Topotekan u liječenju recidiva raka jajnika

Topotecan is an efficacious agent in the treatment of ovarian cancer recurrence after the failure of primary chemotherapy with platinum and its derivatives. Twenty-five patients with recurrent ovarian cancer were treated with topotecan at the Department of Gynecologic Oncology, Clinic for Gynecology and obstetrics, Clinical Hospital Zagreb in the period from January 2004 – January 2005. All patients were primarily operated and assessed as stage III or IV of ovarian cancer, and therefore received chemotherapy with platinum (in combination with paclitaxel or cyclophosphamide). After their first recurrence in a less than a 6-month interval, topotecan was administered. A complete clinical response was achieved in 2 patients (8%), a partial response in 15 patients (60%), progression in 8 patients (32%). All patients receiving topotecan were without early reactions (GI- nausea, vomiting), and experienced only mild late reactions (moderate myelosupression). Eight, 9, 6 and 2 patients received 6, 4, 2 and 1 treatment cycles, respectively. Based upon the low number of patients included in the study, we may say that topotecan is well tolerated, without significant early and late side-effects and with satisfying treatment response in patients with recurrent ovarian cancer, who are resistant to chemotherapy with platinum.Topotekan je djelotvoran citostatik u liječenju recidiva raka jajnika nakon neuspjeha primarne kemoterapije s platinom i njenim derivatima. Na Zavodu za ginekološku onkologiju Klinike za ženske bolesti i porode KBC Zagreb u razdoblju od 01/04 – 01/05 liječili smo 25 bolesnica s recidivom raka jajnika topotekanom. Sve bolesnice su bile primarno operirane i stupnjevane kao III ili IV stadij raka jajnika zbog čega su primale kemoterapiju s platinom (u kombinaciji s paklitakselom ili ciklofosfamidom). Nakon pojave prvog recidiva u vremenu kraćem od 6 mj primjenili smo topotekan. Kompletni klinički odgovor postigli smo kod 2 bolesnice (8%), djelomični odgovor u 15 bolesnica (60%), progresiju u 8 bolesnica (32%). Sve bolesnice podnijele su primjenu topotekana bez ranih reakcija (GI- mučnine, povraćanje), uz blage kasne reakcije (umjerena mijelosupresija). Osam bolesnica primilo je 6 ciklusa, 9 je primilo po 4 ciklusa, 6 bolesnica po 2 ciklusa, 2 bolesnice po jedan ciklus. Zaključak: na osnovi našeg malog broja bolesnica možemo reći da se topotekan dobro podnosi bez značajnijih ranih i kasnih nusdjelovanja uz zadovoljavajući odgovor na liječenje u bolesnica s recidivom jajnika koje su rezistentne na kemoterapiju s platinom

