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Impact of management on mortality in patients with invasive cervical cancer in Reunion Island
Accepted Manuscript Title: Impact of management on mortality in patients with invasive cervical cancer in Reunion Island Authors: Phuong Lien Tran, Philippe Morice, Emmanuel Chirpaz, Glorianne Lazaro, Malik Boukerrou PII: DOI: Reference:
S0301-2115(17)30284-1 http://dx.doi.org/doi:10.1016/j.ejogrb.2017.06.010 EURO 9933
To appear in:
EURO
Received date: Revised date: Accepted date:
26-1-2017 31-5-2017 6-6-2017
Please cite this article as: Tran Phuong Lien, Morice Philippe, Chirpaz Emmanuel, Lazaro Glorianne, Boukerrou Malik.Impact of management on mortality in patients with invasive cervical cancer in Reunion Island.European Journal of Obstetrics and Gynecology and Reproductive Biology http://dx.doi.org/10.1016/j.ejogrb.2017.06.010 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Impact of management on mortality in patients with invasive cervical cancer in Reunion Island Phuong Lien Tran (Med Cand) a, Philippe Morice (MD, PhD, Pr) b, Emmanuel Chirpaz (MD) cd, Glorianne Lazaro (PhD) e, Malik Boukerrou (MD, PhD, Pr) afg
a
Gynecology and Obstetrics Unit – University Hospital of Reunion Island,
BP 350 - 97448 Saint Pierre Cedex. Reunion b
Gynecology and Obstetrics Unit - Gustave Roussy Institute
114 rue Edouard Vaillant, 97805 Villejuif cedex, France c
Cancer Registry of Reunion Island,
Reunion University Hospital, 97490 Saint-Denis, France d
INSERM, CIC 1410, Reunion University Hospital, 97448 Saint-Pierre, France
e
Institute of Cancer Research, 15 Cotswold Road, Sutton SM2 5NG, London, UK
f
Centre d’Etudes Périnatales de l’Océan Indien, University Hospital of Reunion Island
BP 350 - 97448 Saint Pierre Cedex. Reunion g
Faculty of Medicine - University of Reunion
97490 St Denis. Reunion Corresponding author : Phuong Lien Tran Gynecology and Obstetrics Unit University Hospital of Reunion Island BP 350 - 97448 Saint Pierre Cedex, Reunion Tél: +262(0)2 62 35 90 00 Fax: +262 (0)2 62 35 91 14 [email protected] The study was conducted in Reunion Island, France.
Impact of management on mortality in patients with invasive cervical cancer in Reunion Island ABSTRACT
OBJECTIVE. In Reunion Island, the standardized mortality rate for cervical cancer is 4.8/100,000 women, twice higher than in Metropolitan France. For locally advanced disease, the standard of care includes a treatment by brachytherapy. Nevertheless, brachytherapy was not available on the Island before 2016. The objective of this study was to assess the impact of the management of patients with invasive cervical cancer on mortality in Reunion. METHODS. We have identified all the women hospitalized in one of the health care centers of the Island diagnosed with invasive cervical cancer between 01/01/2010 and 31/12/2015. The guidelines of the French Society of Gynecological Oncology (FSGO) were considered as the reference to evaluate professional practices. The characteristics that had an influence on global survival after log-rank test were included in a multivariate analysis according to the Cox Model. RESULTS. Retrospective analysis identified 303 women meeting inclusion criteria. The assessment of professional practices showed that the decisions on 11.6% of the patients discussed during multidisciplinary meetings, were not applied, consequentially leading to a decrease in survival (p=0.001). A total of 156 patients (51.5%) were administered a treatment in accordance with the guidelines of the FSGO and had a better survival, even after multivariate analysis (HR 2.53 [CI 95% 1.55-4.14], p<10-3). Nonconformity was associated with the lack of access to brachytherapy on the Island. Women on the Island presented low rates of screening tests (cover rates 53.2%). CONCLUSION. The absence of treatment in accordance with the guidelines and decisions taken during multidisciplinary meetings and the absence of brachytherapy were associated to a higher mortality among patients with invasive cervical cancer in Reunion Island. We hope that the implementation of brachytherapy in Reunion will address these deficiencies. Keywords: mortality; cervical cancer; management; guidelines
INTRODUCTION
It is estimated that one million women worldwide are currently living with cervical cancer. Cervical cancer is the fourth most common cancer in women, with an estimated 528,000 incident cases and 266,000 deaths in 2012 alone, accounting for 7,5% of all female cancer deaths (1). Cervical cancer is frequently associated with infection by human papillomavirus (HPV), which induces cervical cell abnormalities that progress to cervical carcinogenesis. Behaviourally-based factors implicated in the increased risk of HPV infection include: being sexually active at a young age, having many sexual partners. Once infected with HPV, other factors including parity, smoking, and the use of oral contraceptives also become associated with an increased risk of cervical cancer. We have the technical knowledge to prevent hundreds of thousands of unnecessary deaths of women worldwide because cervical cancer is one of the most preventable types of cancer. A safe and effective HPV vaccine exists, targeting young girls between 11 and 14 years old. Because pre-cancerous lesions take many years to develop, screening by a Pap smear is recommended for every woman aged between 25 to 65 years. When screened early, treatment of cervical cancer is highly effective. Cervical cancer is staged clinically using the FIGO system developed by the International Federation of Gynecology and Obstetrics (FIGO). The initial work-up should include a cervical biopsy for histopathologic diagnosis. Additional imaging can provide valuable information to guide prognosis, determine management and assist in treatment planning. For locally advanced disease (stage IB2 to IVA), the standard of care consists of combined external beam radiation therapy (EBRT) with concurrent chemotherapy plus brachytherapy. Brachytherapy involves the application of a radioactive source in close proximity to the
tumour, allowing a very high dose to the tumour with relative sparing of the surrounding normal structures. It has been shown by a number of studies that it significantly improves disease control and survival (2-4). In Reunion Island, a French territory located near the Eastern Coast of Madagascar in the Indian Ocean, the standardized incidence rate in 2012 was 10,8 for 100 000 women, twice higher than in Metropolitan France. The standardized mortality rate follows a similar trend whereby in Reunion, it accounts for 4.8 for 100 000 women, whereas the Metropolitan rate was 2.2 for 100 000 women (5,6). On the Island, there are 7 health facilities that treat cervical cancer: 4 hospitals and 3 clinics. Surgery is available in all these structures, however for brachytherapy, only vaginal high dose rate brachytherapy used after radical hysterectomy was possible until 2016, and only in one hospital (3 weekly sessions, each one delivering 7Gy within 5-10min). Patients who needed utero-vaginal brachytherapy had to be sent in Metropolitan France to be treated. In our study, we assessed whether the absence of brachytherapy on the Island was detrimental in the management of patients with invasive cervical cancer and we aimed at understanding why the mortality rate is high. Thus, the main objective was to evaluate the impact of professional practices in the different health care centers upon the mortality rate of women with invasive cervical cancer in Reunion Island. The secondary objective was to evaluate epidemiological factors that may influence survival.
MATERIAL AND METHODS Population This observational retrospective study concerns all cervical cancer cases diagnosed between 1st January 2010 and 31st December 2015 in Reunion Island and treated in the 7 heath facilities that treat cancers. The cases were identified by two sources of information: the Cancer Registry of Reunion Island, a population based registry which records all incident malignancies in the population of the island, and the records from the health facilities of the territory. For this study, only invasive cervical cancers were considered, cancer recurrences and carcinomas in situ were excluded. The data were collected from medical records, concerning socio-demographic information, tumor characteristics at diagnosis (histology, stage, …), treatments and follow-up. The study was approved by the advisory committee on the information processing research and the national commission for computing and liberties (CCTIRS and CNIL). The guidelines of the French Society of Gynaecological Oncology (FSGO) were used as reference to evaluate the clinical practices in Reunion, although other regional guidelines were consulted as well (7-12). Similarly to the guidelines, we separated the patients into 4 groups according to FIGO stage: Ia1, Ia2-Ib1, Ib2-IVa, IVb. For each group, we assessed the percentage of medical records that were discussed during multidisciplinary meetings and compared the treatment planning decisions made during the meetings and the final treatment received by the patients. Moreover, we evaluated whether the treatment received by the patients was in accordance to the guidelines.
