uterine cervical cancer in the population of Nosy Be, Madagascar

Pathologist at the microscope and local staff reviewing the cytological reports

In a previous post I described the results of a medical mission we made in september 2010 to promote secondary prevention of uterine cervical cancer by pap smear cytological screening in women living in Nosy Be Island, Madagascar. The mission was repeated in April 2011 and took place at the Dispensaire of the Organisation Medicale Interenterpresises of Nosy Be (OMINO) in Hellville. The data we collected confirm our previous results that in the population of Nosy Be the incidence of uterine cervical carcinoma and its precursor lesions is significantly high. 
So far, we have examined cumulatively 278 women aged 16 to 57. In both missions we managed to perform pap smear evaluation with immediate reporting and immediate colposcopy and biopsy on a same-day basis. To summarize, pap smear sampling started early in the morning and was performed by two physicians, then slides were immediately stained and interpreted by a Pathologist who was able to release a cytopathological report at the end of the morning. Then, women bearing abnormalities in their pap smear were invited to undergo immediate colposcopy which was performed in the  early afternoon. Biopsy samples were then collected and processed for histological evaluation. Histological processing was completed in Italy at the department of Pathology, Fatebenefratelli Hospital, in Milano, Italy. 

women waiting for their turn for pap smear sampling

Immediate cytological reporting allowed for women with pap smear abnormalities to undergo immediate colposcopy thus preventing the risk of patients’ drop out in the screening programme. This is the most rewarding result for our efforts because women in these countries often fail to show up again when they are subsequently (i.e. many days or even months later) invited to undergo further evaluation, and the screening procedure thus fails to confirm cervical lesions by colposcopy and histology. 
Overall, we detected 5 women with high grade lesions according to the Bethesda System, 2001, and three of them were diagnosed as having squamous cell carcinoma in situ on biopsy examination.  Low grade lesions were found in other 25 women who are going to be re-evaluated within 6 months after the first pap smear. The overall cumulative incidence of pap smear abnormalities in this population is 10.79%, and this value is higher than the World Health Organization’s estimates of 10% (see "Comprehensive Cervical Cancer Control. A guide to essential practice", p. 40, World Health Organization, 2006) for the previously unscreened population in Madagascar. The above value is about 5-fold to 8-fold higher than the incidence of abnormalities in the screened population living in countries of the high-income developed world.

In un precedente post ho parlato della missione medica da noi eseguita in settembre del 2010 e finalizzata a promuovere la prevenzione del carcinoma della cervice uterina nella popolazione residente di Nosy Be, in Madagascar. Tale missione è stata ripetuta in Aprile 2011 e ha avuto luogo presso il Dispensario della Organisation Medicale Interenterprises di Nosy Be (OMINO) a Hellville, il capoluogo dell'isola. I dati raccolti confermano la nostra precedente impressione che l’incidenza di questa neoplasia in quell’area geografica è decisamente elevata. Abbiamo esaminato in tutto 278 donne e identificato 5 casi con lesioni ad "alto rischio" di cui 3 con carcinoma. Sono state identificate inoltre 25 donne portatrici di lesioni a “basso rischio” che verranno sottoposte a controllo ravvicinato. In entrambe le missioni abbiamo provveduto a eseguire la lettura immediata del pap test allo scopo di poter sottoporre le pazienti che necessitavano di colposcopia e biopsia nello stesso giorno. Questa modalità operativa ha consentito di annullare la quota di casi che solitamente non si ripresenta al controllo quando le pazienti vengono riconvocate a distanza di tempo dal pap test e ciò ha ottimizzato gli effetti dello screening. L’incidenza di lesioni riscontrate, pari al 10,79%, appare decisamente elevata se si pensa che l’Organizzazione Mondiale della Sanità stima un’incidenza massima del 10% per la popolazione del Madagascar. L’incidenza è da 5 a 8 volte superiore a quella riscontrata nella popolazione femminile sottoposta a regolare screening nei paesi occidentali.