Oncogenic Aspects HPV Infections of the Female Genital Tract

Humani papilomavirus (HPV) glavni je etiološki čimbenik zloćudne preobrazbe vrata maternice. Najvećim dijelom zloćudna preobrazba stidnice i rodnice također je inducirana ovim virusom. Humani papilomavirusi odlično su prilagođeni svom prirodnom domaćinu, epitelnim stanicama kože i sluznica, koristeći se njihovim staničnim mehanizmima za svoje potrebe. U prvom koraku nastaje mikrotrauma i infekcija bazalnog sloja višeslojnoga pločastog epitela genitalnog trakta. Virus se veže za staničnu membranu, ulazi u stanicu i razmnožava se u jezgri. Ključnu ulogu u replikaciji virusa imaju virusni proteini E6 i E7. Vezanje onkoproteina E7 za protein Rb aktivira transkripcijski faktor E2F, koji je odgovoran za ekspresiju proteina potrebnih za replikaciju DNK. Nepravilnosti u tijeku S-faze staničnog ciklusa u fi ziološkim uvjetima dovode do apoptoze posredovane proteinom p53. Međutim, u stanicama inficiranim HPV-om taj je proces onemogućen djelovanjem proteina E6, koji dovodi do proteolitičke razgradnje p53. Stalna aktivnost virusnih proteina E6 i E7 dovodi do nestabilnosti genoma, nakupljanja mutacija, gubitka kontrole staničnog rasta i na kraju do razvoja karcinoma. Putem prirođenog i stečenog imunosnog odgovora organizam prepoznaje i suzbija strane agense, ali u slučaju HPV-infekcije taj je odgovor ponekad nedovoljan. Nadalje, HPV-infekcija dovodi do gubitka ekspresije citokina djelovanjem E6 i E7- onkoproteina, posebice suprimiranjem ekspresije gena interferona. U oko 10% zaraženih nastaje perzistentna infekcija HPV-om što donosi značajan rizik od nastanka prekursorskih ("premalignih") lezija, kao i od nastanka invazivnog karcinoma.The causal role of human papilloma virus (HPV) in all cancers of the uterine cervix has been fi rmly established biologically and epidemiologically. Most cancers of the vulva and vagina are also induced by HPV. Papillomaviruses are perfectly adapted to their natural host tissue, the differentiating epithelial cell of skin or mucosae, and exploit the cellular machinery for their own purposes. The infectious cycle is initiated when infectious particles reach the basal layer of the epithelium, where they bind to and enter into cells. The critical molecules in the process of virus replication are the viral proteins E6 and E7, which interact with a number of cellular proteins. In experimental system these interactions have been shown to induce proliferation and eventually immortalization and malignant transformation of cells. Binding of E7 to pRb activates the E2F transcription factor, which triggers the expression of proteins necessary for DNA replication. Unscheduled S-phase would normally lead to apoptosis by the action of p53. However, in HPV-infected cells, this process is counteracted by the viral E6 protein, which targets p53 for proteolytic degradation. As an aberration of virus infection, constant activity of the viral proteins E6 and E7 leads to increasing genomic instability, accumulation of oncogene mutations, further loss of cell-growth control and ultimately cancer. The immune system uses innate and adaptive immunity to recognize and combat foreign agents that invade the body, but these methods are sometimes ineffective against human papillomavirus. HPV has several mechanisms for avoiding the immune system. Furthermore, HPV infections disrupt cytokine expression with the E6 and E7 oncoproteins, particularly targeting the expression of interferon genes. Approximately 10% of individuals develop a persistent infection, and it is this cohort who are at risk of cancer progression, with the development of high-grade precursor lesions and eventually invasive carcinoma