Statistical analyses
Qualitative variables were expressed as numbers and percentages, and quantitative variables as median with 25th (p25) and 75th (p75) percentiles. Bivariate comparisons of continuous variables were performed using the Student’s t-test or the Mann-Whitney test; bivariate comparisons of percentages were performed using the Chi2 test or the Fisher's exact test, as appropriate.
The overall survival was evaluated at 1 year (1YOS) and 2 years (2YOS) by Kaplan Meier method. Vital status at the date of point (February 29, 2016) was obtained from medical records. Prognostic factors were identified by univariate analysis using the logrank test. Multivariate analysis was performed using Cox proportional hazards model. The variables retained in the final models were those with a p value of less than 0.2 on univariate analysis. Schoenfeld residuals were used to check the proportional hazard assumptions in Cox models.
Confidence intervals were calculated at 95% (95%CI) and all hypotheses tested with a twotailed alpha of 5%. Statistics were carried out with Stata V11.2 (StataCorp, Texas, USA). RESULTS A total of 344 patients were identified who met study inclusion criteria; approximately 57 cervical cancers were diagnosed every year in Reunion Island over the past six years. All patients were adults with a mean ± standard deviation age of 55.6 ± 3.1 years. Their detailed characteristics are summarized in Table 1. Patients had on average 4.4 ± 2.9 pregnancies and 3.9 ± 2.7 children. 4 cases of cancer were diagnosed during pregnancy, at 21, 24, 26 and 36 weeks of gestation. We acquired few Pap smear data from the patients and we report a 53.2% (49/92) coverage rate for effective screening (≤ 3 years).
The most frequent symptoms that lead to the diagnosis of the cancer at this time were bleeding (78.8%), particularly post-coital bleeding. The majority (83.5%) of the patients treated in Reunion Island resided on the Island itself. The others were sent as sanitary evacuation from other territories of the Indian Ocean for treatment, such as patients from the Mayotte, another Island that belongs to France which has a convention with Reunion Island, accounting for 11.2% of our study population. Amongst the 344 patients, 41 (11.9%) had several missing data concerning tumour stage or treatment received, and therefore were excluded. Eventually, 303 patients were included in this retrospective cohort. For these patients, first treatment was administered on average at 93.0 ± 103.8 days after the date of the histological diagnosis. Of these, 65 patients were aged 70 years old and over, of which 13 benefited from an oncogeriatric consultation. A total of 257 cases (84.8%) were discussed in multidisciplinary meetings for whom we were able to initially evaluate 241 cases but were unable to follow 35 cases (14.5%) due to incomplete data. Of the patients, 156 (51.5%) were administered a treatment in accordance with the guidelines of the FSGO. Finally, 18 patients (5 stage Ib2-IVa and 13 stage IVb) received no treatment
but
palliative
care.
The median duration of follow-up for the 303 patients was 15.1 months (0.2-68.1 months); at the date of point 82 patients were deceased, 23 were alive and 198 were lost to followup (65.3%). The overall survival for all the patients was 87.0% [95%CI 82.2 - 90.5] at 12 months, and 73.8% [95%CI 67.1 - 79.3] at 24 months (Figure 1). The evaluation of professional practices is summarized in Table 2. The comparisons of survival according to the sociodemographic and clinical data are presented in Table 3. Patients for whom decisions of the multidisciplinary meeting were applied had a better survival than those for whom the decisions not followed (p=0.001) (Figure 2). Similarly, the patients for whom FSGO guidelines were applied had a better survival than those who had an incomplete treatment (p = 0.01) (Figure 3). These differences of survival persist in spite of adjusted
analysis by Cox regression (HR 2.53 [CI 95% 1.55-4.14], p<10-3). The Cox regression has been stratified by FIGO stage because of the lack of proportional-hazards assumption. Of the 189 patients with a FIGO stage Ib2 to IVa, only 92 (48.7%) had received full treatment, including a combination of EBRT, chemotherapy and brachytherapy. Herein, we reported the principle cause of this incomplete treatment regime was the lack of brachytherapy as such, only 96 (50.8%) of the patients benefited from it. Therefore, 93.9% of the patients for whom FSGO recommendations were not followed did not received a treatment by brachytherapy. Patients who benefited from brachytherapy survived better than those who did not receive that treatment (p < 10-3) (Figure 4). For this group of locally advanced tumour, none of the following variables significantly influenced overall survival in univariate analysis (Table 4): age class (p=0.3), place of residence (p=0.1), period of diagnosis (p=0.2), histological type (p=0.4), FIGO stage (p=0.09), accordance between final treatment and the decisions made during multidisciplinary meetings (p=0.1): The adjusted analysis by Cox regression (retaining age classes and variables with a p value of less than 0.2 on univariate analysis excepted the variable “lack of brachytherapy” too closely linked to the variable “FSGO Guidelines accordance” confirm the significant impact on the prognostic of the follow-up of the recommendations. Patients for whom treatment was in accordance with FSGO guidelines survived 2.88 times better than patients for whom treatment was not following the guidelines (HR 2.88 [CI 95% 1.45-5.76], p=0.003). DISCUSSION In this study, we tried to assess the impact of professional practices and epidemiological factors on survival for patients with invasive cervical cancer in Reunion Island. 1. Evaluation of professional practices Approximately half of the patients (52.3%) received treatment in accordance with the French guidelines, and presented a better survival than the 47.7% of restant patients. Our rate of
accordance with the guidelines is below the rate reported by Kang. Therein, 79% of 1085 patients in Manitoba, Canada, received guidelines treatment. Amongst these, only patients with stage IIB-IVA had a significantly decreased risk of death when treated according to the guidelines (p=0.002) (13). In our study of patients at stage IB2-IVA, only 48.7% received the 3 components of the treatment (EBRT, chemotherapy, brachytherapy). Eighty-six percent of patients received at least EBRT and chemotherapy, but only 50.2% received at least brachytherapy. This low rate of incomplete treatment was also reported in the United States by others in 2015 (whereby 33.1% of the 1048 patients of their study received the 3 treatments, and 54% had at least brachytherapy (14)). As previously mentioned, only vaginal brachytherapy was available in Reunion island until 2016, and in this culture where family is of utmost importance, many patients refused to go to Metropolitan France to benefit from utero vaginal brachytherapy due to the travel distance and being away from their families. Moreover, the sanitary evacuation raised other difficulties, such as administrative obstacles (patients from the Comores with no identity paper), financial problems (the cost of this transfer is approximately 3185€ for each patient), and technical adversities (such as the transfer of patients requiring oxygen or heavy medical support). Nevertheless, we proved the impact of brachytherapy on the global survival, and the patients who benefited from it survived better than those who did not receive such a treatment. The last prognostic survival factor highlighted by our study is the accordance between the decision made up during multidisciplinary meetings and the actual treatment received by the patients. Of the decisions, 81.7% were followed, and these patients had a better survival. One of the reasons for the discordances is probably the absence of oncogeriatric consultation for 80.9% of the patients who were over 70 years old. Indeed, Puts suggested that 30% of the treatment decisions did not consider the performance status of the patients.
