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

这次内容实在太长太多，所以只能一段一段翻译，有兴趣者大家认领。

 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]

该项研究资料的其它方面也支持了这个假说，即偏倚被引入到那些已进展为宫颈癌病人接受治疗的研究小组中。例如，HPV组中HPV检测阴性组临床检查处的宫颈癌病人死亡率为0%，而细胞学组中细胞学阴性组中临床检出的宫颈癌病人死亡率为40.9%（表3）。但是值得注意的是，尽管HPV组中死亡率为0%，但事实是62.5%HPV检测阴性的宫颈癌是处于“进展期”（II期及以上）。在阳性筛查结果的病人中，相似的意外结果差异也非常明显【表1】。 即使在该2组筛查中宫颈癌的数量本质上是相同的（HPV87例，细胞学88例），但筛查检出的IA期癌在细胞学组（58）高于HPV组（45）。而预后不好的II期及以上的癌在细胞学组的检出数为10例，低于HPV组（14例）。虽然从表3中可看出HPV检测具有较高的阴性预测值，但HPV组宫颈癌死亡人数比较高分期预后的细胞学组出乎意料地低1/3。2005年出版的文章指出：“那些怀疑为浸润性癌的女性被推荐到NDMCH肿瘤外科进行检查和手术及放疗。”该研究也指出：“干扰组中大多数浸润性癌最常见的治疗方法是根治性子宫切除术和放疗。”在检测组中有关癌症治疗的相似性或差异性的程度没有资料报道。HPV组这种意想不到的较好治疗后果的偏倚，其结果是导致该研究得出了HPV筛查（而不是其它因素）可优先防止宫颈癌死亡的结论。这篇NEJM论文的作者也承认“研究者和受试者都知道该研究的实验分组。”

 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.

To the Editor: Sankaranarayanan et al. found that a single DNA screening test for cervical-cancer–related HPV strains can be cost-effective in a resource-limited setting. An additional strat­egy could stretch a public health budget even fur-

ther, increasing the number of early cancers de­tected by extending screening to more women. In 1943, Dorfman¹ proposed a clever pooling ap­proach for screening military recruits for syphi­lis. His idea was that if the available assay per­forms well under a dilution of 1:k, then one can assay pools of specimens, each based on k per­sons, testing only individual specimens if their pool tested positive. To screen N persons in a population with a low prevalence, α, the number of assays one would need to conduct, on average, would be only

ther, increasing the number of early cancers de­tected by extending screening to more women. In 1943, Dorfman¹ proposed a clever pooling ap­proach for screening military recruits for syphi­lis. His idea was that if the available assay per­forms well under a dilution of 1:k, then one can assay pools of specimens, each based on k per­sons, testing only individual specimens if their pool tested positive. To screen N persons in a population with a low prevalence, α, the number of assays one would need to conduct, on average, would be only

1

N× _[κ+1−(1−α)κ_].

In the study by Sankaranarayanan et al., α was approximately 0.10. Suppose an assay tolerates a dilution of 1:3 and the budget permits N assays. Pooling in groups of three would require (0.6)N assays, and the number of women who could be screened would be (1/0.6)N, or 1.67N. Further gains would accrue if women who presented for screening could be grouped according to risk, with individual-level assays reserved for high-risk women and pooling used for lower-risk women.

Clarice R. Weinberg, Ph.D.

National Institute of Environmental Health Sciences Research Triangle Park, NC 27709

1. Dorfman R. The detection of defective members of large populations. Ann Math Stat 1943;14:436-40.

The Authors Reply: Suba et al., Ankit et al., and Cremer et al. call for more explanation regarding the lack of significant reductions in mortality from cervical cancer during the 8-year follow-up period after VIA screening or cytologic testing in our study. Although interstudy differences are not new, the discrepant results after VIA screen­ing in the two randomized trials in India¹ have caused concern, especially in some countries that are beginning to implement VIA-based screen-and-treat programs.

The above possibilities may account for the apparent lack of effectiveness of VIA and cyto­logic screening at this time. However, since we plan to continue the follow-up of the study groups for cervical-cancer incidence and mortal­ity for several years, we will clarify the long-term effects of the interventions, including any delayed reductions in mortality in the cytologic-testing and VIA groups.

In reply to Mwanahamuntu et al. and Wein­berg: approaches to the screening of women older than 30 years of age that involve using fewer rounds of screening with a highly sensitive test and targeting early diagnosis among women who are positive for high-risk HPV types are al­ready good strategies to maximize the utiliza­tion of public health budgets. We hope that HPV testing will become affordable in all settings in the near future.

Rengaswamy Sankaranarayanan, M.D.

International Agency for Research on Cancer 69372 Lyon CEDEX 08, France sankar@iarc.fr

Kasturi Jayant, M.Sc.

Nargis Dutt Memorial Cancer Hospital Barshi 413 401, India

Surendra S. Shastri, M.D.

Tata Memorial Center Mumbai 400 012, India

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.

科学就是要这样的认真态度。

We analized the India paper with very detailed  study of their data and background. Our comment paper is very long. There is limitation of word number for the letter to editor in NEJM. This is why we sent our comment paper to CytoJournal as a View Point. Our comment was just available online yesterday. We are waiting for the correspondence from Dr. Rengaswamy Sankaranarayanan,the author for the india trial paper.

By the way CytoJournal is the only one free online journal for cytology. Dr. DeMay is the Editors-in chief. Every one can get in to read the papers for free. You also can submit your studis for publication.

http://www.cytojournal.com/

 Ok. I spend more than one hour to paste these information here. Just hope more our Chinese physicians, researchers know some hot issues in the world.

Mao is right: class struggle is present every where. Ha, ha, just kidding.

Test group biases and ethical concerns mar New England Journal of Medicine articles promoting HPV screening for cervical cancer in rural India
R Marshall Austin, Chengquan Zhao
 Department of Pathology, Magee-Womens Hospital of University of Pittsburgh Medical Center, 300 Halket Street, Pittsburgh, PA 15213, USA

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)(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.

印度乡村宫颈癌HPV筛查的论文发表于《新英格兰医学杂志》（2009 Apr 2;360(14):1385-94.）。该杂志是全世界医学杂志中最著名的杂志之一。

发表于该杂志的这篇文章得出的结论是：在医疗资源欠发达地区，单一的HPV检测可明显减少进展期宫颈癌及其死亡率。而且，这篇论文的摘要指出：“与对照组比较，细胞学检查或醋酸检查没有明显减少宫颈癌的发生及其死亡率。”

换句话说，印度的这个临床实验证实了HPV检测能减少宫颈癌及其死亡率，但与未进行任何检测一样（对照组），宫颈涂片和醋酸实验却不能减低宫颈癌相关的死亡。

这些作者对统计数字进行了人为控制，使得结果成为他们所希望的。

为什么？这是因为有企业参与了这项临床实验。这正是这些人所希望的。

这里我贴出了原始摘要，也贴出了我和Austin博士写给编辑部的评论。