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作者：Roxanne Nelson  
出處：WebMD醫學新聞

　　January 21, 2010 — 對於35歲以上的婦女而言，人類乳突病毒(HPV)篩檢可以比細胞學檢查更有效偵測高等級病灶以及預防侵犯性子宮頸癌，不過，這個篩檢方法對於比較年輕的婦女較無效，因為它會導致子宮頸上皮內贅瘤(cervical intraepithelial neoplasia，CIN)的過度診斷，而這會自己復原。
　　
　　研究者在線上發表於1月19日Lancet Oncology期刊的研究中結論表示，對於35歲以上婦女，HPV檢測應取代細胞學檢查作為例行篩檢。
　　
　　編輯評論指出，HPV檢測顯示相當有助於子宮頸癌篩檢的改革，特別是開發中國家。
　　
　　該試驗的第一部份中，偵測出的侵犯性癌症數量相似，細胞學篩檢組(n= 9)、HPV檢測篩檢組(n= 7)，但是在第二回篩檢中，HPV組沒有侵犯性癌症，細胞學組有9人，表示以HPV為基礎的篩檢在預防疾病惡化成癌症上更有效，因為較早偵測到臨床相關病灶以及進行癌前治療。
　　
　　第一作者、義大利杜林腫瘤預防中心的Guglielmo Ronco醫師表示，我認為有足夠的證據改為單獨使用HPV檢測，細胞學檢查應只用於分類為HPV陽性的婦女。
　　
　　他向Medscape Oncology表示，在以人口為基礎的篩檢計畫的國家中，建議以此合理的先驅計畫來作為轉變，這將幫助評估費用和品質管理，確認和婦女們溝通的最佳方式。
　　
　　Ronco醫師解釋，此外，也需要訓練專業人員；運用適當的評估規範對HPV陽性的婦女而言是重要的。
　　
　　【延長篩檢間隔 年輕婦女則不變】
　　對於年輕婦女的篩檢計畫，Ronco醫師不建議任何改變，他表示，目前，她們應繼續使用巴氏抹片(Pap [tests])，未來，生物標記的研究將讓我們可以辨識哪些CIN2案例會惡化，而可以避免過度治療。
　　
　　不過，他指出，這在目前還不可能。
　　
　　研究者們也結論表示，HPV檢測的篩檢間隔可以延長，但是需要更多追蹤，以確認多久的篩檢間隔是可接受的安全範圍，Ronco醫師表示，就我的觀點，已經有證據認為5年的間隔是安全的。
　　
　　相較於細胞學檢查，在偵測高等級CIN方面，HPV檢測敏感性較高，但是專一性較差，如同Medscape Oncology之前所報導的，當使用HPV DNA檢測作為一線篩檢策略時，對於持續的HPV特定類型感染，後續須以細胞學分類和反覆篩檢，可以提升子宮頸癌篩檢的準確度。
　　
　　HPV檢測或許也是資源不足情況下最有效的子宮頸癌篩檢方法，它顯示可以顯著降低侵犯性子宮頸癌的發生率 (N Engl J Med. 2009;360:1385-1394)。
　　
　　【以HPV檢測改善偵測率】
　　在目前的研究中，Ronco醫師等人評估不同的HPV篩檢政策的效果，以及最適合篩檢的年紀。他們的大型第3期隨機試驗包括了兩回合的篩檢，每個都有兩次各自的招募期，主要終點是，在第一和第二回合篩檢時偵測CIN2/3以及侵犯性子宮頸癌。
　　
　　就這兩次試驗期而言，47,001名婦女被隨機指派接受細胞學檢查，47,369名婦女接受HPV檢查，其中，細胞學檢查組有33,851名婦女、HPV檢查組有32,998名婦女參加第二回合篩檢。
　　
　　第1期時，35-60歲的HPV陽姓婦女被轉診進行陰道鏡檢查，25-34歲婦女只有在細胞學檢查異常或HPV檢查持續陽性時，才被轉診進行陰道鏡檢查，第2期時，HPV檢查組的婦女如果HPV陽性則轉診進行陰道鏡檢查，每1期都包括兩回合的篩檢，所有婦女都只有在第二回合接受細胞學檢查。
　　
　　第二回合篩檢時，細胞學檢查組偵測有18例侵犯性癌症，HPV檢查組有7例(P= .028)，全部在第二回合診斷有侵犯性癌症，但是在第一回合的細胞學檢查是正常的。
　　
　　對於35-60歲婦女，在第一回合時，在HPV組偵測CIN2或CIN3顯著高於細胞學檢查組，偵測比為2.03 (95%信心區間[CI]為1.60- 2.57)，相反地，在第二回合時，HPV組的CIN2/3相對比率顯著低於細胞學檢查組(偵測比為0.51；95% CI，0.28- 0.93)。
　　
　　整體而言，對於最初兩次篩檢回合的整體疾病偵測率，HPV組和細胞學檢查組之間的比為1.66 (95% CI，1.34- 2.06)，對於偵測CIN2和CIN3的結果相似。
　　
　　25-34歲婦女中，研究者觀察發現，在兩次招募期中，HPV檢查對於CIN3的相對偵測有顯著差異。第1期中，第一回合和第二回合時，兩組之間的偵測比都接近 1 ，第2期中，第一回合時，HPVY組的CIN3偵測顯著高於細胞學檢查組，但是在第二回合時較低。
　　
　　第2期中，HPV相較於細胞學檢查，兩次篩檢回合的整體CIN3偵測比為2.14 (95% CI，1.28- 3.59) ，至於CIN2，彙整兩期資料時，HPV相較於細胞學檢查，第一回合偵測比為4.09 (95% CI，2.24- 7.48)，第二回合為0.64 (95% CI，0.23- 1.27)。
　　
　　【顯示有效 需要研究確認最佳策略】
　　國家癌症研究中心的Philip E. Castle博士與Hormuzd A. Katki博士在編輯評論中寫道，HPV檢查有潛力「改革」子宮頸癌篩檢，不過，仍有改善空間，例如減少預防性治療手術、改善低侵犯性之有疑慮的疾病處置。
　　
　　他們寫道，我們呼籲，臨床處置應根據婦女個人的子宮頸癌風險，而不是複雜的演算，可使用目前的研究資料來發展風險評估，以實現更有效、更具成本效益的子宮頸癌預防。
　　
　　Ronco醫師表示同意，他表示，我們正在進行一個完整的成本效益分析，顯然地，延長篩檢間隔將有助於降低整體成本，還有診斷檢查與治療時的經濟與人力成本。
　　
　　Ronco醫師指出，HPV婦女的適當處置是重要的，顯然，這些婦女不能直接轉診進行陰道鏡檢查，不過，需要繼續研究以獲得最適當的篩檢計畫，我認為，在這個領域很快就會有後續的改善。
　　
　　歐盟；義大利衛生部；Piemonte, Tuscany, Venetoand Emilia-Romagna等地健康當局；Lazio 公共衛生局等資助本研究。Ronco醫師報告偶爾擔任Gen-Probe的顧問。共同作者之一、英國倫敦瑪莉皇后大學的Jack Cuzick博士報告偶爾擔任Qiagen、Roche、Gen-Probe以及Abbot的顧問，另一位共同作者、義大利佛羅倫斯癌症研究與預防研究中心的Francesca Carozzi博士報告偶爾擔任Gen-Probe、Abbott、Sanofi以及GlaxoSmithKline的顧問。編輯們接宣告沒有相關財務關係。
　　
　　Lancet Oncol. 線上發表於2010年1月19日。