Whereas when oncogeriatricians were consulted prior to the multidisciplinary meetings, the appropriate decision was applied in more than 90% of the cases (15). Thus, possible ways to improve quality of care and patient survival are to ensure decision implementation discussed during multidisciplinary meetings and to follow treatments in accordance to the FSGO guidelines, with particular focus on use of brachytherapy. 2. Epidemiology 2.1 Incidence For reminder, the definition of the incidence is the number of new cases over a defined period. The standardized rate is the rate that would be observed for patients living in one particular region, if it had the same age structure than the reference population (population in the world). To determine the standardized incidence rate of patients with cervical cancer over our study period, we should be exhaustive in the collection of patients with cervical cancer in the Island, and we should exclude patients who did not live in Reunion Island at the moment when the cancer was diagnosed. In our population cohort, the patients were treated in a health care centre, not taking into account women who were diagnosed with cervical cancer but not treated. Moreover, 16.5% of our patients were living outside Reunion Island at the time of diagnosis. Thus, we could not obtain a satisfactory standardized incidence rate. Nevertheless, last available data in 2012 point out a higher incidence of cervical cancer in Reunion (10.8/100,000 women), compared to metropolitan France (6.7/100,000 women) (5,6). Our study cohort had a higher parity (3.9 children VS 2.01 in metropolitan France, p<0.001). Moreover, precocity of sexual intercourse was observed in a study in 2010 "Health Behaviour in school-age children » (16). It was reported that 37% of teenagers in Reunion declared sexual intercourse before the age of 14-15 years, compared with only 26.7% in
metropolitan France. Thus, a higher incidence rate of cervical cancer in the island may be a contributing factor for a higher mortality rate. 2.2. Age In some studies (17-19), a young age below 30 or 35 years old at diagnosis seems to be a pejorative prognostic factor in patients with cervical cancer. Nevertheless our patients, present a mean age of 55.6 years, and were not significantly younger than patients in metropolitan France (56.0 years, p = 0.6). 2.3. FIGO stage Approximately 17.4% of cervical cancers were metastatic at the time of diagnosis. Key typical symptoms such as metrorrhagia were associated with 78.8% of the cases. In our population, patients had numerous comorbidities (diabetes, hypertension...). All these findings incite us to believe that at the time of diagnosis patients in Reunion Island may have higher FIGO stage than those in metropolitan. Accordingly, a previous study proved that patients with more comorbidities had significantly higher FIGO stage (20). We interrogated all the departmental cancer registries in metropolitan France. Only 3 departments had available data on FIGO stage: Herault, Poitou Charentes, Somme (21,22). When compared, our patient cohort did not have significantly higher FIGO stages (p = 0.3), in spite of physicians’ comments that they had more severe cases on the Island. To conclusively refute this hypothesis, a larger-scale comparison with all the Metropolitan regions should be conducted. 2.4. Histological type It has been previously reported that cervical adenocarcinomas have a poorer prognosis compared to squamous cell carcinoma (23). In the analysis, the only cancer registry with available data on histological types was that of Herault (21). We reported 15% of adenocarcinomas, which was, in comparison with that French region, an equivalent rate (p
= 0.85). Once more, a larger-scale comparison with all the Metropolitan regions should be conducted to comfort this idea. 2.5. Screening Reunion Island was a pilot department for organized screening, the coverage rate in the target population is 59.1%. It was lower in our population (53.1%) though it did not differ to the rate in metropolitan France (57%). However, the National Institute for Cancer in France would like to obtain 80% of coverage rate by 2019. To date, screening in Reunion Island although not different from metropolitan France, is insufficient and below expectations. An anthropologic study (24) tried to understand the apprehension of women in Reunion, facing Pap smear. Women are very superstitious and would be afraid of getting cancer solely by mentioning the word. Moreover, cervical cancer is a taboo subject, linked with sexuality and intimacy, which explains their reluctance to undergo pelvic examination. They also believe that cervical cancer is only associated with loosemoralled women and exclude themselves.
2.6. Vaccination Data concerning HPV vaccination coverage in our study population was not available. Indeed, with a mean age of 55.6 years, the patient cohort did not benefit from vaccination campaigns, which only started in 2007. However, in 2015, it was reported a 9.8% vaccination coverage in Reunion Island among girls aged 11-14 years old (25).
In Metropolitan France in 2015, the coverage for HPV vaccine was 20% for one dose for girls aged 15 years old, and 14% for the three doses at 16 years old. The National Institute for Cancer in France would like to obtain a coverage rate up to 60% (26). HPV vaccine delivery strategies such as school-based immunization program should be considered in order to obtain high vaccine uptake rates. Countries like Brazil and the United States demonstrated high rates of completion of three vaccine doses in children (88-97.2%) (27-29). Moreover, a cost-effectiveness study in Singapore showed that school-based quadrivalent HPV vaccination offered clinical and economic benefits (30).
Raising vaccination coverage would most probably decrease long-term mortality rate due to cervical cancer and vaccination should be promoted and reinforced. 2.7.HPV Cervical cancer is also associated with infection by HPV. We reasoned that different HPV genotypes exist in the Island, which could explain the higher mortality rate. Although HPV data for the screening of our population was not available, in an unpublished study (Michault et al, 2010), HPV genotyping of 97 biopsies, conisations after loop electro excision procedure, or hysterectomies of patients with cervical cancer living in Reunion Island were performed. Prevalence of HPV 16 and 18 was 68.2%, similar to metropolitan France (64%) (31). Other frequent high risk-HPV were 52, 33, 31, usually found in Eastern Africa and Asia, giving evidence of the ethnical diversity of the Island. 3. Strength and Limits The demonstration of the role of brachytherapy on disease control and survival is not an unknown fact (2-4). Nevertheless, we were able to describe the specificities of the management of invasive cervical cancer in a community, in Reunion Island, and point out the problems that occur with the lack of basic requirements, in spite of its belonging to a developed country. This gave us keys to understand the high mortality rate, although no such study has been performed in Metropolitan France for a real comparison; and to see how survival can be improved by easy efforts in the management of the patients. We were unfortunately limited by the retrospective nature of the study wherein there were many incomplete data for a more robust analysis. One major limit of our study is the lack of hindsight concerning the patients. Last patients included were on the 31st December 2015, and data were collected only 2 months later. Thus, global survival was only calculated over 24 months (73.8% [CI 95% 67.1 - 79.3]), and though not strictly comparable with the available data, it seems to be lower than the survival rate in Metropolitan France (32).
Follow-up was difficult to assess since patients were examined alternatively by either one of the specialists in the hospital, or by their general practitioner, for which the details of the consultation was difficult to obtain. Mean follow-up time for the patients was 15.1 months, and 65.3% of the patients were lost to follow-up. CONCLUSION In this study, we highlight the problems that occur in a community such as Reunion Island, with the lack of basic requirements, that are translatable to other areas in the world; and we tried to evaluate the impact of management on the mortality. The survival of patients for whom treatment was not in accordance with the guidelines or with the propositions of the multidisciplinary meetings, was poorer. Similarly, patients who did not benefit from brachytherapy also had poorer survival. Cervical cancer is most effectively prevented by vaccination and screening; however coverage rates in the island are below expectations. It is expected that organized screening program of cervical cancer foreseen by 2019 in all French departments will raise the coverage rate. In order to reduce the mortality rate of cervical cancer, we highlight the importance of prevention, and the utmost necessity to follow the decisions made up during multidisciplinary meetings, and the guidelines elaborated by the French Society of Oncological Gynecology. Moreover, brachytherapy has a major role in the treatment of locally advanced cancer, and it is fortunate that utero vaginal brachytherapy was inaugurated on the Island on the 17th October 2016.
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Figure 1. Global survival over the months (303 patients, Reunion Island, 2010-2015) Figure 2. Kaplan-Meier survival estimates if in accordance with the decisions made during the multidisciplinary meetings (solid line) or if not in accordance (dotted line). (303 patients, Reunion Island, 2010-2015) Figure 3. Kaplan-Meier survival estimates if in accordance with the respect of the guidelines of the SFOG French Society of Gynaecological Oncology (solid line) or if not in accordance (dotted line). (303 patients, Reunion Island, 2010-2015) Figure 4. Kaplan-Meier survival estimates according to treatment by brachytherapy (solid line) or the absence of brachytherapy (dotted line). (189 patients stage Ib2-IVa, Reunion Island, 2010-2015)
Figr-1
Figr-2
Figr-3
Figr-4
Table 1. Characteristics of 344 patients with cervical cancer in Reunion Island (2010-2015) Characteristics
N = 344
%
Stage - I - II - III - IV - missing data
101 105 42 82 14
29.4 30.5 12.2 23.8 4.1
Socio economical status - High - Medium - Low - Unemployed - Missing data
6 26 20 52 240
1.7 7.6 5.8 15.1 69.8
Place of residence - Reunion Island - Mayotte - Comores - Madagascar - Mauritius - Other territories of Indian Ocean - Missing data
284 38 8 7 2 1 4
82.6 11.0 2.3 2.0 0.6 0.3 1.2
Histological types - Squamous cell carcinoma - Adenocarcinoma - Other histological types - Missing data
266 49 12 17
77.3 14.2 3.6 4.9
Medical history* - Smoking - Dyslipidemia - Diabetes - Hypertension - Kidney failure - Obesity
69 28 65 114 21 56
20,1 8,1 18.9 33.1 6.1 16.3
Last screening by Pap smear - ≤ 3 years - > 3 years - Never - Missing data
50 30 14 250
14.5 8.7 4.1 72.7
Discovery mode of the cancer - Symptoms - Screening - Accidental discovery - Missing data
245 56 10 49
71.2 16.3 2.9 9.6
* Concerning medical history, patients had possible multiple comorbidities.
