cervical cancer: global facts to file

Cervical cancer is central to the emerging cancer pandemic in low- and middle-income countries. This malignancy is caused by a chronic infection of selected types of the human papilloma virus (HPV). In 2008 cervical cancer was the fourth leading cause of cancer death in women worldwide, and the leading cause of cancer death in Africa and Southeast Asia.  The number of lives lost to this preventable disease is a global failure of the largest scale if one considers that the health system in western and high income countries have developed very efficient programmes to prevent, detect, and treat cervical cancer which, in fact, have reduced disease incidence and mortality. In 2008, cervical cancer caused an estimated 275,100 deaths globally. Ninety percent of these deaths occurred in developing parts of the world, where access to screening and treatment are often non-existent and adolescent girls are not receiving vaccination for HPV. The HPV vaccine represents a major tool for primary prevention of the disease as it can prevent up to 70 percent of cervical cancer cases. Moreover, cost-effective procedures are now available to detect and treat cervical pre-cancer thus promoting secondary prevention. We ought to promote public awareness about cervical cancer in African countries, educate health professionals, and improve access to screening.  Issues that are critical to cervical cancer screening are public awareness (by women and local general practitioners), diagnostic capacity (in terms of availability of properly trained people in cytology and gynaecologists capable of managing cervical cancer and precancer), updating treatment modalities and outlets, the network of referral centres, and HIV coinfection.

male circumcision to prevent HIV and HPV infections

Male circumcision, i.e.  the surgical removal of some or all of the foreskin (or prepuce) from the penis, has been associated with a lower risk for HIV infection in international observational studies and in three randomized controlled clinical trials. How can it be explained? Compared with the dry external skin surface, the inner mucosa of the foreskin is thinner than other penile skin, has a higher density of cells which are targets for HIV, and shows greater susceptibility to traumatic epithelial disruptions (tears) during intercourse, providing a portal of entry for pathogens, including HIV. In addition, the microenvironment in the preputial sac between the unretracted foreskin and the glans penis may be conducive to viral survival. Removal of prepuce from the penis causes a transformation of this mucosa which becomes thicker and less susceptible to trauma and infection.  It has been shown that  male circumcision could reduce male-to-female transmission of HIV, although probably to a lesser extent than female-to-male transmission. Although links between circumcision, culture, religion, and risk behavior may account for some of the differences in HIV infection prevalence, the countries in Africa and Asia with prevalence of male circumcision of less than 20% have HIV infection prevalences several times higher than those in countries in these regions where more than 80% of men are circumcised. Lack of male circumcision has also been associated with sexually transmitted genital ulcer disease and chlamydia, infant urinary tract infections, penile cancer, and cervical cancer in female partners of uncircumcised men. The latter two conditions are related to human papillomavirus (HPV) infection. Male circumcision may represent an effective additional procedure to primarily prevent cervical cancer in women living in African countries, the other being safe sex, vaccination of females and males against HPV.

Diversi studi scientifici hanno dimostrato che la circoncisione nel maschio, cioè la rimozione del prepuzio dal pene, si associa ad una diminuzione del rischio di infezione da HIV. Quale ne è il motivo? In effetti, la mucosa del pene che sta all’interno del prepuzio è più sottile della cute esterna del prepuzio stesso, contiene una quantità superiore di cellule che sono il bersaglio del virus HIV ed, essendo più delicata, risulta più suscettibile a microtraumi. Infine il microambiente del sacco prepuziale favorisce la concentrazione del virus. Se invece si rimuove la porzione retraibile di cute e mucosa che riveste il sacco prepuziale, la mucosa sottostante si trasforma diventando più spessa e più simile alla cute. Ciò riduce fortemente il rischio di contrarre l’infezione e di ritrasmetterla. A riprova di ciò è stato osservato che nei paesi in cui la circoncisione è praticata in meno del 20% della popolazione maschile, la prevalenza della malattia è di molto superiore a quella riscontrata nei paesi in cui la circoncisione è praticata in più dell’80% dei maschi. La mancanza di circoncisione favorisce inoltre l’incremento di altre malattie sessualmente trasmesse, come le ulcere genitali, le infezioni urinarie infantili, le infezioni da clamidia, il carcinoma del pene e il carcinoma della cervice uterina nelle partner degli uomini non circoncisi. Queste due forme di carcinoma sono dovute all’infezione da virus papilloma umano (HPV). La circoncisione maschile può rappresentare un ulteriore mezzo per favorire la prevenzione primaria del carcinoma della cervice uterina aggiungendosi alla modifica degli stili di vita e alla vaccinazione contro il virus sia delle femmine che dei maschi. 

