Helen Leask
April 19, 2022
A cell phone rings in a red-brick bungalow in a village in India. A woman on the other end of the phone tells Ms. SK, a community health worker, that menstruation has started. Ms. SK guns her scooter through the dusty streets for 15 minutes in 30 °C (86 °F) heat.
A 32-year-old woman, waiting in the shade of a blue corrugated-iron roof, hands over a green polythene bag. Ms. SK whisks the package to the local health center and tucks it into a -20° freezer. The following week, it will ride in dry ice to the National Institute for Research in Reproductive and Child Health Laboratory in Mumbai for human papillomavirus (HPV) testing.
The two women are participants in the world’s first community-based validation trial of cervical screening using menstrual pads.
This moment in rural India at first glance appears to have little relevance to wealthy countries such as the United States.
However, public health officials in both countries are trying to solve the same problem: how to prevent unnecessary deaths from cervical cancer by reaching women who have never or rarely been screened.
The United States has more in common with India than it may care to admit.
“In the US, we still have pockets of disparities that actually have incidence rates [of cervical cancer] comparable to many low and middle-income countries,” said Vikrant Sahasrabuddhe, MBBS, DrPh, MPH, of the National Cancer Institute, where he heads up the HPV and Cervical Cancer Prevention Clinical Research Program for the NIH.
A woman in India hands over a polythene bag containing a menstrual pad. To screen for cervical cancer, the blood on the pad will be tested for human papillomavirus (HPV).
The incidence of cervical cancer in India is approximately 19 per 100,000 women. For the past 15 years incidence in the United States has stalled at approximately 7 per 100,000.
In India, there are no organized screening programs and most cervical cancer is regional or distant metastatic at diagnosis.
In the United States, 52% of new cases are advanced, and half of these are among women who have never or rarely been screened.
“There is a critical need for new strategies to reach this population,” Sahasrabuddhe said. “We absolutely have to do something out-of-the-box creatively.”
Almost all cervical cancers are triggered by HPV, most commonly high-risk HPV16 and HPV18, although there are more than 200 types. HPV testing is taking over from cytology (Papanicolaou test) for secondary prevention of cervical cancer.
The trial of screening for HPV in menstrual pads that is ongoing in India was the brainchild of Atul Budhuk, PhD, a government public-health researcher and professor at the Centre for Cancer Epidemiology, Tata Memorial Centre, in Mumbai.
Budhuk’s eyes were opened to the scale of the problem when he participated in a cluster-randomized trial funded by the Bill and Melinda Gates Foundation. The study, published in 2009 in the New England Journal of Medicine, involved 131,746 rural women in the Osmanabad district of India.
A team of researchers from India and France compared outcomes for women over 8 years after cervical screening by HPV, cytology, or visual inspection with acetic acid (VIA). The control group was “usual care,” where women were advised how to seek screening at local hospitals. Women who screened positive were referred for colposcopy, biopsy, and treatment.
Over the 8-year follow-up, advanced cervical cancer was found in twice as many women left to their own devices compared with women who had HPV testing during the study (82 vs 39; hazard ratio [HR] for HPV, 0.47, 95% CI, 0.32 – 0.69).
Similarly, cervical cancer deaths in the control group were nearly two times higher than among the women who were screened for HPV in the study (64 vs 34; HR for HPV 0.52, 95% CI, 0.33 – 0.83).
The study proved that rural Indian women were dying unnecessarily because they weren’t seeking cervical screening. And education wasn’t the problem.
“When we go and educate [a rural woman] about…risk factors and the need to undergo screening, she understands it very well,” said Budhuk. “She is ready to come but her priority is her bread and butter — she will lose her daily wages.”
Budhuk and his team negotiated with local employers so that women could come to screening clinics, but they soon realized this wasn’t scalable.
One year after the NEJM publication, Budhuk found what he was looking for.
A team of Hong Kong clinicians, headed by Sze Chuen Cesar Wong of the Hong Kong Cancer Institute, published a paper in 2010 in the Journal of Clinical Microbiology showing that menstrual pads provide reliable HPV results in women with and without cervical disease.
The Hong Kong team tested sanitary napkins for HPV from 235 of their patients with cervical intraepithelial neoplasia (CIN) or condyloma acuminatum (CAC) before and after treatment. Samples were compared to those from 323 women without cervical disease. Wong’s team found that for HPV in sanitary napkins the sensitivity was 82.8%, specificity was 93.1%, and positive and negative predictive values were 90% and 87.9%, respectively.
The authors pointed out that menstrual pad testing was the only truly noninvasive approach to HPV screening vs the other self-sampling methods such as tampons and cytobrushes. Also, these self-sampling tests require specialized liquid-based transport media. A menstrual pad needs only a plastic bag.
Budhuk had his at-home solution for the hard-working rural women of India.
With funding from the Indian government, Budhuk’s team put together a validation trial that ran from 2013–2016 in 18 rural villages in two separate districts: Ahmednagar and Pune.
Local health workers went house to house to recruit women and get family buy-in for this culturally delicate project. Participants were instructed to use their regular sanitary protection — most commonly a washable cloth — and told to call the health worker on the first day of menstruation. Health workers gave each woman a Ziploc bag for the pad and, for privacy, an outer polythene sac.