Table 2. Evaluation of professional practices according to the FIGO stage, compared to the guidelines of the French Society of Gynecological Oncology (Reunion, 303 patients)
Ia1
Ia2-Ib1
Ib2-II-III-IVa
IVb
Total
n
20
38
189
56
PET scan(%)
5
60.5
65.1
56.1
patients discussed in multidiciplinary meeting (%)
70
84.2
85.2
77.2
82.6
% of accordance between treatment and decisions of multidisciplinary meetings
100
75
85.1
68.4
81.7
% of accordance between treatment and guidelines
50
42.1
48.7
71.9
52.3
deaths (%)
10
10.5
26.5
43.9
Table 3. Survival of patients with invasive cervical cancer according to sociodemographic and clinical data (Reunion, 303 patients)
Age Class
Place of residence
Year of diagnosis
FIGO stage
Histology
Multidisciplinary meeting
FSGO Guidelines accordance
HR = Hazard Ratio
< 35 years old 35-49 years old 50-64 years old >= 65 years old Reunion island Mayotte Other place 2010 -2011 2012-2013 2014-2015 Ia1 Ia2-Ib1 Ib2-IVa IVb Adenocarcinoma Squamous cell carcinoma and undifferantiated carcinoma unknown No Yes, decision not followed Yes, decision followed yes, but follow-up of the decision not assessable No Yes Total
N 22 91 97 93 247 36 20 101 107 95 20 37 189 57 38
Kaplan Meier estimates 1YOS (95%CI) 2YOS (95%CI) 100 % 71.6 % (35.0 - 89.9) 87.9 % (77.9-93.6) 78.3 % (65.6-86.8) 85.3 % (75.8-91.3) 76.4 % (64.5-84.8) 84.7 % (75.1-90.9) 66.7 % (53.5-76.9) 86.2 % (80.9-90.1) 73.1 % (66.0-78.0) 86.3 % (47.6-97.1) 64.7 % (16.8-89.9) 89.1 % (62.7-97.2) 76.3 % (38.2-92.7) 82.8 % (73.7-88.9) 73.8 % (63.6-81.5) 85.5 % (76.6-91.2) 64.5 % (52.7-74.1) 94.3 % (84.4-98.0) 94.3 % (84.4-98.0) 100 % 100 % 97.1 % (81.4-99.6) 87.9 % (66.0-96.1) 92.5 % (87.1-95.7) 78.1 % (69.5-84.5) 57.5 % (42.5-69.9) 40.2 % (24.3-55.6) 87.4 % (69.1-95.2) 80.2 % (55.3-92.1)
249 16 46 35 206
87.7 % (82.6-91.5) 73.9 % (44.2-89.4) 93.4 % (80.9-97.8) 63.2 % (44.0-77.4) 89.6 % (83.9-93.4)
72.7 % (65.1-78.9) 73.9 % (44.2-89.4) 79.2 % (60.5-89.8) 49.8 % (30.0-66.8) 75.8% (67.5-82.3)
16 147 156 303
86.2 % (55.0-96.4) 83.1 % (75.6-88.5) 90.5 % (83.7-94.5) 87.0 % [82.2-90.5]
86.2 % (55.0-96.4) 70.6 % (60.8-78.4) 76.4 % (66.5-83.8) 73.8 % [67.1-79.3]
Log Rank p
0.15
Cox regression p HR (95%CI 1 0.56 [0.20-1.59] 0.2 0.76 [0.28-2.08] 0.5 1.14 [0.43-3.01] 0.7
0.5
0.01
1 13.6 [0.83-2.24] 0.2 [0.09-0.76] 0.01 stratification on 2 strata: Ia1-IVb vs IVb
<10-3
0.8
1.10-3 0.01
1 1.67 [0.92-3.02] 1.03 [0.52-2.01]
0.08 0.9
0.76 [0.23-2.50] 1 2.53 [1.55-4.14]
0.6 <10-3
Table 4. Survival of patients with invasive cervical cancer stage Ib2-IVa according to sociodemographic and clinical data (Reunion, 189 patients)
Age Class
Place of residence Year of diagnosis
FIGO stage Histology Multidisciplinary meeting
FSGO Guidelines accordance Lack of brachytherapy
HR = Hazard Ratio
< 49 years old 50-64 years old >= 65 years old Reunion island Other place 2010 -2011 2012-2013 2014-2015 Ib2-Iib IIIa-Iva squamous cell carcinoma Other carcinoma or unknown Yes, decision followed No, patient not discussed or Yes but decision not followed or decision not assessable No Yes No Yes Total
N 60 63 66 148 41 61 71 57 127 62 162 27 146
Kaplan Meier estimates 1YOS (95%CI) 2YOS (95%CI) 91.8 % (79.3-96.9) 75.8 % (57.6-870 92.8 % (81.6-97.3) 87.3 % (73.0-94.3) 92.9 % (82.1-97.3) 71.4 % (55.5-82.5) 91.9 % (85.8-95.4) 77.1 % (67.0-84.0) 92.9 % (59.1-97.0) 81.3 % (41.5-95,2) 91.5 % (80.8-96.4) 80.2 % (67.1-88.6) 92.0 % (81.7-96.7) 71.3% (56.7-81.8) 96.4 % (86.3-99.1) 96.4 % (86.3-99.1) 94.8 % (88.0-97.9) 80.0 % (69.2-87.4) 87.6 % (75.6-94.0) 74.0 % (57.8-84.7) 91.9 % (85.7-95.5) 76.1 % (66.5-83.3) 96.3 % (76.5-99.5) 89.4 % (61.9-97.4) 93.8 % (87.4-97.0) 79.3 % (69.2-86.4)
43 99 90 96 93 189
88.3 % (74.0-94.9) 83.1 % (75.6-88.5) 90.5 % (83.7-94.5) 88.5 % (79.5-93.7) 96.9 % (88.2-99.2) 92.5 % (87.1-95.7)
73.2 % (53.8-85.5) 70.6 % (60.8-78.4) 76.4 % (66.5-83.8) 70.5 % (57.2-80.3) 85.8 % (73.5-92.7) 78.1 % (69.5-84.5)
Log Rank p
0.3 0.1
Cox regression HR (95%CI 1 0.92 [0.41-2.06] 1.23 [0.59-2.56] 1 0.31 [0.07-1.35]
p 0.8 0.5 0.1
1 1.17 [0.61-2.25]
0.6
1
-
1.37 [0.71-2.64] 1 2.88 [1.45-5.76]
0.3
0.2 0.09 0.4
0.1 <10-3 <10-3
3.10-3
S0301-2115(17)30284-1 http://dx.doi.org/doi:10.1016/j.ejogrb.2017.06.010 EURO 9933
To appear in:
EURO
Received date: Revised date: Accepted date:
26-1-2017 31-5-2017 6-6-2017
Please cite this article as: Tran Phuong Lien, Morice Philippe, Chirpaz Emmanuel, Lazaro Glorianne, Boukerrou Malik.Impact of management on mortality in patients with invasive cervical cancer in Reunion Island.European Journal of Obstetrics and Gynecology and Reproductive Biology http://dx.doi.org/10.1016/j.ejogrb.2017.06.010 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Impact of management on mortality in patients with invasive cervical cancer in Reunion Island Phuong Lien Tran (Med Cand) a, Philippe Morice (MD, PhD, Pr) b, Emmanuel Chirpaz (MD) cd, Glorianne Lazaro (PhD) e, Malik Boukerrou (MD, PhD, Pr) afg
a
Gynecology and Obstetrics Unit – University Hospital of Reunion Island,
BP 350 - 97448 Saint Pierre Cedex. Reunion b
Gynecology and Obstetrics Unit - Gustave Roussy Institute
114 rue Edouard Vaillant, 97805 Villejuif cedex, France c
Cancer Registry of Reunion Island,
Reunion University Hospital, 97490 Saint-Denis, France d
INSERM, CIC 1410, Reunion University Hospital, 97448 Saint-Pierre, France
e
Institute of Cancer Research, 15 Cotswold Road, Sutton SM2 5NG, London, UK
f
Centre d’Etudes Périnatales de l’Océan Indien, University Hospital of Reunion Island
BP 350 - 97448 Saint Pierre Cedex. Reunion g
Faculty of Medicine - University of Reunion
97490 St Denis. Reunion Corresponding author : Phuong Lien Tran Gynecology and Obstetrics Unit University Hospital of Reunion Island BP 350 - 97448 Saint Pierre Cedex, Reunion Tél: +262(0)2 62 35 90 00 Fax: +262 (0)2 62 35 91 14 [email protected] The study was conducted in Reunion Island, France.