Metronomic chemotherapy to treat cancer in low-resources countries

Treatment of many types of cancer is based on the use of chemotherapy. According to this approach, some special drugs, the chemotherapeutic agents, are administered in high doses which are lethal for cancer cells with the aim of eradicating them from the body. High dosage causes, however, severe side effects and drug resistance, thus chemotherapy has often to be stopped and/or becomes useless. As an alternative to conventional chemotherapy metronomic chemotherapy is gaining a great interest in the current scenario of oncological therapy. The theory behind “metronomic” chemotherapy is to administer very low doses of conventional anti-cancer drugs to attack vascular cells that supply oxygen and nourishment to the tumor (socalled “antiangiogenic” effect). The dosages are too low to kill the cancer cells directly, but high enough to arrest the growth of vessels that supply nutrients to the cancer cells. In other words, giving the drug in very low doses, and for a prolonged period of time (“metronomic” administration), such a therapy can prevent the formation of new capillaries, keeping the cancer from growing. Several studies have established the efficacy of metronomic chemotherapy in the treatment of a variety of cancer types. The efficacy seems not only to be based upon anti-angiogenic effect but also on the restoration of anticancer immune response and induction of tumor dormancy, as recently discussed by Pasquier et al. in an article which appeared in Nature Review Clinical Oncology. The chance of obtaining a successful treatment while minimizing side effects and drug resistance also means that chemotherapeutic agents can be administered in small cancer centers with minimal supportive care and this is of paramount importance to provide effective cancer treatment in the low-income and low-resources developing countries.  In fact, in many types of childhood and adult cancers, metronomic treatment protocols prove to be effective even if used on a totally outpatient basis and, most importantly, with no significant side effect. Thus the metronomic approach  represents a promising, innovative, simple, and affordable tool to treat cancer patients in the low-resources settings of the world. Metronomic protocols are now being implemented to treat leukemia and malignant lymphomas, but also cancer of the breast, ovary and the gastrointestinal tract.

HPV vaccination in male to prevent uterine cervical cancer

The origin of cancer of the cervix uteri is directly linked to a chronic infection of selected (so called “high risk”) types of human papilloma virus (HPV).  The virus is readily transmitted from men to women by the sexual intercourse and greatly affects the risk of disease in women. It is for this reason that understanding the nature of HPV in men is of crucial public health importance and can be used in modeling to establish whether vaccinating men against HPV would be cost effective. An Article published by Professor Anna R Giuliano and colleagues, of the H Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA, in the prestigous medical journal the Lancet  shows that approximately 50% of men from a sample of the general population are infected with the virus. The study analysed 1159 men aged 18 to 70 years (mean 32 years) from the USA, Brazil, and Mexico, all of whom were HIV negative and had no history of cancer. They were assessed every six months for an average of more than two years. The incidence of a new genital HPV infection with any HPV type was 38.4 per 1000 person months. The chances of cancer-causing (oncogenic) HPV infection was 2.4 times higher from men who had had many female partners compared with no partners or just one partner. The authors say: 'We noted no association with age and incidence of any, oncogenic, or non-oncogenic HPV types, although the probability of clearing these infections increased with age." They conclude: "The incidence of genital HPV infection in men was high and relatively constant across age groups in Brazil, Mexico, and the USA. The results from this study provide much needed data about the incidence and clearance of HPV infection in men; these data are essential for the development of realistic cost-effectiveness models for male HPV vaccination internationally". HPV vaccination of men will protect not only them but will also have great implications for their sexual partner. Vaccination of both females and males could represent the best way to fight uterine cervical cancer.

Education to breast health promotes early diagnosis of cancer

Women living in the developing countries have a higher probability of dying from breast cancer as compared to those of the high income western world. According to the Globocan/IARC data  the number of deaths as a percentage of incident cases in 2008 was 48% in the former and 24% in the latter. Exactly twofold.  Available evidence on stage at diagnosis indicate that a much higher proportion of cases in the developing world are detected in late stages thus the potential of survival is poorer. Many reasons are given to explain these data: the stigma of breast cancer and the associated societal implications of its treatments (especially mastectomy) discourage women from seeking care early on; lack of knowledge about breast health; scant options for early detection due to limited access to routine care and examinations; and lack of access to mammography and to affordable, high-quality treatment options. In summary, lack of education to breast health awareness and complex cultural barriers do play a significant role in delaying breast cancer detection in developing countries. Increased awareness of breast cancer symptoms and potential of successful treatment of the tumor in early stages would be of great help to improve survival even without widespread use of mammography, advanced surgical procedures, and adjuvant therapies. In fact, if we examine the reasons for the remarkable improvements in the probability of survival for women diagnosed with breast cancer in the USA as compared to 60 years ago it is possible to realize that a significant result had been achieved also prior to the introduction of massive screening of the tumor simply by means of education to improve breast health awareness and to breast self examination. In the low-income developing world, the provision of better education is bound to provide a solid foundation for reducing stigma and fear that will make more effective the introduction of complex technologies for early diagnosis and the use of highly expensive drugs for adjuvant therapy.