Human Papillomavirus Infections and Cervical Carcinoma

Karcinom vrata maternice drugi je najčešći karcinom u žena u svijetu. Najveća incidencija ove bolesti u nerazvijenim je zemljama jugozapadne Afrike, Južne Amerike i jugoistočne Azije. U Europi najveća incidencija ove bolesti je u zemljama istočne Europe. Hrvatska ima nižu incidenciju ove bolesti od mnogih država srednje i jugoistočne Europe. Karcinom vrata maternice bolest je mlađih žena. Veliko istraživanje International Agency for Research on Cancer (IARC) iz 1995. godine otkrilo je u 99,7% svih karcinoma vrata maternice genom humanog papilomavirusa (HPV). Genitalni sojevi HPV-a podijeljeni su u tri skupine: sojevi visokog onkogenog rizika, mogući karcinogeni sojevi i sojevi niskog onkogenog rizika. Sojevi 16 i 18 odgovorni su za oko 70% karcinoma cerviksa podrijetla pločastih stanica i oko 86% adenokarcinoma vrata maternice. Infekcija HPV-om danas je najčešća spolno prenosiva bolest. 90–95% slučajeva infekcija HPV-om prolazi spontano. Za razvoj preinvazivnih lezija vrata maternice (CIN – cervikalna intraepitelna neoplazija) i potom karcinoma potrebna je trajna infekcija visokoonkogenim sojevima HPV-a. Pretpostavka je da od trajne infekcije HPV-om do invazivnog karcinoma vrata maternice treba proći 7–10 godina, što ostavlja dovoljno vremena za prevenciju. Teoretski karcinom vrata maternice bolest je od koje ni jedna žena ne bi smjela oboljeti, a kamoli umrijeti. Ipak incidencija ove bolesti “stabilna” je. Razlog tomu je oportunistički program probira u Hrvatskoj. Na PAPA-obrisak uglavnom dolaze uvijek iste žene individualnom inicijativom. Stoga se nameće potreba organiziranog programa probira. Prošle godine u mnogim zemljama registrirano je cjepivo protiv HPV-a. Organizaciju nacionalnih imunizacijskih programa moguće je aplicirati samo u zemljama s dobro organiziranim programima sekundarne prevencije i u zemljama koje to mogu platiti.Cervical carcinoma is the second most frequent carcinoma in women worldwide. The highest incidence is recorded in developing countries of southwest Africa, South America and Southeast Asia. In Europe, the highest incidence is recorded in eastern European countries. In Croatia, its incidence is lower than in many CEE countries. Cervical carcinoma is the disease of young women. The major study conducted by the International Agency for Research on Cancer (IARC) in 1995 revealed that 99.7% of all cervical carcinoma cases could be attributed to human papillomavirus (HPV). Genital HPV strains are divided into three groups: high oncogenic risk strains, potentially carcinogenic strains, and low oncogenic risk strains. Strains 16 and 18 are responsible for about 70% of cervical epithelial cancers, and about 86% of cervical adenocarcinomas. Nowadays the HPV infection is the most frequent sexually transmitted disease. Remission can be spontaneous in 90-95% of HPV cases. Pre-invasive cervical lesions (CIN - cervical intraepithelial neoplasia) and subsequent carcinoma develop after a persistent infection with highly oncogenic HPV strains. The presumed interval between a persistent HPV infection and invasive cervical carcinoma is seven to ten years, which leaves suffi cient time for prevention. Theoretically, no woman should develop cervical carcinoma, or let alone die. However, the incidence of cervical carcinoma is stable. The reason is opportunistic screening in Croatia. These are mostly the same women who have Pap smears, and it is on their own initiative. Therefore, there is a need for organized screening program. Last year, HPV vaccine was registered in many countries. National immunization programs can be realized only in countries with well-organized secondary prevention and fi nancial prerequisites