Impact of management on mortality in patients with invasive cervical cancer in Reunion Island ABSTRACT
OBJECTIVE. In Reunion Island, the standardized mortality rate for cervical cancer is 4.8/100,000 women, twice higher than in Metropolitan France. For locally advanced disease, the standard of care includes a treatment by brachytherapy. Nevertheless, brachytherapy was not available on the Island before 2016. The objective of this study was to assess the impact of the management of patients with invasive cervical cancer on mortality in Reunion. METHODS. We have identified all the women hospitalized in one of the health care centers of the Island diagnosed with invasive cervical cancer between 01/01/2010 and 31/12/2015. The guidelines of the French Society of Gynecological Oncology (FSGO) were considered as the reference to evaluate professional practices. The characteristics that had an influence on global survival after log-rank test were included in a multivariate analysis according to the Cox Model. RESULTS. Retrospective analysis identified 303 women meeting inclusion criteria. The assessment of professional practices showed that the decisions on 11.6% of the patients discussed during multidisciplinary meetings, were not applied, consequentially leading to a decrease in survival (p=0.001). A total of 156 patients (51.5%) were administered a treatment in accordance with the guidelines of the FSGO and had a better survival, even after multivariate analysis (HR 2.53 [CI 95% 1.55-4.14], p<10-3). Nonconformity was associated with the lack of access to brachytherapy on the Island. Women on the Island presented low rates of screening tests (cover rates 53.2%). CONCLUSION. The absence of treatment in accordance with the guidelines and decisions taken during multidisciplinary meetings and the absence of brachytherapy were associated to a higher mortality among patients with invasive cervical cancer in Reunion Island. We hope that the implementation of brachytherapy in Reunion will address these deficiencies. Keywords: mortality; cervical cancer; management; guidelines
INTRODUCTION
It is estimated that one million women worldwide are currently living with cervical cancer. Cervical cancer is the fourth most common cancer in women, with an estimated 528,000 incident cases and 266,000 deaths in 2012 alone, accounting for 7,5% of all female cancer deaths (1). Cervical cancer is frequently associated with infection by human papillomavirus (HPV), which induces cervical cell abnormalities that progress to cervical carcinogenesis. Behaviourally-based factors implicated in the increased risk of HPV infection include: being sexually active at a young age, having many sexual partners. Once infected with HPV, other factors including parity, smoking, and the use of oral contraceptives also become associated with an increased risk of cervical cancer. We have the technical knowledge to prevent hundreds of thousands of unnecessary deaths of women worldwide because cervical cancer is one of the most preventable types of cancer. A safe and effective HPV vaccine exists, targeting young girls between 11 and 14 years old. Because pre-cancerous lesions take many years to develop, screening by a Pap smear is recommended for every woman aged between 25 to 65 years. When screened early, treatment of cervical cancer is highly effective. Cervical cancer is staged clinically using the FIGO system developed by the International Federation of Gynecology and Obstetrics (FIGO). The initial work-up should include a cervical biopsy for histopathologic diagnosis. Additional imaging can provide valuable information to guide prognosis, determine management and assist in treatment planning. For locally advanced disease (stage IB2 to IVA), the standard of care consists of combined external beam radiation therapy (EBRT) with concurrent chemotherapy plus brachytherapy. Brachytherapy involves the application of a radioactive source in close proximity to the
tumour, allowing a very high dose to the tumour with relative sparing of the surrounding normal structures. It has been shown by a number of studies that it significantly improves disease control and survival (2-4). In Reunion Island, a French territory located near the Eastern Coast of Madagascar in the Indian Ocean, the standardized incidence rate in 2012 was 10,8 for 100 000 women, twice higher than in Metropolitan France. The standardized mortality rate follows a similar trend whereby in Reunion, it accounts for 4.8 for 100 000 women, whereas the Metropolitan rate was 2.2 for 100 000 women (5,6). On the Island, there are 7 health facilities that treat cervical cancer: 4 hospitals and 3 clinics. Surgery is available in all these structures, however for brachytherapy, only vaginal high dose rate brachytherapy used after radical hysterectomy was possible until 2016, and only in one hospital (3 weekly sessions, each one delivering 7Gy within 5-10min). Patients who needed utero-vaginal brachytherapy had to be sent in Metropolitan France to be treated. In our study, we assessed whether the absence of brachytherapy on the Island was detrimental in the management of patients with invasive cervical cancer and we aimed at understanding why the mortality rate is high. Thus, the main objective was to evaluate the impact of professional practices in the different health care centers upon the mortality rate of women with invasive cervical cancer in Reunion Island. The secondary objective was to evaluate epidemiological factors that may influence survival.
MATERIAL AND METHODS Population This observational retrospective study concerns all cervical cancer cases diagnosed between 1st January 2010 and 31st December 2015 in Reunion Island and treated in the 7 heath facilities that treat cancers. The cases were identified by two sources of information: the Cancer Registry of Reunion Island, a population based registry which records all incident malignancies in the population of the island, and the records from the health facilities of the territory. For this study, only invasive cervical cancers were considered, cancer recurrences and carcinomas in situ were excluded. The data were collected from medical records, concerning socio-demographic information, tumor characteristics at diagnosis (histology, stage, …), treatments and follow-up. The study was approved by the advisory committee on the information processing research and the national commission for computing and liberties (CCTIRS and CNIL). The guidelines of the French Society of Gynaecological Oncology (FSGO) were used as reference to evaluate the clinical practices in Reunion, although other regional guidelines were consulted as well (7-12). Similarly to the guidelines, we separated the patients into 4 groups according to FIGO stage: Ia1, Ia2-Ib1, Ib2-IVa, IVb. For each group, we assessed the percentage of medical records that were discussed during multidisciplinary meetings and compared the treatment planning decisions made during the meetings and the final treatment received by the patients. Moreover, we evaluated whether the treatment received by the patients was in accordance to the guidelines.
Statistical analyses
Qualitative variables were expressed as numbers and percentages, and quantitative variables as median with 25th (p25) and 75th (p75) percentiles. Bivariate comparisons of continuous variables were performed using the Student’s t-test or the Mann-Whitney test; bivariate comparisons of percentages were performed using the Chi2 test or the Fisher's exact test, as appropriate.
The overall survival was evaluated at 1 year (1YOS) and 2 years (2YOS) by Kaplan Meier method. Vital status at the date of point (February 29, 2016) was obtained from medical records. Prognostic factors were identified by univariate analysis using the logrank test. Multivariate analysis was performed using Cox proportional hazards model. The variables retained in the final models were those with a p value of less than 0.2 on univariate analysis. Schoenfeld residuals were used to check the proportional hazard assumptions in Cox models.
