CDC video series: How to make HPV Vaccine recommendation to your patients?

CDC encourages healthcare practitioners, partner organizations, and other state programs to create awareness in the community about HPV virus, different pathologies caused by the virus and its mode of transmission. CDC also promotes adolescent’s HPV vaccination programs and provides guidance on achieving high HPV vaccination rates.

Healthcare providers are often faced with the dilemmas about initiating the conversation with parents and adolescents about HPV vaccination. This short informative video offers simple and practical guidance to have a successful conversation with parents about the vaccine.

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FDA broadens the age range of Gardasil 9 to cover individuals 27 through 45 years old

The US Food and Drugs Administration (FDA) extended the use of Merck’s cervical cancer vaccine Gardasil 9 to include men and women aged 27 through 45 years.

"Today's approval represents an important opportunity to help prevent HPV-related diseases and cancers in a broader age range," Peter Marks, MD, Ph.D., director of the FDA's Center for Biologics Evaluation and Research, says in a news release.

"The Centers for Disease Control and Prevention has stated that HPV vaccination prior to becoming infected with the HPV types covered by the vaccine has the potential to prevent more than 90% of these cancers, or 31,200 cases every year, from ever developing," Marks says.

 "The CDC has made increasing HPV vaccination rates a public health priority,” said Jacques Cholat, M.D., president, Merck Vaccines, “and today’s recommendation for GARDASIL 9 is an important milestone in the shared effort to help further reduce the burden of HPV-related cancers and diseases.”

According to CDC, every year about 14 million Americans become infected with HPV; about 12,000 women are diagnosed with, and about 4,000 women die from cervical cancer caused by certain HPV viruses. Additionally, HPV viruses are associated with several other forms of cancer affecting men and women. 

FDA first approved Gardasil in 2006, to prevent certain cancers and diseases caused by HPV Types 6, 11, 16, and 18. Gardasil is no longer available in the US. Gardasil 9 received approval in 2014 for use in girls and women 9 through 26 years of age and boys 9 through 15 years of age for the prevention of the cancers and precancerous lesions of cervix, vulva, vagina, and anus caused by HPV types 6, 11, 16, 18, 31, 33, 45, 52, and 58.

The approval is based on results of a study involving 3,200 women, aged 27 through 45 years, followed for an average of 3.5 years, Gardasil was 88 percent effective in the prevention of a combined endpoint of persistent infection, genital warts, vulvar and vaginal precancerous lesions, cervical precancerous lesions, and cervical cancer related to HPV types covered by the vaccine.

"The FDA’s approval of Gardasil 9 in women 27 through 45 years of age is based on these results and new data on long-term follow-up from this study," the FDA said.

Similarly, in men aged 27 through 45 years of age, vaccine effectiveness was inferred based on data described above in women, along with efficacy data of Gardasil 9 in younger men aged 16 through 25 years, and immunogenicity data from a clinical trial in which 150 men, 27 through 45 years of age, received a 3-dose regimen of Gardasil over 6 months.

In all the safety and efficacy of Gardasil 9 was evaluated in a total of 13,000 males and females, the most commonly reported side effect being injection site pain, swelling, redness, and headaches.

The FDA granted the Gardasil 9 application priority review status. This program facilitates and expedites the review of medical products that address a serious or life-threatening condition.

Important Information about GARDASIL 9 (Human Papillomavirus 9-Valent Vaccine, Recombinant)

GARDASIL 9 does not eliminate the necessity for women to continue to undergo recommended cervical cancer screening.

Recipients of GARDASIL 9 should not discontinue anal cancer screening if it has been recommended by a health care provider.

GARDASIL 9 has not been demonstrated to protect against disease from vaccine HPV types to which a person has previously been exposed through sexual activity.

GARDASIL 9 has not been demonstrated to protect against diseases due to HPV types other than 6, 11, 16, 18, 31, 33, 45, 52, and 58.

GARDASIL 9 is not a treatment for external genital lesions; cervical, vulvar, vaginal, and anal cancers; or cervical intraepithelial neoplasia (CIN), vulvar intraepithelial neoplasia (VIN), vaginal intraepithelial neoplasia (VaIN), or anal intraepithelial neoplasia (AIN).

Not all vulvar, vaginal, and anal cancers are caused by HPV, and GARDASIL 9 protects only against those vulvar, vaginal, and anal cancers caused by HPV 16, 18, 31, 33, 45, 52 and 58.

