PracticeUpdate: Haematology & Oncology

GYNAECOLOGY

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Declines in cervical cancer precursors in the era of HPV vaccine Comment by Jonathan Temte MD, MS, PhD O n the eve of potential changes to the US Advisory Com- mittee on Immunization after this month, as the manufac- turer is suspending production and producing only HPV9. www.cdc.gov/vaccines/acip/meet- ings/downloads/agenda-archive/ agenda-2016-10.pdf.

of cervical intraepithelial neoplasia (CIN). Accordingly, the estimated rates of cervical cancer precursors emerging here can be corrected for changing cervical cancer screening recommendations and rates. And what it tells us is very reassuring and positive. There have been significant and dramatic reductions in CIN 1, CIN 2, and CIN 3 in young women (aged 15–19 years) since the introduction

of the HPV vaccine. The annual percentage declines in incidence for these three pathological grades were estimated at 9%, 10.5%, and 41.3%, respectively. CIN 2 inci- dence declined by an estimated 6.3% per year for women aged 20 to 24 years. No declines were noted for older and mostly unvaccinated women (aged 25–29 years). The authors suggest that the declines are in excess of what would be expected solely from individual protection. Accordingly, cross-protection (non- vaccine serotypes) and herd effects (population protection) are likely contributors. Declines in cancer precursors will translate into declines in cancer. First and foremost, HPV9 (the soon-to-be only choice in HPV vaccines in the US) is a cancer prevention interven- tion. Data fromNewMexico strongly reinforce this theme. Early provision of vaccine prior to sexual debut is essential for protecting our patients, our daughters, and our sons.

The New Mexico HPV Pap Reg- istry steering committee provides us with a wonderful, state-level assessment of the effects of HPV vaccine over the first 7 years fol- lowing introduction. This registry is the only system that collects population-based data of both cervi- cal cancer screening and prevalence

• The bivalent HPV vaccine (HPV2) will no longer be available in the US. • ACIP will consider a reduced- dose schedule for younger ado- lescents. See the draft agenda for the October 2016 meeting of the Advisory Committee on Immu- nization Practices: available at

Practices (ACIP) recommendations for the routine use of the human papillomavirus vaccine (HPV9), we are treated to additional good news about the tremendous benefits of this safe and effective vaccine. First some timely updates for readers: • The quadrivalent HPV vaccine (HPV4) will no longer be available

Population-based incidence rates of cervical intraepithelial neoplasia in the human papillomavirus vaccine era JAMA Oncology Take-home message • To investigate trends in population-based cervical intraepithelial neoplasia (CIN), this study evaluated 13,520 CIN1, 4296 CIN2, and 2823 CIN3 lesions diagnosed in women aged 15 to 29 years in 2007 to 2014 from the New Mexico HPV Pap Registry. Incidence of all grades of CIN were significantly decreased in female individuals aged 15 to 19 years, and CIN2 incidence was significantly decreased in women aged 20 to 24 years, after adjusting for cervical screening changes over the study period. • These population-based decreases in CIN may support increased age for screening, especially in cohorts who have been partially vaccinated for HPV. Abstract

high-grade CIN (grade 2 [CIN2] and grade 3 [CIN3]). RESULTS From 2007 to 2014, a total of 13 520 CIN1, 4296 CIN2, and 2823 CIN3 lesions were diagnosed among female individuals 15 to 29 years old. After adjustment for changes in cervical screening across the period, reductions in the CIN incidence per 100 000 women screened were significant for all grades of CIN among female individuals 15 to 19 years old, dropping from 3468.3 to 1590.6 for CIN1 (annual percentage change [APC], –9.0; 95% CI, –12.0 to –5.8; P<0.001), from 896.4 to 414.9 for CIN2 (APC, –10.5; 95% CI, –18.8 to –1.2; P = 0.03), and from 240.2 to 0 for CIN3 (APC, –41.3; 95% CI, –65.7 to 0.3; P=0.05). Reductions in the CIN2 incidence were also significant for women 20 to 24 years old, dropping from 1027.7 to 627.1 (APC, –6.3; 95% CI, –10.9 to –1.4; P=0.02). CONCLUSIONS AND RELEVANCE Population-level decreas- es in CIN among cohorts partially vaccinated for HPV may be considered when clinical practice guidelines for cervical cancer screening are reassessed. Evidence is rapidly growing to suggest that further increases in raising the age to start screening are imminent, one step toward integrating screening and vaccination. JAMA Oncol 2016 Sep 29;[Epub ahead of print], Benard VB, Castle PE, Jenison SA, et al.

estimates of both cervical screening prevalence and CIN, was used to compute CIN trends from January 1, 2007, to December 31, 2014. Under New Mexico Administrative Code, the New Mexico HPV Pap Reg- istry, a statewide public health surveillance program, receives mandatory reporting of all cervical screening (cytologic and HPV testing) and any cervical, vulvar, and vaginal histopathological findings for all women residing in New Mexico irrespective of outcome. MAIN OUTCOME MEASURES Prespecified outcome measures included low-grade CIN (grade 1 [CIN1]) and

