The paper HPV screening for cervical cancer in rural India published in N Engl J Med.(one of the most important journal of medicine in the world) 2009 Apr 2;360(14):1385-94.

The conclusion of the paper: In a low resource setting, a single round of HPV testing was associated with a significant reduction in the numbers of advanced cancers or deaths from cervical cancer.Furthermore, the study abstract asserted, "No significant reductions in the numbers of associated deaths were observed in the cytology testing group or in the VIA group, as compared with the control group".

In other words, this clinical trial in India demostrate HPV testing can reduce the rate of cervical cancer and its related death, but Pap cytology and VIA have no reduction of cervical cancer related death, same as no any test group (control).

The authors manupulated the statistical numbers and made the results they hope to have.

Why? Industry-company involved the clinical trials. Interests are what people are looking for.

I pasted the original abstract here and also Dr. Austin and I wrote the editorial commentary.

Test group biases and ethical concerns mar New England Journal of Medicine articles promoting HPV screening for cervical cancer in rural India

新英格兰医学杂志发表的文章中在印度农村地区进行HPV筛查宫颈癌的试验组的偏见和伦理问题

R Marshall Austin, Chengquan Zhao
 Department of Pathology, Magee-Womens Hospital of University of Pittsburgh Medical Center, 300 Halket Street, Pittsburgh, PA 15213, USA

Correspondence Address:
R Marshall Austin
Department of Pathology, Magee-Womens Hospital of University of Pittsburgh Medical Center, 300 Halket Street, Pittsburgh, PA 15213
USA

©

The study conclusions, released from prepublication embargo by the New England Journal of Medicine (NEJM) at 5:00 PM on April 1, 2009, were dramatic. "In a low resource setting, a single round of HPV testing was associated with a significant reduction in the numbers of advanced cancers or deaths from cervical cancer." Furthermore, the study abstract asserted, "No significant reductions in the numbers of associated deaths were observed in the cytology testing group or in the VIA group, as compared with the control group." ^[1]

至2009年4月1日下午5:00点，这项研究的结论被新英格兰医学杂志（NEJM）从预发表的禁止期到发表，是戏剧性的。“在低资源环境中，一个单轮的HPV检测在减少晚期宫颈癌和死亡的宫颈癌人数有显著的相关性。”此外，研究摘要断言：“与对照组比较细胞学检测组或VIA（直视下醋酸检查）组在晚期癌症或死亡病例的数据同对照组比较没有显著的减少”.
Simultaneously, at 5:00 PM on April 1, 2009, a press release from Qiagen, a Netherlands Holding Company and a manufacturer of the digene HPV test, stated: "Landmark study in New England Journal of Medicine shows HPV testing significantly reduces deaths from cervical cancer, compared to other methods including Pap." ^[2] It is now known that the manufacturer received pre-embargo access to contents of the article and the accompanying editorial. The NEJM customer service office confirmed on April 14 that pre-embargo release was not from the journal.