Podnošljivost bevacizumaba u bolesnica starije dobi oboljelih od raka jajnika: iskustvo Zavoda za ginekološku onkologiju u Kliničkom bolničkom centru Zagreb

Introduction: Bevacizumab is a recombinant humanized anti-VEGF monoclonal antibody. It is an effective treatment for epithelial ovarian cancer, both in primary and recurrent disease. The incidence of ovarian cancer increases with advancing age. Despite the high prevalence of the ovarian cancer in elderly, the management of these patients is often less aggressive than in younger patients. In Croatia, from February 2017, we have opportunity to treat patients with epithelial ovarian, fallopian tube, or primary peritoneal cancer with bevacizumab in the first-line and second-line settings. Our aim was to investigate the safety of bevacizumab administration in patients older than 65 years. Methods: We have retrospectively analyzed the archive data of 65 patients with epithelial ovarian, fallopian tube, or primary peritoneal cancer who started treatment with bevacizumab in primary advanced and in first relapse setting at the Department of Gynecologic Oncology in the University Hospital Centre Zagreb in the period from January 2017 to December 2018. Patients were divided in two categories according to age: group 1 (≤65 years) and group 2 (>65 years). Results: Our analysis included 65 patients:47 (72.3%) patients in group 1 compared with 18 (27.7%) in group 2. Bevacizumab was administered to 39 (60%) patients as first-line treatment and to 26 (40%) patients as second-line treatment. The median age was 70 years (range 66-76 years) in group 2 and 55 years (range 35-65 years) in group 1. ECOG status 0 had 44.7% of patients in group 1 compared with only 22% in group 2. At the time of diagnosis, elderly patients had presented with at least one comorbidity in 94.4% of the cases, compared with 42.6% in group 1. The median number of cycles of bevacizumab was 9 in elderly patients and 17 cycles in group 1. Among those patients receiving bevacizumab in the first-line setting, median progression free interval (PFI) was 12 months in younger patients versus 7 months in elderly patients. Similarly, among those receiving bevacizumab in the second-line setting PFI was 9 months in younger patients versus 1 months in elderly patients. The occurrence of non-hematological adverse events did not increase in elderly patients; 51.1% of patients in group 1 reported some of non-hematological adverse events versus only 27.8% in elderly patients. Conclusion: Our experience in treating patients with bevacizumab shows good results with acceptable toxicity and our findings suggest that its use in the elderly population should be considered as safe and manageable.Uvod: Bevacizumab je rekombinantno humanizirano anti-VEGF monoklonsko antitijelo. Učinkovit je u liječenju epitelnog raka jajnika, kako u primarnom liječenju tako i kod pojave recidiva bolesti. Incidencija raka jajnika povisuje se sa starosnom dobi. Unatoč velikoj prevalenciji raka jajnika u starijih osoba, liječenje starijih bolesnica često je manje agresivno nego kod mlađih bolesnica. U Hrvatskoj, od veljače 2017. imamo mogućnost liječenja bevacizumabom u bolesnica s epitelnim rakom jajnika, jajovoda i primarnim peritonealnim rakom, kako u prvolinijskom liječenju tako i u prvom recidivu bolesti. Cilj nam je bio istražiti sigurnost primjene bevacizumaba u bolesnica starijih od 65 godina. Metode: Retrospektivno, analizirali smo medicinske podatke 65 bolesnica s epitelnim rakom jajnika, jajovoda ili primarnim peritonealnim rakom koji su započeli liječenje bevacizumabom u prvolinijskom liječenju u bolesnica s uznapredovalom bolesti kao i prvom recidivu bolesti u Zavodu za ginekološku onkologiju, KBC Zagreb u razdoblju 01.01.2017. do 31.12.2018. Bolesnice su bile podijeljene u dvije skupine prema dobi: skupina 1 (≤65 godina) i skupina 2 (>65 godina). Rezultati: U naše istraživanje bilo je uključeno 65 bolesnica: 47 (72,3%) bolesnica u skupini 1 u usporedbi s 18 (27,7%) u skupini 2. Bevacizumab je primijenjen kod 39 (60%) bolesnica kao prvolinijsko liječenje te kod 26 (40% ) bolesnica kao drugolinijsko liječenje. Medijan dobi bio je 55 godina (raspon 35-65 godina) u skupini 1 i 70 godina (raspon 66-76 godina) u skupini 2. ECOG status 0 imalo je 44,7% bolesnica u skupini 1 u usporedbi sa samo 22% u skupini 2. U vrijeme postavljanja dijagnoze, u starijih bolesnica zabilježen je barem jedan komorbiditet u 94,4% slučajeva, u usporedbi s 42,6% u skupini 2. Medijan broja apliciranih ciklusa bevacizumaba bio je 9 u bolesnica starijih od 65 godina , a 17 apliciranih ciklusa u skupini 1. U bolesnica koji su primale bevacizumab kao prvolinijsko liječenje, medijan intervala bez progresije bolesti (PFI) bio je 12 mjeseci u skupini 1 u odnosu na 7 mjeseci u bolesnica starijih od 65 godina. Slično tome, među onima koji su primali bevacizumab u drugoj liniji liječenja medijan PFI bio je 9 mjeseci u mlađih bolesnica u odnosu na 1 mjesec u bolesnica starijih od 65 godina. Pojava ne-hematoloških nuspojava nije se povećala u starijih bolesnika; 51,1% bolesnica u skupini 1 prijavilo je neku ne-hematološku nuspojavu nasuprot samo 27,8% u starijih bolesnica. Zaključak: Naše iskustvo liječenja bolesnica bevacizumabom pokazuje dobre rezultate s prihvatljivom toksičnošću, a naše istraživanje sugerira da je primjena bevacizumaba sigurna i podnošljiva i u bolesnica starijih od 65 godina

Prvolinijsko liječenje raka jajnika FIGO stadija IIIB-IV: naglasak na liječenju bevacizumabom - naše iskustvo