IMPORTANCE A substantial effect of human papilloma- virus (HPV) vaccines on reducing HPV-related cervical disease is essential before modifying clinical practice guidelines in partially vaccinated populations. OBJECTIVE To determine the population-based cervical intraepithelial neoplasia (CIN) trends when adjusting for changes in cervical screening practices that over- lapped with HPV vaccination implementation. DESIGN, SETTING, AND PARTICIPANTS The New Mexico HPV Pap Registry, which captures population-based JOURNAL SCAN Topotecan plus carboplatin vs standard platinum-based combinations in platinum-sensitive recurrent ovarian cancer Annals of Oncology Take-home message • This was a randomized, multicenter phase III study evaluating the safety and efficacy of topotecan plus carboplatin (TC) vs three established platinum-containing doublet therapies in 550 patients with recurrent platinum-sensitive ovarian cancer. Progression-free survival (PFS) at 12 months was 37% vs 42% (P = 0.47) in the TC vs standard-regimen groups, respectively. Overall response rates were 73.1% vs 75.1% in the same groups, respectively (P = 0.149). Median overall survival (OS) was 25 vs 31 months in the TC and standard groups, respectively (P = 0.163). Severe hematologic toxicities were significantly lower in the TC arm. BACKGROUND Randomized, phase III trial to evaluate safety and efficacy of topotecan and carboplatin (TC) compared with stand- ard platinum-based combinations in platinum-sensitive recurrent ovarian cancer (ROC). PATIENTS AND METHODS Patients were randomly assigned in a 1:1 ratio to the experimental TC arm (topotecan 0.75 mg/m(2)/ days 1-3 and carboplatin AUC 5 on day 3 every 3 weeks) or to one of the standard regimes [(PC) paclitaxel plus carboplatin; (GC) gem- citabine plus carboplatin; (PLDC) pegylated liposomal doxorubicin and carboplatin] which could be chosen by individual preference but before randomization. The primary end point was progression- free survival (PFS) after 12 months. Overall survival (OS), response rate, toxicity, quality of life and treatment preference regarding standard treatment were defined as secondary end points. RESULTS A total of 550 patients were recruited. The PFS rate after 12 months was 37.0% for TC compared with 40.2% in the standard combinations (P = 0.470). The overall response rate was 73.1% for TC versus 75.1% for standard combinations (P = 0.149). After a

Dr Temte is Professor, University of

Wisconsin School of Medicine and Public Health, Department of Family Medicine, Madison, Wisconsin.

JOURNAL SCAN Association between timing of initiation of adjuvant therapy and survival of early-stage

ovarian cancer Gynecologic Oncology Take-home message

• This study included 497 patients with stage I–II epithelial ovarian cancer to evaluate the association between timing of adjuvant therapy initiation and survival. Patients were grouped based on time between surgery and adjuvant therapy, including <2 weeks, 2 to 4 weeks, and >4 weeks. No significant differences in 5-year recurrence-free or overall survival rates were found. Age, grade, stage, and cytology were found to be prognostic factors. • This study did not find an association between adjuvant therapy initiation timing and survival in patients with early-stage epithelial ovarian cancer. Abstract OBJECTIVES To determine the association between timing of adjuvant therapy initiation and survival of early stage ovarian cancer patients. METHODS Data were obtained from women who underwent primary surgical staging followed by adjuvant therapy from two Gynecologic Oncology Group trials (protocols # 95 and 157). Kaplan-Meier estimates and Cox proportional hazards model adjusted for covariates were used for analyses. RESULTS Of 497 stage I-II epithelial ovarian cancer patients, the median time between surgery and initiation of adjuvant therapy was 23 days (25th–75th%: 12–33 days). The time interval from surgery to initiation of adjuvant therapy was categorized into three groups: <2 weeks, 2–4 weeks, and >4 weeks. The corresponding 5-year recurrence-free survival rates were 72.8%, 73.9%, and 79.5% (p=0.62). The 5-year overall survival rates were 79.4%, 81.9%, and 82.8%, respectively (p=0.51; p=0.33 - global test). As compared to <2 weeks, the hazard ratio for recurrence-free survival was 0.90 (95% CI=0.59–1.37) for 2–4 weeks and 0.72 (95% CI=0.46–1.13) for >4 weeks. Age, stage, grade, and cytology were important prognostic factors. CONCLUSIONS Timing of adjuvant therapy initiation was not associated with survival in early stage epithelial ovarian cancer patients. The association between timing of initiation of adjuvant therapy and the survival of early stage ovarian cancer patients – an analysis of NRG Oncology/Gynecologic Oncology Group trials Gynecol Oncol 2016 Oct 19;[Epub ahead of print], Chan JK, Java JJ, Fuh K, et al.

• The authors concluded that TC was well-tolerated and feasible in relapsed, platinum-sensitive ovarian cancer patients, but it did not reduce PFS or OS compared with standard platinum doublets in this population. The 3-day dosing schedule of topotecan may also pose undue inconveniences for patients. Abstract

median follow-up of 20 months, the median PFS was 10 months [95% confidence interval (CI) 9.4-10.6] and did not differ between both arms (P = 0.414). The median OS was 25 months in the TC arm versus 31 months in the standard arm (95% CI: 22.4-27.6 resp. 26.0-36.0; P = 0.163). Severe hematologic toxicities (grade 3/4) were rare in the experimental arm (P < 0.001), with 17.4% leucopenia, 27.8% neutropenia and 15.9% thrombopenia. CONCLUSION The combination of carboplatin and topotecan was well tolerated with significant lower rates of severe hematological toxicities but did not improve PFS or OS in platinum-sensitive relapsed ovarian cancer compared with established standard regimens. Topotecan plus carboplatin versus standard therapy with paclitaxel plus carboplatin (PC) or gemcitabine plus carbopl- atin (GC) or pegylated liposomal doxorubicin plus carboplatin (PLDC): a randomized phase iii trial of the NOGGO-AGO- Study Group-AGO Austria and GEICO-ENGOT-GCIG Inter- group Study (HECTOR) Ann Oncol 2016 Oct 26;[Epub ahead of print], Sehouli J, Chek- erov R, Reinthaller A, et al.

PRACTICEUPDATE HAEMATOLOGY & ONCOLOGY