Confidence intervals were calculated at 95% (95%CI) and all hypotheses tested with a twotailed alpha of 5%. Statistics were carried out with Stata V11.2 (StataCorp, Texas, USA). RESULTS A total of 344 patients were identified who met study inclusion criteria; approximately 57 cervical cancers were diagnosed every year in Reunion Island over the past six years. All patients were adults with a mean ± standard deviation age of 55.6 ± 3.1 years. Their detailed characteristics are summarized in Table 1. Patients had on average 4.4 ± 2.9 pregnancies and 3.9 ± 2.7 children. 4 cases of cancer were diagnosed during pregnancy, at 21, 24, 26 and 36 weeks of gestation. We acquired few Pap smear data from the patients and we report a 53.2% (49/92) coverage rate for effective screening (≤ 3 years).
The most frequent symptoms that lead to the diagnosis of the cancer at this time were bleeding (78.8%), particularly post-coital bleeding. The majority (83.5%) of the patients treated in Reunion Island resided on the Island itself. The others were sent as sanitary evacuation from other territories of the Indian Ocean for treatment, such as patients from the Mayotte, another Island that belongs to France which has a convention with Reunion Island, accounting for 11.2% of our study population. Amongst the 344 patients, 41 (11.9%) had several missing data concerning tumour stage or treatment received, and therefore were excluded. Eventually, 303 patients were included in this retrospective cohort. For these patients, first treatment was administered on average at 93.0 ± 103.8 days after the date of the histological diagnosis. Of these, 65 patients were aged 70 years old and over, of which 13 benefited from an oncogeriatric consultation. A total of 257 cases (84.8%) were discussed in multidisciplinary meetings for whom we were able to initially evaluate 241 cases but were unable to follow 35 cases (14.5%) due to incomplete data. Of the patients, 156 (51.5%) were administered a treatment in accordance with the guidelines of the FSGO. Finally, 18 patients (5 stage Ib2-IVa and 13 stage IVb) received no treatment
but
palliative
care.
The median duration of follow-up for the 303 patients was 15.1 months (0.2-68.1 months); at the date of point 82 patients were deceased, 23 were alive and 198 were lost to followup (65.3%). The overall survival for all the patients was 87.0% [95%CI 82.2 - 90.5] at 12 months, and 73.8% [95%CI 67.1 - 79.3] at 24 months (Figure 1). The evaluation of professional practices is summarized in Table 2. The comparisons of survival according to the sociodemographic and clinical data are presented in Table 3. Patients for whom decisions of the multidisciplinary meeting were applied had a better survival than those for whom the decisions not followed (p=0.001) (Figure 2). Similarly, the patients for whom FSGO guidelines were applied had a better survival than those who had an incomplete treatment (p = 0.01) (Figure 3). These differences of survival persist in spite of adjusted
analysis by Cox regression (HR 2.53 [CI 95% 1.55-4.14], p<10-3). The Cox regression has been stratified by FIGO stage because of the lack of proportional-hazards assumption. Of the 189 patients with a FIGO stage Ib2 to IVa, only 92 (48.7%) had received full treatment, including a combination of EBRT, chemotherapy and brachytherapy. Herein, we reported the principle cause of this incomplete treatment regime was the lack of brachytherapy as such, only 96 (50.8%) of the patients benefited from it. Therefore, 93.9% of the patients for whom FSGO recommendations were not followed did not received a treatment by brachytherapy. Patients who benefited from brachytherapy survived better than those who did not receive that treatment (p < 10-3) (Figure 4). For this group of locally advanced tumour, none of the following variables significantly influenced overall survival in univariate analysis (Table 4): age class (p=0.3), place of residence (p=0.1), period of diagnosis (p=0.2), histological type (p=0.4), FIGO stage (p=0.09), accordance between final treatment and the decisions made during multidisciplinary meetings (p=0.1): The adjusted analysis by Cox regression (retaining age classes and variables with a p value of less than 0.2 on univariate analysis excepted the variable “lack of brachytherapy” too closely linked to the variable “FSGO Guidelines accordance” confirm the significant impact on the prognostic of the follow-up of the recommendations. Patients for whom treatment was in accordance with FSGO guidelines survived 2.88 times better than patients for whom treatment was not following the guidelines (HR 2.88 [CI 95% 1.45-5.76], p=0.003). DISCUSSION In this study, we tried to assess the impact of professional practices and epidemiological factors on survival for patients with invasive cervical cancer in Reunion Island. 1. Evaluation of professional practices Approximately half of the patients (52.3%) received treatment in accordance with the French guidelines, and presented a better survival than the 47.7% of restant patients. Our rate of
accordance with the guidelines is below the rate reported by Kang. Therein, 79% of 1085 patients in Manitoba, Canada, received guidelines treatment. Amongst these, only patients with stage IIB-IVA had a significantly decreased risk of death when treated according to the guidelines (p=0.002) (13). In our study of patients at stage IB2-IVA, only 48.7% received the 3 components of the treatment (EBRT, chemotherapy, brachytherapy). Eighty-six percent of patients received at least EBRT and chemotherapy, but only 50.2% received at least brachytherapy. This low rate of incomplete treatment was also reported in the United States by others in 2015 (whereby 33.1% of the 1048 patients of their study received the 3 treatments, and 54% had at least brachytherapy (14)). As previously mentioned, only vaginal brachytherapy was available in Reunion island until 2016, and in this culture where family is of utmost importance, many patients refused to go to Metropolitan France to benefit from utero vaginal brachytherapy due to the travel distance and being away from their families. Moreover, the sanitary evacuation raised other difficulties, such as administrative obstacles (patients from the Comores with no identity paper), financial problems (the cost of this transfer is approximately 3185€ for each patient), and technical adversities (such as the transfer of patients requiring oxygen or heavy medical support). Nevertheless, we proved the impact of brachytherapy on the global survival, and the patients who benefited from it survived better than those who did not receive such a treatment. The last prognostic survival factor highlighted by our study is the accordance between the decision made up during multidisciplinary meetings and the actual treatment received by the patients. Of the decisions, 81.7% were followed, and these patients had a better survival. One of the reasons for the discordances is probably the absence of oncogeriatric consultation for 80.9% of the patients who were over 70 years old. Indeed, Puts suggested that 30% of the treatment decisions did not consider the performance status of the patients.