Epithelial ovarian cancer is the seventh most common cancer among women and the leading cause of gynecological cancer related deaths in Croatia. Approximately 70% of patients are diagnosed at an advanced stage of the disease (FIGO III and IV). The usual approach to treatment involves complete surgical cytoreduction (R0), followed by combined platinumbased chemotherapy. Bevacizumab is recommended to add to paclitaxel/carboplatin chemotherapy in patients diagnosed at FIGO IIIB and IIIC stage with residual disease after surgery and all patients FIGO IV stage of disease, which can extend the time to progression of the disease in these patients. In this retrospective study, we analyzed the medical data of 98 patients with newly diagnosed advanced FIGO IIIB-IV epithelial ovarian, fallopian tube, or primary peritoneal cancer treated at the Department of Gynecology and Obstetrics in the University Hospital Centre Zagreb in the period from January 2017 to December 2018. We have analyzed the followingdata: age, ECOG status, FIGO stage of disease, principle of surgery, pathohistological type of the tumor, number and type of adjuvant chemotherapy, application of bevacizumab, number of bevacizumab cycles, side effects related to bevacizumab therapy. Data from 98 patients were obtained. The median age was 60 years. The most patients were ECOG status 0-1 (78 %). According to the pathohistological findings, 89 % of patients had serous carcinoma, 5% endometrioid carcinoma, 3% mucinous carcinoma, 1% clear cell carcinoma, 1% borderline tumors and 1% poorly differentiated epithelial carcinoma. Most of the patients (68.5%) were underwent to primary cytoreduction, 12% “interval debulking” operation, whereas biopsy was performed in only 19.5% patients. HIPEC during surgery had 6% of patients. Resection without residual disease was achieved in only 25.5% of patients underwent surgery, while in others were reported macroscopic residual disease after surgery. 87% of patients were treated with chemotherapy with paclitaxel and carboplatin in three weeks schedule. 38 patients received antiangiogenetic drug bevacizumab. After exclusion of patients with a poor general condition (ECOG 2-4) and patients with FIGO stage IIIB and IIIC without residual disease after surgery, the percentage of patients receiving bevacizumab was 56% in 2017 and 75% in 2018. The average number of received cycles was 13 (range 1-22), and 8 patients continued the therapy in May 2019. Sixty-eight percent of the patients which received bevacizumab did not have any side effects associated with the bevacizumab therapy. The most common side effects associated with the bevacizumab were hypertension, development of deep vein thrombosis, ileus and proteinuria. In Croatia, since February 2017, we have the possibility of using bevacizumab for the treatment of newly diagnosed ovarian cancer patients stage IV or incompletely resected patients stages III B and III C. Our results are in concordance with the literature data and show that we can safely add bevacizumab to the first line chemotherapy of advanced ovarian cancer.Epitelni rak jajnika je sedmi najčešći maligni tumor u ženskoj populaciji i najčešći uzrok smrti od malignih ginekoloških tumora u Hrvatskoj. U vrijeme dijagnoze, oko 70% bolesnica nalazi se u uznapredovalom stadiju bolesti (stadiji FIGO III i IV). Uobičajeni pristup liječenju uključuje pokušaj kompletne kirurške citoredukcije (R0), nakon koje slijedi kombinirana kemoterapija na bazi platine. Kod bolesnica stadija bolesti FIGO IIIB i IIIC kod kojih postoji ostatna bolest nakon operativnog zahvata ili pak kod stadija FIGO IV, preporučuje se kemoterapiji dodati inhibitor angiogeneze (bevacizumab), kojim se može produžiti vrijeme do progresije bolesti u tih bolesnica. Ovom retrospektivnom analizom obuhvatili smo medicinske podatke 98 bolesnica s novodijagnosticiranim uznapredovalim (FIGO IIIB-IV) epitelnim rakom jajnika, jajovoda ili primarnog peritonealnog raka liječenih u Klinici za ginekologiju i porodništvo, Kliničkog bolničkog centra Zagreb u razdoblju od 01.01.2017. do 31.12.2018. Ispitivali smo slijedeće parametre: dob, ECOG status, stadij bolesti, princip kirurškog liječenja, patohistološki tip tumora, tip i broj kemoterapijskih ciklusa, aplikacija bevacizumaba, broj ciklusa bevacizumaba, te nuspojave povezane sa terapijom bevacizumabom. Obrađeni su podaci 98 bolesnica. Prosječna dob bolesnica bila je 60 godina. Većina bolesnica bila je ECOG status 0-1 (78 %). Prema patohistološkom nalazu, serozni karcinom utvrđen je u 89% bolesnica, u 5% endometrioidni, 3% mucinozni, a po 1% su bili zastupljeni klarocelularni, bordeline tumori i slabo diferencirani epitelni karcinom. Većina bolesnica (68.5%) je podvrgnuta primarnoj citoredukciji, 12% “interval debulking” operaciji, dok je u 19.5% učinjena samo biopsija tumora. U 6% bolesnica je tijekom operacije proveden HIPEC. Resekcija bez rezidualne bolesti postignuta je u 25.5% bolesnica podvrgnutih operativnom zahvatu, dok je u drugih bolesnica zabilježena ostatna makroskopska bolest nakon operativnog zahvata. Trotjednom kemoterapijom paklitaksel/karboplatin liječeno je 87% bolesnica. Terapiju inhibitorom angiogeneze (bevacizumab) primilo je 38 bolesnica. Kada isključimo bolesnice lošeg općeg stanja (ECOG 2-4) te bolesnice bez ostatne makroskopske bolesti nakon operativnog zahvata stadija FIGO IIIB i IIIC, postotak bolesnica koje su primile bevacizumab bio je 56 % u 2017. godini i 75% u 2018.g. Prosječni broj primljenih ciklusa je 13 (raspon 1-22), a 8 bolesnica nastavilo je navedenu terapiju i u svibnju 2019. 68% bolesnica koje su liječene bevacizumabom nisu imale nikakvih nuspojava povezanih sa navedenom terapijom. Najčešće zabilježene nuspojave povezane s terapijom bevacizumabom bile su hipertenzija, razvoj duboke venske tromboze, ileus i proteinurija. U Hrvatskoj, od veljače 2017. godine imamo mogućnost primjene bevacizumaba u liječenju bolesnica s novodijagnosticiranim rakom jajnika stadija IV ili stadija IIIB i IIIC kod kojih postoji ostatna bolest nakon operativnog zahvata. Naši rezultati su u skladu s literaturnim podacima i pokazuju da sigurno možemo dodati bevacizumab prvolinijskom liječenju u bolesnica s uznapredovalim rakom jajnika