Vaccination with GARDASIL 9 may not result in protection in all vaccine recipients.

FDA press release

Merck news release

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KEYTRUDA gains FDA approval for treatment of recurrent or metastatic cervical cancer

The U.S. Food and Drug Administration (FDA) has approved Merck’s pembrolizumab (KEYTRUDA®), for the treatment of patients with recurrent or metastatic cervical cancer whose disease had worsened on or after chemotherapy and whose tumors express programmed cell death ligand 1 (PD-L1), as determined by an FDA approved test.

The US FDA has approved the Dako PD-L1 IHC 22C3 pharmDx assay for expanded use as a companion diagnostic test for Keytruda for cervical cancer.

The approval comes in way ahead of the previously decided date of June 28. Furthermore, the drug is approved under the FDA’s accelerated approval regulations based on tumor response rate and durability of response.

Continued approval in future will be based upon verification and description of clinical benefit in the ongoing trials ahead.

The accelerated approval was based on results of ongoing KEYNOTE-158, a multi-center, non-randomized, open-label, multi-cohort trial (NCT02628067). The trial enrolled patients with multiple types of advanced solid tumor, who have not responded to usual chemotherapy or are intolerant to it.

Patients with autoimmune diseases or requiring immunosuppression were excluded from the trial.

The patients received KEYTRUDA intravenously at a dose of 200 mg every three weeks until unacceptable toxicity or documented disease progression or for 24 months in patients without disease progression.

Among the 98 patients with advanced cervical cancer, 77 (79%) had tumors that expressed PD-L1 with a Combined Positive Score (CPS) ≥1 and have received at least one line of chemotherapy in the metastatic setting.

The objective response rate in these 77 patients was 14.3 percent, with a complete response in 2 patients (2.6%) and partial response in 9 patients (11.7%).

Ninety-one percent of patients experienced duration of response exceeding 6 months or longer. Eight patients discontinued the drug because of serious side effects like anemia, fistula, hemorrhage, and infection.

The other common side effects of KEYTRUDA are fatigue, musculoskeletal pain, diarrhea, pain and abdominal pain and decreased appetite (21%).

 No responses were observed in patients whose tumors did not have the PD-L1 expression (CPS<1).

KEYTRUDA is a humanized monoclonal antibody that blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2, thereby activating T lymphocytes which may affect both tumor cells and healthy cells. This increases the ability of the body's immune system to help detect and fight tumor cells.

Dr. Roy Baynes, senior vice president and head of global clinical development, chief medical officer, Merck Research Laboratories said, “KEYTRUDA is now the first anti-PD-1 therapy approved for the treatment of advanced cervical cancer, providing an important new second-line option for certain patients with this disease. This approval also marks the first indication for KEYTRUDA in gynecologic cancer and reflects our ongoing commitment to bring forward innovative treatment options across a broad range of cancers, including cancers that disproportionately affect women,” in a news release.

KEYTRUDA has already been approved by FDA for treatment of melanoma, head and neck cancer, lung cancer, urothelial cancer, and gastric cancer.

Merck News Release 

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3-D Printed Models of cervix developed to train doctors in cervical cancer screening and treatment

The researchers from Rice University

Many resource-poor settings are not able to provide cervical cancer screening, diagnosis, and treatment of women population because of lack of training. A team of students from Rice University has designed a 3-D Printed Models of the cervix that can help the healthcare providers to train them to carry out screening and provide treatment for cervical cancer.

This will be specifically used for training doctors and nurses in developing countries and low-resource areas in the U.S.

Cervical cancer kills nearly 300,000 women every year and more than 80% deaths are reported in developing countries. In about 90% of patients, the cervical cancer is preventable.

Rice students Christine Luk, Elizabeth Stone and Rachel Lambert are senior design students enrolled in the course Global Health Design. Together with graduate student Sonia Parra, they developed a low-cost, interactive training model that mimics a woman’s pelvic region and can be used to practice different cervical cancer screening and treatment procedures.

The simple device includes different models of cervix showing evolving stages of cervical cancer from entirely normal to pre-cancerous to definitive cancer.  The models fit into holder placed at the back of the device.

The training doctor or nurse can have real-life experience of what it looks like at the doctor’s office after the speculum is inserted and the cervix is visualized. The models can easily be switched around to simulate different conditions of the cervix and they also respond to the application of hot water just as a gynecologist applies acetic acid in clinical settings.