Whereas when oncogeriatricians were consulted prior to the multidisciplinary meetings, the appropriate decision was applied in more than 90% of the cases (15). Thus, possible ways to improve quality of care and patient survival are to ensure decision implementation discussed during multidisciplinary meetings and to follow treatments in accordance to the FSGO guidelines, with particular focus on use of brachytherapy. 2. Epidemiology 2.1 Incidence For reminder, the definition of the incidence is the number of new cases over a defined period. The standardized rate is the rate that would be observed for patients living in one particular region, if it had the same age structure than the reference population (population in the world). To determine the standardized incidence rate of patients with cervical cancer over our study period, we should be exhaustive in the collection of patients with cervical cancer in the Island, and we should exclude patients who did not live in Reunion Island at the moment when the cancer was diagnosed. In our population cohort, the patients were treated in a health care centre, not taking into account women who were diagnosed with cervical cancer but not treated. Moreover, 16.5% of our patients were living outside Reunion Island at the time of diagnosis. Thus, we could not obtain a satisfactory standardized incidence rate. Nevertheless, last available data in 2012 point out a higher incidence of cervical cancer in Reunion (10.8/100,000 women), compared to metropolitan France (6.7/100,000 women) (5,6). Our study cohort had a higher parity (3.9 children VS 2.01 in metropolitan France, p<0.001). Moreover, precocity of sexual intercourse was observed in a study in 2010 "Health Behaviour in school-age children » (16). It was reported that 37% of teenagers in Reunion declared sexual intercourse before the age of 14-15 years, compared with only 26.7% in
metropolitan France. Thus, a higher incidence rate of cervical cancer in the island may be a contributing factor for a higher mortality rate. 2.2. Age In some studies (17-19), a young age below 30 or 35 years old at diagnosis seems to be a pejorative prognostic factor in patients with cervical cancer. Nevertheless our patients, present a mean age of 55.6 years, and were not significantly younger than patients in metropolitan France (56.0 years, p = 0.6). 2.3. FIGO stage Approximately 17.4% of cervical cancers were metastatic at the time of diagnosis. Key typical symptoms such as metrorrhagia were associated with 78.8% of the cases. In our population, patients had numerous comorbidities (diabetes, hypertension...). All these findings incite us to believe that at the time of diagnosis patients in Reunion Island may have higher FIGO stage than those in metropolitan. Accordingly, a previous study proved that patients with more comorbidities had significantly higher FIGO stage (20). We interrogated all the departmental cancer registries in metropolitan France. Only 3 departments had available data on FIGO stage: Herault, Poitou Charentes, Somme (21,22). When compared, our patient cohort did not have significantly higher FIGO stages (p = 0.3), in spite of physicians’ comments that they had more severe cases on the Island. To conclusively refute this hypothesis, a larger-scale comparison with all the Metropolitan regions should be conducted. 2.4. Histological type It has been previously reported that cervical adenocarcinomas have a poorer prognosis compared to squamous cell carcinoma (23). In the analysis, the only cancer registry with available data on histological types was that of Herault (21). We reported 15% of adenocarcinomas, which was, in comparison with that French region, an equivalent rate (p
= 0.85). Once more, a larger-scale comparison with all the Metropolitan regions should be conducted to comfort this idea. 2.5. Screening Reunion Island was a pilot department for organized screening, the coverage rate in the target population is 59.1%. It was lower in our population (53.1%) though it did not differ to the rate in metropolitan France (57%). However, the National Institute for Cancer in France would like to obtain 80% of coverage rate by 2019. To date, screening in Reunion Island although not different from metropolitan France, is insufficient and below expectations. An anthropologic study (24) tried to understand the apprehension of women in Reunion, facing Pap smear. Women are very superstitious and would be afraid of getting cancer solely by mentioning the word. Moreover, cervical cancer is a taboo subject, linked with sexuality and intimacy, which explains their reluctance to undergo pelvic examination. They also believe that cervical cancer is only associated with loosemoralled women and exclude themselves.
2.6. Vaccination Data concerning HPV vaccination coverage in our study population was not available. Indeed, with a mean age of 55.6 years, the patient cohort did not benefit from vaccination campaigns, which only started in 2007. However, in 2015, it was reported a 9.8% vaccination coverage in Reunion Island among girls aged 11-14 years old (25).
In Metropolitan France in 2015, the coverage for HPV vaccine was 20% for one dose for girls aged 15 years old, and 14% for the three doses at 16 years old. The National Institute for Cancer in France would like to obtain a coverage rate up to 60% (26). HPV vaccine delivery strategies such as school-based immunization program should be considered in order to obtain high vaccine uptake rates. Countries like Brazil and the United States demonstrated high rates of completion of three vaccine doses in children (88-97.2%) (27-29). Moreover, a cost-effectiveness study in Singapore showed that school-based quadrivalent HPV vaccination offered clinical and economic benefits (30).
Raising vaccination coverage would most probably decrease long-term mortality rate due to cervical cancer and vaccination should be promoted and reinforced. 2.7.HPV Cervical cancer is also associated with infection by HPV. We reasoned that different HPV genotypes exist in the Island, which could explain the higher mortality rate. Although HPV data for the screening of our population was not available, in an unpublished study (Michault et al, 2010), HPV genotyping of 97 biopsies, conisations after loop electro excision procedure, or hysterectomies of patients with cervical cancer living in Reunion Island were performed. Prevalence of HPV 16 and 18 was 68.2%, similar to metropolitan France (64%) (31). Other frequent high risk-HPV were 52, 33, 31, usually found in Eastern Africa and Asia, giving evidence of the ethnical diversity of the Island. 3. Strength and Limits The demonstration of the role of brachytherapy on disease control and survival is not an unknown fact (2-4). Nevertheless, we were able to describe the specificities of the management of invasive cervical cancer in a community, in Reunion Island, and point out the problems that occur with the lack of basic requirements, in spite of its belonging to a developed country. This gave us keys to understand the high mortality rate, although no such study has been performed in Metropolitan France for a real comparison; and to see how survival can be improved by easy efforts in the management of the patients. We were unfortunately limited by the retrospective nature of the study wherein there were many incomplete data for a more robust analysis. One major limit of our study is the lack of hindsight concerning the patients. Last patients included were on the 31st December 2015, and data were collected only 2 months later. Thus, global survival was only calculated over 24 months (73.8% [CI 95% 67.1 - 79.3]), and though not strictly comparable with the available data, it seems to be lower than the survival rate in Metropolitan France (32).
Follow-up was difficult to assess since patients were examined alternatively by either one of the specialists in the hospital, or by their general practitioner, for which the details of the consultation was difficult to obtain. Mean follow-up time for the patients was 15.1 months, and 65.3% of the patients were lost to follow-up. CONCLUSION In this study, we highlight the problems that occur in a community such as Reunion Island, with the lack of basic requirements, that are translatable to other areas in the world; and we tried to evaluate the impact of management on the mortality. The survival of patients for whom treatment was not in accordance with the guidelines or with the propositions of the multidisciplinary meetings, was poorer. Similarly, patients who did not benefit from brachytherapy also had poorer survival. Cervical cancer is most effectively prevented by vaccination and screening; however coverage rates in the island are below expectations. It is expected that organized screening program of cervical cancer foreseen by 2019 in all French departments will raise the coverage rate. In order to reduce the mortality rate of cervical cancer, we highlight the importance of prevention, and the utmost necessity to follow the decisions made up during multidisciplinary meetings, and the guidelines elaborated by the French Society of Oncological Gynecology. Moreover, brachytherapy has a major role in the treatment of locally advanced cancer, and it is fortunate that utero vaginal brachytherapy was inaugurated on the Island on the 17th October 2016.
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(28) Fregnani JH, Carvalho AL, Eluf-Neto J, Ribeiro Kde C, Kuil Lde M, da Silva TA, et al. A schoolbased human papillomavirus vaccination program in barretos, Brazil: final results of a demonstrative study. PLoS One 2013 Apr 24;8(4):e62647. (29) Vanderpool RC, Breheny PJ, Tiller PA, Huckelby CA, Edwards AD, Upchurch KD, et al. Implementation and Evaluation of a School-Based Human Papillomavirus Vaccination Program in Rural Kentucky. Am J Prev Med 2015 Aug;49(2):317-323. (30) Tay SK, Hsu TY, Shcheprov A, Walia A, Kulkarni AS. The clinical and economic benefits of schoolbased quadrivalent HPV vaccination in Singapore. Int J Gynaecol Obstet 2017 May;137(2):129-137. (31) Pretet JL, Jacquard AC, Carcopino X, Monnier-Benoit S, Averous G, Soubeyrand B, et al. Human papillomavirus genotype distribution in high grade cervical lesions (CIN 2/3) in France: EDITH study. Int J Cancer 2008 Jan 15;122(2):424-427. (32) Grosclaude P, Remontet L, Belot A, Dnazon A, Rasamimanana Cerf N, Bossard N. Survie des personnes atteintes de cancer en France 1989-2007. Available at: http://www.cancerenvironnement.fr/Portals/0/Documents%20PDF/Rapport/Invs/InVS,%20INCa,%202013%2 0%20Survie%20des%20personnes%20atteintes%20de%20cancer%20en%20France%201 989-2007.pdf. Accessed 11/02, 2016.