HPV Testing More Effective Than Cytology in Preventing Cervical Cancer in Women Over 35

By Roxanne Nelson
Medscape Medical News

January 21, 2010 — For women 35 years of age or older, human papillomavirus (HPV)-based screening is more effective in detecting high-grade lesions and preventing invasive cervical cancer than cytology. However, this screening modality is less effective in younger women because it can lead to overdiagnosis of cervical intraepithelial neoplasia (CIN), which is likely to regress on its own.

In a study published online January?19 in the Lancet Oncology, the researchers conclude that for women older than 35 years, HPV testing should replace cytology in routine screening.

An accompanying editorial notes that HPV testing "shows a great deal of promise to revolutionize cervical cancer screening, especially in developing countries."

In the first part of the trial, a similar number of invasive cancers were detected in the group screened with cytology (n?= 9) and that screened with HPV testing (n?= 7). But in the second round of screening, there were no invasive cancers detected in the HPV group and 9 in the cytology group, suggesting that HPV-based screening is more effective in preventing progression to cancer because of earlier detection of clinically relevant lesions and treatment of precancers.

I think that there is sufficient evidence to shift to stand-alone HPV testing.

"I think that there is sufficient evidence to shift to stand-alone HPV testing," said lead author Guglielmo Ronco, MD, from the Centro per la Prevenzione Oncologica in Turin, Italy. "Cytology should be used only to triage HPV-positive women."

In countries that have population-based screening programs, plausible pilot programs are advisable for making the transition, he told Medscape Oncology. This will help to assess costs and quality assurance and to determine the best method of communicating with women.

"In addition," explained Dr. Ronco, "there is a need for training professionals; the application of appropriate assessment protocols of HPV-positive women is crucial."

Extended Screening Intervals and No Changes for Younger Women

Dr. Ronco does not recommend any changes in the screening paradigm for younger women. "For the moment, they should continue with Pap [tests]," he said. "In the future, research on biomarkers could allow us to identify which CIN2 cases have the potential to progress, so as to avoid overtreatment."

"However," he added, "that is not possible at the moment."

The researchers also conclude that intervals between screenings can be extended with HPV testing, but more follow-up is needed to define how long screening intervals can be safely extended. "In my view, there is already evidence to say that 5-year intervals are safe," said Dr. Ronco.