In addition to the training aspect, the device also is handy in teaching the doctors and nurses about how to proceed with abnormal results of the screening tests or a lesion is seen during the examination.

Some cervical models are made of a ballistic gel, that allows the doctors to practice colposcopy, cervical biopsy; cryotherapy, and loop electrosurgical excision procedure at low costs.

“Here in the states we have the ability to perform Pap smears and other practices, but in other countries where this model is used, such as Mozambique and El Salvador, they may not have the necessary infrastructure to do so,” Christine Luk said. “That’s why it’s important that this model can train as many procedures as possible.”

The students have already tested the device in training clinics in El Salvador and the Rio Grande Valley in Texas. Each training session is modified to fit the specific needs of an area.

The team from Rice is trying to collaborate with manufacturers to mass produce the device for areas in need so newly trained medical providers can train others.

Rice News Release

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Here is a video about how the device works

News from SGO annual meeting: Cervical cancer screening should not be stopped at age 65

One in every 5 women diagnosed with cervical cancer is above the age of 65 years in the USA, which suggests a reconsideration of current cervical cancer screening guidelines which advice to stop the screening at the age 65 years for women who are at low risk and have received adequate screening in the past.

The data was presented by the lead researcher Sarah Dilley, MD, MPH, a fellow in gynecologic oncology at The University of Alabama at Birmingham at the Society of Gynecologic Oncology’s 2018 Annual Meeting on Women’s Cancer.

The current recommendations by American Cancer Society, American Society for Clinical Pathology and American Society of Colposcopy and Cervical Pathology advice that cervical screening should stop after women turn 65 years of age if they have had adequate screening and are at low risk. The guidelines do not address the risk stratification for cervical cancer in women over the age of 65. 

The researchers analyzed the 2014-15 data Surveillance, Epidemiology and End Results (SEER-18) program database which showed that 19.7 percent of cervical cancer cases were diagnosed in women age 65 or older.

Analysis of the National Cancer Database for the year 2014-15 showed that 18.9% of cervical cancer were diagnosed in women who were who were 65 years or older.

Risk stratification by ethnicity showed that in 22.9 percent of African American women were age 65 or older, compared to 20.5 percent of non-Hispanic white women at the time of diagnosis of cervical cancer.

When the incidence was analyzed by age, only 5.1 percent of cervical cancer cases were diagnosed from age 20 to 29, while 8 percent were diagnosed from age 70 to 79.

Dr. Dilley said in a news release, “This data point contradicts the misperception that women usually only are diagnosed with cervical cancer at a younger age.”

“Our data suggest that a considerable proportion of women are diagnosed with cervical cancer after age 65, which suggests that patients are being aged out too soon or not getting screened at all,” Dr. Dilley continued. “Professional societies should consider extending the age screening requirements to improve outcomes for this older population of women.”

The results of this study suggest that the decision to stop cervical cancer screening should only be taken after an informed shared decision-making between patient and her doctor and some women over the age of 65 years may still benefit from screening to prevent age-based disparities in cervical cancer diagnoses.

News Release 

Media courtesy: LA times and JAMA

Biop launches accurate, on the spot, 3 minutes screening and detection system for cervical cancer

Biop Medical announced the launch of its high tech, point of care cervical cancer screening and detection device at MEDICA 2017 in Düsseldorf, Germany, Nov. 13-16. This "sample free biopsy" device helps gynecologist in screening and diagnosis of pre-cancerous and cancerous lesions in real time without the painful wait for the biopsy results.

Biop system is a digital colposcope that make use of advanced and high-resolution optics to obtain a magnified view of vagina, cervix and external genitalia, allowing doctors to identify abnormalities such as lesions or cancer and selecting areas for biopsy.

The innovative system consists of a main control unit, that can be connected to the Digital Colposcope unit or the Micro-Colposcope Probe unit.

A fully digital and high-resolution imaging of the cervix can be performed by connecting the Digital Colposcope unit to the control unit. Panoramic color images, using LED lights are acquired by the camera.

On the other hand, the Micro- Colposcope Probe unit captures a macro-image of the cervix, using its macro-camera. Using a sterile and disposable cover, the probe is advanced in the vagina, upon coming in contact with the cervix, the unit captures high-resolution, high-magnification images within a radius of 11mm around the external os, which serves as the center of the scan.

The physician does not need to constantly adjust the magnification, to focus on the specific areas, as with the current colposcopy units.  