与此同时，在2009年4月1日下午5:00点，一个由荷兰控股公司和digene病毒检测的制造商Qiagen公司发了一份新闻稿指出： “在新英格兰医学杂志发表具有划时代意义的研究表明HPV检测能显著降低宫颈癌的死亡率，相对于包括巴氏在内的其他方法。”现在已经知道，制造商在预发表禁止期内获得了文章的内容和社论。新英格兰医学杂志客户服务办公室证实说：在4月14日之前是预发表禁止期而不是从杂志上获得。
A close look at the NEJM paper suggests that unexpected biases might have occurred in some of the test group arms of the study which sought to compare a single round of cervical cancer screening with HPV testing, cytology, and visual inspection with acetic acid (VIA) among over 131,746 "healthy women between the ages of 30 and 59 years" in rural India. In fact, the study acknowledged that the positive predictive value (PPV) for detecting CIN 2 - 3 was 19.3% in the cytologic testing group, higher than 11.3% in the HPV testing group, and study results indicate that essentially the same numbers of cervical cancers were detected after positive screening test results in the cytology arm (88) as in the HPV arm (87). Cervical cancer detection rates were 0.344% in the cytologic testing group and 0.321% in the HPV testing group [Table 1]. Among cervical cancers detected after a positive screening test, more cervical cancers were detected in the earliest and most favorable Stage (IA) in the cytology arm (58/88, 65.9%) than in the HPV arm (45/87, 51.7%), and there were fewer advanced (Stage II+) screening-detected cervical cancers in the cytology arm (10/88, 11.4%) than in the HPV arm (14/87, 16.1%) [Table 1]. The preliminary 2005 publication of study data had earlier reported that cytology had a higher detection rate for CIN 2 - 3 (1.0%) than for HPV testing (0.7%) and observed the following: "Our present findings indicate that the detection rates of HPV testing did not show any improvement over cytology. Furthermore, the currently available test (HC2) is expensive and requires a relatively sophisticated laboratory operation." ^[3] Only the individuals performing HPV testing are specifically described in the 2005 report as having been trained "intensively." What new information then led to the quite different study conclusions reported in the 2009 publication and the simultaneous manufacturer's press release?
仔细观察了新英格兰医学杂志的该文章表明：意想不到的偏见发生在一些试验组中，该研究试图比较在印度农村地区“30岁到59岁之间的健康妇女”超过131746人群中，用单一轮的HPV检测进行宫颈癌筛查、细胞学筛查和直视下醋酸（VIA）筛查。事实上，这项研究获取诊断CIN2-3的阳性预测值（ PPV ）：细胞学筛查组为19.3 ％，高于HPV筛查组的11.3 ％。研究结果表明：阳性的筛查结果在细胞学筛查组（88例）与HPV筛查组（87例）基本上是相同的宫颈癌检出。宫颈癌检出率细胞学筛查组为0.344 ％ ，而HPV筛查组为0.321% [表1 ] 。在筛查阳性之后的子宫颈癌诊断中，更多更早期和更有意义阶段（IA期）的宫颈癌在细胞学筛查组（58/88， 65.9 ％）比HPV筛查组（45 /87，51.7 ％），而更少的晚期（Stage II+）癌，细胞学筛查组（ 10/88 ，11.4 ％）比HPV筛查组（ 14/87 ， 16.1 ％ ） [表1 ] 。 2005年公布的初步研究数据报告：细胞学有较高的检出率在CIN2-3（1.0％）相比HPV检测（0.7％），并注意到了以下内容：“我们目前的研究结果显示，HPV的检出率没有出现任何改善细胞学检测。此外，现有的测试（ HC2 ）非常昂贵，而且需要一个相对先进的实验室作业”[ 3 ]。在2005年的报告中指出只有专门被“密集”训练有素的人才能进行HPV检测”。有什么新信息导致了完全不同的研究结论在2009年并同时与生产商的新闻稿发表呢？
The 2009 publication employed the well-recognized "intention-to-treat-principle" in which all eligible patients assigned to a study arm are included in the final analyses for each study arm, whether or not the patients adhere to the research protocol management strategy. ^[4] Therefore, the final study analyses included in each arm cervical cancer patients who had not been screened, 32 in the HPV arm and 42 in the cytology arm [Table 2]. Since there were 10 more unscreened cancer patients and 5 more cervical cancer deaths in the cytology arm than in the HPV arm and since these unscreened cancer patients predictably had higher rates of cervical cancer, more advanced stages, and less favorable outcomes, the net effect of the inclusion of the larger number of unscreened cervical cancer patients in the cytology arm was to make the cytology arm appear more like the unscreened control arm of the study. Of 54 cervical cancer-related deaths in the cytology cohort, 27 deaths were in the "assigned but not screened" group and another 18 deaths were in patients who had abnormal cytology results. For cervical cancer deaths in the HPV arm, 19% fewer deaths (22) were in the "assigned but not screened" group, and 33% fewer deaths (12) occurred in women with abnormal screening HPV test results. Given the higher PPV and specificity of cytology compared to HPV testing, the outcomes suggest that follow-up colposcopic examinations, tissue sampling procedures, and treatments were not equally effective in the two groups. Significantly inconsistent adherence to management strategies in different study arms may also introduce study bias in investigations, even in studies applying the intention-to-treat-principle. ^[4]
2009年出版采用公认的“意向处理原则”，使所有符合研究条件的患者都分配到一个研究组包括在列入最后分析的每一个研究组。不论患者是否坚持研究的意向管理[ 4 ]。因此，最终的研究分析所包含每一组的子宫颈癌患者谁没有被筛选， 在HPV组中有32例和细胞学组有42例[表2 ] 。由于多了10例未经筛查的宫颈癌患者和多了5例宫颈癌死亡患者在细胞学组比HPV组，由于这些未经筛查患者预示了较高的子宫颈癌比率、更晚期的阶段和不良的预后，其净效应的列入了大量未经筛查的宫颈癌患者在细胞学组中，使细胞学组看起来更象未经筛查的对照组。在细胞学组54例宫颈癌死亡病例中， 27例死亡是“分配但没筛查”组和另外18例死亡患者有异常的细胞学结果。子宫颈癌死亡的HPV组，死亡人数减少19 ％（22例）是在“分配但不筛查”组，死亡人数减少33 ％（12例）发生在妇女异常HPV检测结果。给出了细胞学较高的阳性预测值（PPV）和特异性比HPV检测，结果表明：后续阴道镜检查、组织活检和治疗在两组中不是等同。明显不遵守研究的管理在不同的研究组中可能引入偏见的调查研究，即使是在研究过程中运用意向处理原则。

