rate‡ Cases† Rate‡
CIN 2/3+ <0.1 81 0.4 99 93-100§
CIN 2 1 <0.1 55 0.3 98 89-100
CIN 3/AIS 0 0 52 0.3 100 93-100
†Subjects counted once in each applicable category.
‡Rate = n/Subject years at risk*100
§P < 0.001

Conclusion:
In this combined analysis, prophylactic quadrivalent HPV vaccination prevented HPV 16/18-related CIN 2/3 and AIS. This intervention is expected to greatly reduce the risk of cervical cancer.

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