Clinicopathological characteristic and prognostic factors for FIGO stage 1A2-1B2 of cervical cancer

Introduction: Cervical cancer is one of the most common malignant tumors of the female reproductive system in women between 15-35 years of age. It takes third place in the frequency of all reproductive system cancers in Croatia. The aim of the present study was to analyze prognostic factors influencing on reccurence to improve therapeutic management. Materials and Methods: We reviewed medical records and pathological materials obtained from 61 patients with stage IA2-IB2 between 2003 and 2013. The comparison of women with and without recurrence showed statistical significance in certain factors; age when diagnosed, size of tumor, depth of stromal invasion, lymph vascular space invasion, infiltration of the uterine isthmus and lymph node metastases. Results: Median age at diagnosis was 46 years. Lymph-vascular space invasion (LVSI) was present in 22 (36.1%) with cervical isthmus involvement in 18 (29.5%) patients. Tumor recurrence within observation interval was present in 6 (9.8%) patients. Median time of reccurrence was 24 (range 14-48) months. In univariate statistical analysis lymph-vascular space invasion (P=0.011), cervical isthmus involvement (P=0.002) and positive lymph nodes (P=0.005) were significant parameters for occurrence of recidive while in multivariate statistical analysis cervical isthmus involvement (P=0.036) remained as only independent risk factor for recidive occurrence. Conclusion: Cervical isthmus involvement could be of prognostic importance especially in the early stage of cervical cancer when we might decide in adding radiotherapy and concomitant chemotherapy to improve overall survival and lower recurrence rate

Cervical Cancer as a Public Health Issue – What Next?

Cervical cancer is the second most common cancer in women worldwide. There are about 60,000 newly detected cases and 30,000 deaths annually in Europe, with the highest incidence reported from Eastern Europe countries. According to data from the National Institute of Public Health, in Croatia the incidence of cervical cancer was 14.9/100,000 in 2006, ranking eighth most common malignancy in women. Croatia has a lower incidence of the disease compared to many countries of Central and Southeast Europe. A large study carried out in 1995 by the International Agency for Research on Cancer, which included cervical cancer material collected from 22 countries all over the world revealed HPV genome in 99.7% of cases. Efficient methods of cervical cancer detection and screening methods for identification of precancerous lesions (conventional Pap smear) are available. Cervical cancer prevention programs should include education (of health care providers and women), stressing the benefits of screening, the age of the peak cervical cancer incidence, and the signs and symptoms of precancerous lesions and invasive disease. The aim of screening actions is to detect precancerous lesions that may lead to cancer if left untreated. Screening can only be effective if there is a well-organized system of follow up, diagnosis and treatment. Cervical cytology, or Papanicolaou (Pap) testing, has for decades been a cornerstone of cervical cancer screening. According to recent guidelines issued by the World Health Organization Regional Office for Europe, the primary task of the public health system is the introduction of secondary prevention through properly organized screening programs. Launching the national immunization program is only possible in the countries with well-organized secondary prevention programs and in those that can afford it