Figure 1. Global survival over the months (303 patients, Reunion Island, 2010-2015) Figure 2. Kaplan-Meier survival estimates if in accordance with the decisions made during the multidisciplinary meetings (solid line) or if not in accordance (dotted line). (303 patients, Reunion Island, 2010-2015) Figure 3. Kaplan-Meier survival estimates if in accordance with the respect of the guidelines of the SFOG French Society of Gynaecological Oncology (solid line) or if not in accordance (dotted line). (303 patients, Reunion Island, 2010-2015) Figure 4. Kaplan-Meier survival estimates according to treatment by brachytherapy (solid line) or the absence of brachytherapy (dotted line). (189 patients stage Ib2-IVa, Reunion Island, 2010-2015)
Figr-1
Figr-2
Figr-3
Figr-4
Table 1. Characteristics of 344 patients with cervical cancer in Reunion Island (2010-2015) Characteristics
N = 344
%
Stage - I - II - III - IV - missing data
101 105 42 82 14
29.4 30.5 12.2 23.8 4.1
Socio economical status - High - Medium - Low - Unemployed - Missing data
6 26 20 52 240
1.7 7.6 5.8 15.1 69.8
Place of residence - Reunion Island - Mayotte - Comores - Madagascar - Mauritius - Other territories of Indian Ocean - Missing data
284 38 8 7 2 1 4
82.6 11.0 2.3 2.0 0.6 0.3 1.2
Histological types - Squamous cell carcinoma - Adenocarcinoma - Other histological types - Missing data
266 49 12 17
77.3 14.2 3.6 4.9
Medical history* - Smoking - Dyslipidemia - Diabetes - Hypertension - Kidney failure - Obesity
69 28 65 114 21 56
20,1 8,1 18.9 33.1 6.1 16.3
Last screening by Pap smear - ≤ 3 years - > 3 years - Never - Missing data
50 30 14 250
14.5 8.7 4.1 72.7
Discovery mode of the cancer - Symptoms - Screening - Accidental discovery - Missing data
245 56 10 49
71.2 16.3 2.9 9.6
* Concerning medical history, patients had possible multiple comorbidities.
Table 2. Evaluation of professional practices according to the FIGO stage, compared to the guidelines of the French Society of Gynecological Oncology (Reunion, 303 patients)
Ia1
Ia2-Ib1
Ib2-II-III-IVa
IVb
Total
n
20
38
189
56
PET scan(%)
5
60.5
65.1
56.1
patients discussed in multidiciplinary meeting (%)
70
84.2
85.2
77.2
82.6
% of accordance between treatment and decisions of multidisciplinary meetings
100
75
85.1
68.4
81.7
% of accordance between treatment and guidelines
50
42.1
48.7
71.9
52.3
deaths (%)
10
10.5
26.5
43.9
Table 3. Survival of patients with invasive cervical cancer according to sociodemographic and clinical data (Reunion, 303 patients)
Age Class
Place of residence
Year of diagnosis
FIGO stage
Histology
Multidisciplinary meeting
FSGO Guidelines accordance
HR = Hazard Ratio
< 35 years old 35-49 years old 50-64 years old >= 65 years old Reunion island Mayotte Other place 2010 -2011 2012-2013 2014-2015 Ia1 Ia2-Ib1 Ib2-IVa IVb Adenocarcinoma Squamous cell carcinoma and undifferantiated carcinoma unknown No Yes, decision not followed Yes, decision followed yes, but follow-up of the decision not assessable No Yes Total
N 22 91 97 93 247 36 20 101 107 95 20 37 189 57 38
Kaplan Meier estimates 1YOS (95%CI) 2YOS (95%CI) 100 % 71.6 % (35.0 - 89.9) 87.9 % (77.9-93.6) 78.3 % (65.6-86.8) 85.3 % (75.8-91.3) 76.4 % (64.5-84.8) 84.7 % (75.1-90.9) 66.7 % (53.5-76.9) 86.2 % (80.9-90.1) 73.1 % (66.0-78.0) 86.3 % (47.6-97.1) 64.7 % (16.8-89.9) 89.1 % (62.7-97.2) 76.3 % (38.2-92.7) 82.8 % (73.7-88.9) 73.8 % (63.6-81.5) 85.5 % (76.6-91.2) 64.5 % (52.7-74.1) 94.3 % (84.4-98.0) 94.3 % (84.4-98.0) 100 % 100 % 97.1 % (81.4-99.6) 87.9 % (66.0-96.1) 92.5 % (87.1-95.7) 78.1 % (69.5-84.5) 57.5 % (42.5-69.9) 40.2 % (24.3-55.6) 87.4 % (69.1-95.2) 80.2 % (55.3-92.1)
249 16 46 35 206
87.7 % (82.6-91.5) 73.9 % (44.2-89.4) 93.4 % (80.9-97.8) 63.2 % (44.0-77.4) 89.6 % (83.9-93.4)
72.7 % (65.1-78.9) 73.9 % (44.2-89.4) 79.2 % (60.5-89.8) 49.8 % (30.0-66.8) 75.8% (67.5-82.3)
16 147 156 303
86.2 % (55.0-96.4) 83.1 % (75.6-88.5) 90.5 % (83.7-94.5) 87.0 % [82.2-90.5]
86.2 % (55.0-96.4) 70.6 % (60.8-78.4) 76.4 % (66.5-83.8) 73.8 % [67.1-79.3]
Log Rank p
0.15
Cox regression p HR (95%CI 1 0.56 [0.20-1.59] 0.2 0.76 [0.28-2.08] 0.5 1.14 [0.43-3.01] 0.7
0.5
0.01
1 13.6 [0.83-2.24] 0.2 [0.09-0.76] 0.01 stratification on 2 strata: Ia1-IVb vs IVb
<10-3
0.8
1.10-3 0.01
1 1.67 [0.92-3.02] 1.03 [0.52-2.01]
0.08 0.9
0.76 [0.23-2.50] 1 2.53 [1.55-4.14]
0.6 <10-3
Table 4. Survival of patients with invasive cervical cancer stage Ib2-IVa according to sociodemographic and clinical data (Reunion, 189 patients)
Age Class
Place of residence Year of diagnosis
FIGO stage Histology Multidisciplinary meeting
FSGO Guidelines accordance Lack of brachytherapy
HR = Hazard Ratio
< 49 years old 50-64 years old >= 65 years old Reunion island Other place 2010 -2011 2012-2013 2014-2015 Ib2-Iib IIIa-Iva squamous cell carcinoma Other carcinoma or unknown Yes, decision followed No, patient not discussed or Yes but decision not followed or decision not assessable No Yes No Yes Total
N 60 63 66 148 41 61 71 57 127 62 162 27 146
Kaplan Meier estimates 1YOS (95%CI) 2YOS (95%CI) 91.8 % (79.3-96.9) 75.8 % (57.6-870 92.8 % (81.6-97.3) 87.3 % (73.0-94.3) 92.9 % (82.1-97.3) 71.4 % (55.5-82.5) 91.9 % (85.8-95.4) 77.1 % (67.0-84.0) 92.9 % (59.1-97.0) 81.3 % (41.5-95,2) 91.5 % (80.8-96.4) 80.2 % (67.1-88.6) 92.0 % (81.7-96.7) 71.3% (56.7-81.8) 96.4 % (86.3-99.1) 96.4 % (86.3-99.1) 94.8 % (88.0-97.9) 80.0 % (69.2-87.4) 87.6 % (75.6-94.0) 74.0 % (57.8-84.7) 91.9 % (85.7-95.5) 76.1 % (66.5-83.3) 96.3 % (76.5-99.5) 89.4 % (61.9-97.4) 93.8 % (87.4-97.0) 79.3 % (69.2-86.4)
43 99 90 96 93 189
88.3 % (74.0-94.9) 83.1 % (75.6-88.5) 90.5 % (83.7-94.5) 88.5 % (79.5-93.7) 96.9 % (88.2-99.2) 92.5 % (87.1-95.7)
73.2 % (53.8-85.5) 70.6 % (60.8-78.4) 76.4 % (66.5-83.8) 70.5 % (57.2-80.3) 85.8 % (73.5-92.7) 78.1 % (69.5-84.5)
Log Rank p
0.3 0.1
Cox regression HR (95%CI 1 0.92 [0.41-2.06] 1.23 [0.59-2.56] 1 0.31 [0.07-1.35]
p 0.8 0.5 0.1
1 1.17 [0.61-2.25]
0.6
1
-
1.37 [0.71-2.64] 1 2.88 [1.45-5.76]
0.3
0.2 0.09 0.4
0.1 <10-3 <10-3
3.10-3