countdown to zero cases of newborn HIV infections

A baby is born with HIV nearly every minute, almost all of them in sub-Saharan Africa. In 2009, an estimated 370,000 children were infected at birth with HIV, almost all in low- and middle-income countries. The United Nations (UN) and the United States (US) government have recently launched an initiative to eliminate HIV among babies by 2015 by treating HIV-positive pregnant women, cutting infection among their babies to less than 5%. The plan, called Countdown to Zero, was developed by a team led by UNAids and the US President's Emergency Plan for AIDS Relief. It will cost an estimated $2.5bn (£1.5bn) to care for 15 million women, double those currently being treated. A key element of the campaign is to ensure that all women, especially pregnant ones, have access to quality life-saving HIV prevention and treatment services for themselves and their children. Achieving the goal could be "the beginning of the end of the story, because that opens the prospect for an Aids-free generation," said Michel Kazatchkine, head of the Global Fund to Fight AIDS, Tuberculosis and Malaria."We are here today to ensure that all children are born healthy and free of disease. We are here to ensure that their mothers live to see them grow," UN Secretary General Ban Ki-moon said at the launch of the plan."We believe that by 2015 children everywhere can be born free of HIV and that their mothers can remain healthy," said Michel Sidibe, executive director of UNAids.  Cutting the number of new cases of HIV infection will also play a major role in reducing the number of immunodepression-related cancers in the developing world. In women, it will result in the reduction of new cases of cancer of the uterine cervix as HIV and HPV coinfection represents a major risk for the tumor to develop and behave aggressively. An HIV-infection free generation is really a major goal for mankind. 

Quasi ogni minuto nell’Africa sub sahariana nasce un bambino portatore di infezione da HIV acquisita per trasmissione materno-fetale. Si stima che nel 2009 ne siano nati 370000, la maggioranza di essi nei Paesi in via di sviluppo. I governi delle Nazioni Unite e degli Stati Uniti hanno recentemente lanciato l’iniziativa di ridurre per il 2015 l’incidenza di infezione neonatale da HIV al di sotto del 5%. Per fare ciò si tenterà di fornire alle donne Africane, in particolar modo quelle in gravidanza, l' accesso a cure efficaci dell'infezione con l’intento di trattare soprattutto i loro bambini. Questo programma denominato “cowntdown to zero” è stato concepito dalla UNAids e dal Piano di Emergenza anti-AIDS del Presidente degli Stati Uniti, dovrebbe interessare 15 milioni di donne e costerà 2.5 miliardi di dollari. Ottenere questo risultato potrebbe rappresentare l’inizio della fine dell’AIDS e la creazione della prima generazione Africana senza la malattia. La riduzione dell’incidenza dei nuovi casi di AIDS contribuirà inoltre ad abbattere l'incidenza dei tumori correlati all’immunodeficienza acquisita che colpiscono duramente le popolazioni dei paesi più poveri. Per ciò che riguarda le donne si potrà anche verificare la riduzione dei nuovi casi di carcinoma della cervice uterina in quanto questo tumore, dovuto all'infezione cronica da virus papilloma umano (HPV), si sviluppa con particolare frequenza nelle donne portatrici di infezione da HIV. In conclusione, la sconfitta dell’AIDS rappresenta un obiettivo primario per l’umanità intera.

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.