 Continue:

Other aspects of the study data also support the hypothesis that bias was introduced in the study group arms during treatment of patients who developed cervical cancer. For example, the death rate for clinically detected cervical cancer patients in the HPV test-negative group of the HPV arm was 0% as compared to 40.9% among clinically detected cancer patients in the cytology-negative group of the cytology arm [Table 3]. Remarkably, the 0% death rate occurred in the HPV group despite the fact that 62.5% of the HPV test-negative cervical cancers were "advanced stage" (Stage II+). Among patients with positive screening results, similar unexpected outcome differences are also evident [Table 1]. Even though the numbers of cervical cancers in both screen-detected groups were essentially the same (HPV 87; cytology 88), more favorable Stage IA screen-detected cancers were detected in the cytology arm (58) than in the HPV arm (45). Also, fewer unfavorable Stage II+ cancers were screen detected in the cytology arm (10) than in the HPV arm (14). Even after acknowledging the higher negative predictive value of HPV testing reflected in [Table 3], deaths in the HPV arm were unexpectedly one-third lower (12) than in the more stage-favorable cytology arm (18). The 2005 publication ^[3] states that "Women with suspected invasive cancer were referred to the surgical oncology department of NDMCH (Nargis Dutt Memorial Cancer Hospital) for investigations and treatment with surgery and radiation." The study also notes that "The most common form of treatment for invasive carcinoma in the intervention arm was radical hysterectomy followed by radical radiotherapy." No data are reported on the extent of similarities or differences in cancer treatments between the test group arms. The effect of the bias of unexpectedly favorable treatment outcomes in the HPV arm contributes to the study conclusion that HPV screening (rather than some other factor) preferentially prevented cervical cancer deaths. The NEJM report does acknowledge that "both practitioners and subjects were aware of the study group assignments." ^[1]

其他方面的研究数据也支持这样的假设，即偏见被引入在治疗期间谁进展为宫颈癌的患者研究组中。例如：与临床诊断宫颈癌患者的死亡率在HPV检测结果是阴性组占HPV组中0％相比，临床诊断宫颈癌患者的死亡率在细胞学结果阴性组占细胞学组中40.9 ％[表3 ] 。值得注意的是，在0 ％的死亡率发生在人乳头状瘤病毒组，尽管实际上62.5 ％的HPV检测结果阴性的宫颈癌是“晚期” （Stage II+）。在患者阳性筛查结果中，类似的意外结果也有很明显的差异性[表1 ] 。尽管在这两个筛查组中获得的子宫颈癌的人数基本上是相同的（HPV87人 、细胞学88人 ） ，但是更多更早期和更有意义阶段（IA期）的宫颈癌在细胞学筛查组（58）比HPV筛查组（45），而更少的晚期（Stage II+）癌，细胞学筛查组（ 10）比HPV筛查组（14）。即使在获得较高的阴性预测值的HPV检测组反应[表3 ] ，死亡人数在HPV组（ 12 ）出意外的比更早期和更有意义阶段的细胞学组（ 18 ）低三分之一。 2005年出版[ 3 ]指出：“被怀疑浸润癌的女性转移到肿瘤外科部NDMCH （ Nargis杜特纪念肿瘤医院）进行随访、治疗、手术和放疗”。这项研究同时指出：“最常见的治疗浸润癌在干预组进行根治性子宫切除术之后，进行放射治疗”。无数据报告在试验组之间进行程度相似或不同的癌症治疗。意外的偏见性的在HPV组进行优先治疗结果的影响有助于研究结论：HPV筛查（而不是其他的一些因素）优先阻断了宫颈癌的死亡。
The NEJM publication reports that the study was supported by the Bill and Melinda Gates Foundation, through the Alliance for Cervical Cancer Prevention (ACCP). The paper also states that "no potential conflict of interest was reported." However, questions have been raised in the peer-reviewed literature as to whether or not the Gates Foundation and the ACCP might have in effect "become enamored with the promise of science and new technologies at the expense of delivering available preventives today". ^[5] Questions have also been raised about the partnership between AACP's coordinating organization and the HPV test manufacturer. ^[5-7] Similarly, the Gates Foundation was recently acknowledged as having funded a large project supporting publication of a special supplemental issue of the journal Vaccine entitled "Overview of Human Papillomavirus-Based and Other Novel Options for Cervical Cancer Screening in Developed and Developing Countries." ^[8] The HPV test manufacturer is also listed as providing corporate support, ^[8] acknowledged as "critical for meetings and travel." The two lead authors of the NEJM article and one of the NEJM editorial writers are specifically listed among the large number of international contributors. The presence of not even a single cytopathologist among the very large number of contributors supported for international travel and meetings clearly suggests an anticytology bias for the proceedings, one perhaps mirrored in the NEJM. The two selected authors of the accompanying NEJM editorial ^[9] also turn out to have co-authored no fewer than 34 PUBMED-cited publications with the former Vice President for Research and Development and Chief Scientific Officer of the HPV test manufacturer. Industry co-authorship was recently cited as the second most common conflict-of-interest in high impact journals such as NEJM. ^[10]