In Ahmednagar, all women who provided their pad also got screened with Hybrid Capture 2 (HC2; Qiagen) by a mobile screening unit. In Pune, only the positive cases underwent HC2. Screening was also extended to anyone who requested it, but these people were not included in the final analysis.
Genomic DNA was extracted from three 5 mm-sized punches in the pad using a commercial kit, QIAamp DNA Micro, and the quality and purity of the DNA checked by Implen NanoPhotometer.
The team followed the same protocol for PCR HPV assay as Wong’s team from Hong Kong.
The results were published in the European Journal of Cancer Prevention in 2018.
The concordance rate for a positive result between the menstrual pad sample and conventional HPV sampling was 98.8% for Ahmednagar and 95.2% for samples from Pune. The sensitivity for the first study was 83% and the specificity 99% — similar to that for the women in Hong Kong. The second study had lower sensitivity and specificity (67% and 88%), partly because of poor storage as a result of frequent power cuts.
The total cost per woman was $30.78.
“I was very excited when we saw the results,” Budhuk recalled. “That day I couldn’t sleep….such a wonderful result! I was excited to start the next phase immediately.”
Budhuk has applied to the Indian government for funding for a larger trial involving 3000 women. If successful, he hopes such evidence would be sufficient to convince the Indian government to make menstrual pad screening standard procedure for the 390 million women who live in India’s countryside.
Testing never-screened women for cervical cancer using menstrual pads appears to be relatively reliable, convenient, private, noninvasive, and incredibly cheap.
So who else has tried it?
The first published account of HPV in menstrual blood was a 2003 study by Tommy Tong and colleagues at the Princess Margaret Hospital in Hong Kong. The authors heralded, with lamentable optimism, “a new paradigm in cervical cancer screening.”
In the following 20 years, just six more studies appeared: two from Budukh’s field trial in India and four from hospital-based pilot studies in Hong Kong (in 2010 and 2018), South Korea (in 2016), and mainland China (in 2021). All these studies, although small, were published in top-flight journals and demonstrate high concordance between conventional high-risk HPV testing and menstrual-blood tests.
Medscape Medical News tried to find a US physician expert who had heard of the approach.
Elizabeth Fontham, MPH, DrPh, is the founding dean of the Louisiana State University Health Center New Orleans School of Public Health and president of the American Cancer Society. Fontham said in an email that she had “no plans to evaluate the impact related to menstrual pads, but perhaps others have looked into that.”
Joy Melnikow, MD, MPH, was first author on the evidence synthesis driving the current cervical-cancer screening recommendations from the US Preventive Services Task Force (USPSTF). When asked about menstrual pad testing for HPV, she said she had “not heard of it before.”
The USPSTF guidelines don’t mention sanitary pads but acknowledge that “self-collection may be one strategy for increasing screening rates among populations where they are currently low.”
The USPSTF methodology excludes data from countries that don’t match the United States on the Human Development Index “or [are] not applicable to US clinical settings or populations.” (Presumably, data from Hong Kong and South Korea would qualify; Indian data would not.)
Sahasrabuddhe of the NCI hadn’t heard of menstrual pad testing either, but he has a different explanation for lack of interest in this approach — or, indeed, any form of self-sampling for cervical cancer screening — in the United States.
“We have not seen movement happen in this space for years…If there is one intervention that we can simplify, that still has not been made widely available, it is self-sampling…[but] we don’t have FDA approval for it,” Sahasrabuddhe said.
“Our system, at least in the US, is based on industry manufacturers seeking an approval for a particular way of collection and then clinicians and clinical-guideline bodies signing on…For a lot of reasons industry has shied away over the past several years, so far, at least, on seeking approval for self-sampling-based approaches,” he commented.
Sahasrabuddhe aims to change that. He heads up a new NCI-led initiative called “The Last Mile,” a nationwide clinical trial supported by federal agencies, industry partners, and professional societies. The goal is to validate self-sampled HPV testing as non-inferior to specimens collected by providers. The team is currently finalizing the methodology of the study, so Sahasrabuddhe could not share the self-sampling methods that will be on trial, nor the industry partners who have signed up.
The following tests are approved in the United States for physician-collected HPV screening:
- Hybrid Capture 2, used in the Indian studies (Qiagen)
- cobas HPV (Roche)
- Aptima (Hologic)
- Cervista (Hologic)
- Onclarity (Becton Dickinson)
Sahasrabuddhe said that, while a sanitary pad in a Ziploc bag is unlikely to make the grade for The Last Mile study, he doesn’t totally dismiss their potential and said the NCI is always open to new ideas.
“We are not supporting anybody specifically for menstrual pad-based collection device development,” Sahasrabuddhe said, “But if they fulfill other criteria for a small business-based grant application, they absolutely are welcome to apply for NCI funding for this.”
Said Melnikow: “Pre-COVID, the head of WHO said that we could eliminate cervical cancer from the Globe and that we have the tools to do that now. And he’s right.”
Budukh, Melnikow, and Sahasrabuddhe have disclosed no relevant financial relationships.
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