HPV testing is more sensitive but less specific than cytology for detecting high-grade CIN. As previously reported by Medscape Oncology, when HPV DNA testing is used as a primary screening strategy, followed by cytological triage and repeat screening for persistent HPV type-specific infection, the accuracy of cervical cancer screening could be increased.

HPV testing might also be the most effective method of cervical cancer screening in low-resource settings, where it has been shown to significantly reduce the incidence of invasive cervical cancer (N Engl J Med. 2009;360:1385-1394).

Improved Detection With HPV Test

In the current study, Dr. Ronco and colleagues assessed the efficacy of different HPV-based screening policies and the most appropriate age of application. Their large phase?3 randomized trial consisted of 2 rounds of screening for each of 2 separate recruitment phases. The primary end point was the detection of CIN2/3 and invasive cervical cancers during the first and second screening rounds.

For both trial phases, 47,001 women were randomly assigned to cytology and 47,369 to HPV testing. Of this group, 33,851 women from the cytology group and 32,998 from the HPV-testing group participated in a second round of screening.

During the first phase, HPV-positive women 35 to 60 years old were referred to colposcopy, whereas those 25 to 34 years old were referred to colposcopy only if cytology was abnormal or HPV testing was persistently positive. In the second phase, participants in the HPV group were referred for colposcopy if the HPV test was positive. Each phase consisted of 2 rounds of screening, and all women underwent cytology testing only in the second round.

In the 2 rounds of screening, 18 invasive cancers were detected in the cytology group and 7 were detected in the HPV group (P?= .028). All participants who were subsequently diagnosed with invasive carcinoma in the second round had normal cytology in the first round.

For women 35 to 60 years of age, the detection of CIN2 or CIN3 was significantly higher in the HPV group than in the cytology group, with a detection ratio of 2.03 (95% confidence interval [CI], 1.60?- 2.57), during the first screening round. Conversely, in the second round, the relative detection ratio for CIN2/3 was significantly lower in the HPV group than in the cytology group (detection ratio, 0.51; 95% CI, 0.28?- 0.93).

Overall, the ratio between the HPV group and the cytology group was 1.66 (95% CI, 1.34?- 2.06) for the total detection of disease during the first 2 screening rounds, and results were similar for the detection of CIN2 and CIN3.

Among women 25 to 34 years of age, the researchers observed a significant difference between the 2 recruitment phases in the relative detection of CIN3 with HPV testing. In phase?1, the detection ratio between groups was close to 1 during both the first and the second rounds. In the second phase, the detection of CIN3 was much higher in the HPV group than in the cytology group during the first screening round, and lower in the second round.

In phase 2, the total detection ratio of CIN3 for both screening rounds was 2.14 (95% CI, 1.28?- 3.59) for HPV vs cytology. For CIN2, when both phases were pooled, the detection ratio was 4.09 (95% CI, 2.24?- 7.48) for HPV vs cytology in round?1, and 0.64 (95% CI, 0.23?- 1.27) in round?2.

Shows Promise, Research Needed to Optimize Strategy

In an accompanying editorial, Philip E. Castle, PhD, MPH, and Hormuzd A. Katki, PhD, both from the National Cancer Institute in Bethesda, Maryland, write that HPV testing has the potential to "revolutionize" cervical cancer screening. However, there is still room for improvement, they add, by reducing the number of prophylactic treatment procedures and improving the management of equivocal disease of low invasive potential.

"We advocate that clinical management be based on estimating a woman's individual risk of cervical precancer, rather than complex algorithms," they write. "Data from the current study could be used to develop risk estimates to make the promise of more effective and cost-effective cervical cancer prevention a reality."

Dr. Ronco agrees. "We are conducting a full cost-effectiveness analysis and, clearly, prolonged screening intervals will contribute to reducing the overall costs," he said. "Another point is the economic and human cost of diagnostic work-up and treatment."

"Appropriate management of HPV-positive women is crucial and, clearly, these women should not be directly referred to colposcopy," Dr. Ronco added. "Nevertheless, there is a need for research in order to optimize screening, and I expect substantial improvements in this field in the near future."

The study was funded by the European Union; the Italian Ministry of Health; the Regional Health Administrations of Piemonte, Tuscany, Veneto, and Emilia-Romagna; and the Public Health Agency of Lazio. Dr. Ronco reports being an occasional adviser to Gen-Probe. One of his coauthors, Jack Cuzick, PhD, from Queen Mary University in London, United Kingdom, reports being an occasional adviser to Qiagen, Roche, Gen-Probe, and Abbot, another coauthor, Francesca Carozzi, PhD, from the Institute for Cancer Study and Prevention in Florence, Italy, reports being an occasional adviser to Gen-Probe, Abbott, Sanofi, and GlaxoSmithKline. The editorialists have disclosed no relevant financial relationships.

Lancet Oncol. Published online January?19, 2010.