Although the NEJM study upon first inspection may be interpreted as applying primarily to low-resource settings where even very limited screening and diagnostic testing are difficult to support, the accompanying editorial, ^[9] press release ^[2] and media coverage all strive to suggest otherwise. According to the editorial writers, "The implications of the study in rural India are immediate and global." ^[9] According to the New York Times (NYT), the study indicates broadly that a "new DNA test outperforms the  Pap smear ^{More Details}." ^[11] Strangely absent from any of the commentary, however, has been any concern that the study included a "control" group of 31,506 "healthy women" who were allowed to largely go without any screening at all during the study, one approved by both local and international "institutional scientific and ethical committees." ^[3] Sixty-four women in the "control" group died of cervical cancer along with another 70 unscreened women "assigned to undergo screening," numbers of cervical cancer deaths substantially in excess of the number which occurred in widely criticized experiments conducted at New Zealand's Auckland National Women's Hospital in the latter half of the last century. ^[12] The deaths of so many unscreened study "control" subjects made the NYT-quoted comment by a Stanford gynecologist, "The study is another nail in the coffin for Pap smears," seem particularly insensitive and ironic. ^[11]

The unexpected increase in the presence of cervical cancer in both the unscreened cytology and VIA arms of the study was a key foundation for the authors' surprising statement that "no significant reductions in the numbers of advanced cancers or deaths were observed in the cytologic-testing group or in the VIA group, as compared with the control group." ^[1] When unscreened study cancer victims are included in the "control" group, it becomes clear that significant reductions in advanced stage cervical cancers occurred in virtually all screening group arms [Table 4]. The comparative reductions in advanced stage cervical cancer after a single round of (less expensive) conventional cytology are not significantly different from those achieved with a single round of (more expensive) HPV testing (P = 0.2655), even before taking into consideration other study biases. Furthermore, the study's cytology screeners were trained for only 3 months, one-fourth of the usual year-long training for cytotechnologists. This was almost certainly suboptimal to confront the challenging conditions in the rural Osmanabad district. Pap screening, when successfully implemented, reduces cervical cancer rates by 60 - 90% within 3 years of introduction to populations that have not been screened; these reductions in incidence and mortality are consistent and dramatic across populations. ^[5,13] Even a single round of screening with conventional cytology and limited training in rural India appears to have been remarkably effective, despite the published interpretations of study data in the NEJM. As noted by many of the same authors in their 2005 publication, "Our results clearly show that good quality cytology can be implemented even in a rural setting of a developing country with reasonable investment, while HPV testing does not give any better detection of CIN2/3 lesions, despite the higher investments." ^[3] Careful reading of the 2009 publication data and assessments of the numerous internal biases suggest that the widely reported conclusions may be significantly misleading.

 Welcome every one write your oppinion.