too little benefit from regular mammogram in women in their 40s

Screening by routine mammogram is intended to catch breast cancer in women while it is still small and presumably easier to treat. So far, annual or biennial mammography has been advised to women starting from the age of 40. Some recently collected data have shown, however, that regular mammogram provides very modest benefit in terms of reducing death for breast cancer in women aged 40 to 49.  In fact, without screening, 3.5 out of every 1,000 women in this age group will die of breast cancer in the next 10 years but regular mammography reduces that number to 3, i.e. the benefit derived from screening is only 0.5 per 1000 women!.  Indeed, it has also been calculated that to save one life  in this age group, 1,900 women must be screened annually for 10 years. The other 1,899 women will receive no benefit from mammography over that period, though they will field 1,330 call-backs for reassessment and 665 breast biopsies, and eight of them will be diagnosed with cancers whose prognosis will not be altered by detection via mammogram — either because they would never become dangerous or because they are so aggressive that there's little to be done. Data reported in recently published studies wherein women were randomly assigned to either a screening and a non screening group seem to confirm this contention. The U.S. Preventative Services Task Force thus decided in November 2009 that whether the benefits are worth the risks is a value judgment each woman should make for herself. Regular mammogram is instead highly reccomended after the age of 50 due to a significantly increased risk of breast cancer.  In developing countries the incidence of breast cancer is significantly lower than in high income developed world but mortality due to the tumor is much higher. Even if the chance of detecting breast cancer in women younger than 50 is rather remote, the higher risk of dying of the disease may suggest that regular mammogram in women of developing countries in their 40s should still be encouraged .

breast cancer and passive smoking

Smoking is associated with an increase in breast cancer risk among postmenopausal women but there seems to be a definite increase also in non smoker women who have been extensively exposed  to second hand smoke.  These data were recently reported in the British Medical Journal. The study was based on the observation of nearly 80,000 women aged between 50 and 79 years  enrolled in the Women’s Health Initiative Observational Study from 1993 to 1998. Invasive breast cancer appeared in 3,250 women during 10 years of follow-up. Smokers had a 16% increased risk of developing breast cancer after the menopause as compared to non smokers.  For ex-smokers the risk was 9% and continued for up to 20 years after an individual had stopped smoking. The highest breast cancer risk was found among women who had smoked for over 50 years or more. What about non smokers? women who had never smoked but had lived or worked with smokers for prolonged times also appeared to be at increased risk for breast cancer. In particular, over 10 years’ exposure in childhood, over 20 years’ exposure as an adult at home and over 10 years’ exposure as an adult at work, increased the risk by 32% compared with those who had never been exposed to passive smoking. In low income and developing countries large declines in mortality are projected to occur in the near future for all of the principal communicable disease, maternal, peri-natal and nutritional causes, with the exception of HIV/AIDS. Meanwhile, the aging of the global population will result in significant increases in the total number of deaths caused by most non-communicable diseases  such as cancer. In particular, increases in the prevalence of tobacco consumption and significant lifestyle changes in the population are bound to produce an increased risk of breast cancer in African women.  Thus, efficient screening procedures for early detection of the disease need urgently to be implemented.

HPV vaccination and cervical cancer

Cervical cancer is the second most common cancer in women worldwide and it is linked to persistent infection by human papilloma virus (HPV). Vaccination against HPV represents an important tool to obtain a primary prevention of the tumor. There are many strains of the virus but only a small number of them causes cancer. An international team of researchers has recently identified eight strains of the HPV responsible for more than 90% of cervical cancer cases. The study, which was published in the prestigious medical journal The Lancet, examined 60 years of data from 10575 cases of invasive cervical cancer in 38 countries. HPV was found in about 85% of cancer samples.  More than 90% of these cases were caused by  HPV types 16, 18, 45, 33, 31, 51, 58 and 35, in descending order of frequency. Only 1% of cases worldwide were linked to the infection by HPV types 26, 30, 61, 67, 69, 82 and 91. The former group of eight strains will represent the target for the next generation of HPV vaccines. Currently two vaccines are available in the market, Cervarix and Gardasil, which cover the infection by HPV strains 16 and 18. Gardasil covers 11 additional non oncogenic HPV strains which are responsible for genital warts.  Prophilactic efficacy of the two HPV vaccines is almost 100% and they can prevent cancer cases directly linked to infection by HPV strains 16 and 18. Efficacy of the vaccination is obviously dependent upon the recipient not having been already infected with that type of HPV.  Cancer cases due to 16 and 18 HPV strains represent about 60%-70% of total cases. Future efforts will focus on the production of second generation vaccines covering in addition the other six HPV strains (45, 33, 31, 51, 58 and 35) in order to prevent more than 90% of cases.