Our editorial comment paper is relative long. I will appreciate it if some one with good English can translate it in Chinese.

 All the following comment letters were published in NEJM.

To the Editor: Sankaranarayanan et al. (April 2 issue)¹ report no significant differences in rates of detection of high-risk cervical neoplasia among women who underwent screening by cytologic testing, testing for human papillomavirus (HPV) with the Hybrid Capture II assay, or visual in­spection of the cervix with acetic acid (VIA). Re­ductions in mortality from cervical cancer were observed only among women screened by HPV testing. The unexpected lack of a correlation be­tween detection rates reported for the screening tests and subsequent mortality rates requires care­ful consideration. Sankaranarayanan et al. ac­knowledge that unidentified differences in follow-up care, rather than differences in the performance of screening tests, account for differences in mor­tality between women screened by VIA in their current study and women screened by VIA in an earlier study.² The same logic, applied to the cur­rent data, suggests that unidentified differences in follow-up care, rather than nonsignificant dif­ferences among screening-test detection rates, account for differences in mortality among the groups of women who underwent screening. Within the political structures of many develop­ing countries, there is genuine lack of support for

cervical-cancer prevention efforts,³ which may be further eroded by the questionable conclusion that only an unaffordable screening option is better than none at all.¹

Eric J. Suba, M.D.

Kaiser Permanente Medical Center San Francisco, CA 94115 eric.suba@kp.org

Edmund S. Cibas, M.D.

Harvard Medical School Boston, MA 02115

Stephen S. Raab, M.D.

University of Colorado Health Sciences Center Aurora, CO 80045

1.        Sankaranarayanan R, Nene BM, Shastri SS, et al. HPV screen­ing for cervical cancer in rural India. N Engl J Med 2009;360: 1385-94.

2.        Sankaranarayanan R, Esmy PO, Rajkumar R, et al. Effect of visual screening on cervical cancer incidence and mortality in Tamil Nadu, India: a cluster-randomised trial. Lancet 2007;370: 398-406.

3.        Suba EJ, Murphy SK, Donnelly AD, Furia LM, Huynh ML, Raab SS. Systems analysis of real-world obstacles to successful cervical cancer prevention in developing countries. Am J Public Health 2006;96:480-7.

To the Editor: The study by the Indian Council of Medical Research showed that a down-staging effect of VIA and a reduction in the case fatality rate still hold in the Indian subcontinent.¹ The discrepancy between the authors’ earlier findings and the current findings with regard to the bene­fits of VIA calls for more explanation.²

Jain Ankit, M.D.

Kidwai Memorial Institute of Oncology Bangalore 560030, India ankitjaindm@gmail.com

Jain Prakriti, M.B., B.S., D.G.O.

Bhagwan Mahaveer Jain Hospital Bangalore 560052, India

K.C. Lakshmaiah, M.D., D.M.

Kidwai Memorial Institute of Oncology Bangalore 560030, India

To the Editor: In a previous article,¹ Sankara­narayanan et al. reported a decrease in cervical-cancer mortality with the use of VIA and the “screen and treat” approach, whereas the current article calls for multiple visits and treatment only of women with grade 2 or 3 cervical intraepithe­lial neoplasia confirmed on biopsy. In the current report, there is no discussion of this difference between the two studies.

The current data cast doubt on VIA, which is an invaluable asset to cervical-cancer prevention in developing countries. The benefit of VIA in low-resource settings is that it can be used to detect cervical precancer inexpensively and that it en­ables the examiner to institute immediate and appropriate therapy. This strategy decreases the risk that a patient with a potentially precancerous lesion will be lost to follow-up.

We strongly believe that the lack of survival benefit reported in the current article should not preclude the lifesaving results of screen-and-treat programs that have been demonstrated previ­ously.

Miriam L. Cremer, M.D., M.P.H.

Basic Health International San Salvador, El Salvador mlcremer@hotmail.com

Elizabeth Conlisk, Ph.D.

Hampshire College Amherst, MA 01002

Juan C. Felix, M.D.

University of Southern California Los Angeles, CA 90033

Dr. Felix reports receiving lecture fees from Qiagen and Ho-logic. No other potential conflict of interest relevant to this letter was reported.

1. Sankaranarayanan R, Esmy PO,  Rajkumar R, et al. Effect of visual screening on cervical cancer incidence and mortality in Tamil Nadu, India: a cluster-randomised trial. Lancet 2007;370: 398-406.