The images are enhanced and processed by the software of the system. The high resolution, macro images are than combined with the panoramic images to obtain a full a color map of cervix, that is analyzed by Biop’s proprietary algorithm.

Two pictures are displayed on the physician's screen; a high-resolution photograph of the patient's cervix, immediately next to a hot/cold map indicating a precise classification and location of any diseased lesions.

If needed, the physician can take biopsies from a precise location, and reducing the need for unnecessary biopsies.

The data obtained is uploaded and secured on Bluemix virtual servers in the IBM Cloud and can be used for consultation with any specialist around the world. These new data sets can be used to improve the accuracy of Biop’s diagnostic and create predictive data, which will determine which cells are likely to convert to cancer and which will regress to healthy cells.

With Biop, a woman can be screened in 3 minutes and if precancerous or cancerous lesions are detected, the women can be referred for immediate treatment.

The device is particularly useful in developing countries, and remote access areas where the physician can carry the device to the patients.

Operating the device requires minimum screening, so that healthcare professional can be quickly trained to do the scanning, as compared to years of training required for routine colposcopy.

“With this new precision, physicians can see where to target biopsies and only perform the procedure when necessary,” said Biop Medical CEO Ilan Landesman in a news release. “Patients gain a more accurate and faster diagnosis while avoiding the painful procedure as well as reduced costs for hospitals and healthcare providers.”

Cervical cancer is the number one cause of cancer-related death for women in the developed world. Out of BRICS (Brazil, Russia, India and China and South Africa) countries, India is the leader in overall deaths, with nearly 73,000 annual deaths. China and Brazil follow closely.

Biop Medical is based in Ramat Gan, Israel.

Media courtesy: Biop 

HPV testing vs Pap test in cancer screening: Cochrane Systematic review

A negative HPV test is more reassuring than a negative Pap test, as the cytology screening has a higher chance of being false negative thereby missing some women with precancerous lesions and delaying treatment says the result of a Cochrane Systematic review published ahead of print.

Since decades the usual method of screening for cervical cancer is based on cell cytology, but since the etiological relationship between cervical cancer and HPV infection was confirmed along with advent of HPV testing in 1999, the supremacy of these two tests is debated.

Some physician advice Pap and HPV both, especially for women over 30 years old, who are most at risk of cervical cancer, getting both tests provides the best assurance of finding cervical disease before it becomes cancer.

Younger women (20-30) are advised to get HPV test only if their Pap smear looks "inconclusive" or "borderline.”

This systematic review by Cochrane was aimed at determining efficacy of the two tests in detecting precancerous lesions (CIN 2+ and CIN 3+). Literature search for relevant studies till November 2015 identified about 40 studies amounting to a total of 140,000 women between 20 to 70 years old who underwent cervical cancer screening.

Data analysis identified true positives (TP), false positives (FP), true negatives (TN), and false negatives for each screening test (HPV test and cytology) used in each study.

It was seen that HPV test was more sensitive than conventional Pap test and liquid based test in identifying CIN 2+ and CIN 3+, but less specific than Pap test in detecting precancerous lesion.

Data analysis showed that for every 1000 women screened, around 20 women will have precancerous lesions. If HPV test is used, it will correctly identify 16 of the 20 women to be positive for the lesions (but will miss 4 women who have the lesions). The Pap test will correctly identify 12 of the 20 women (but will miss 8 women).

Similarly, for every 1000 women screened, there will be 980 women who will not have precancerous changes. The HPV test will correctly identify 879 women as disease free (but 101 women will be incorrectly told that they have a lesion). The Pap test will correctly identify 951 women (but 29 will be incorrectly told that they have a lesion).

This high false positive rate of HPV testing will lead to high unnecessary referrals and further tests like colposcopy, biopsy and surgery but at the same time it will also identify 50% more women with precancerous changes as compared to conventional cytology.  

The authors concluded that,” Whilst HPV tests are less likely to miss cases of CIN 2+ and CIN 3+, these tests do lead to more unnecessary referrals. However, a negative HPV test is more reassuring than a negative cytological test, as the cytological test has a greater chance of being falsely negative, which could lead to delays in receiving the appropriate treatment.”

Source: Koliopoulos G, Nyaga VN, Santesso N, Bryant A, Martin-Hirsch PP, Mustafa RA, Schünemann H, Paraskevaidis E, Arbyn M. Cytology versus HPV testing for cervical cancer screening in the general population. Cochrane Database Syst Rev. 2017;8:CD008587. doi: 10.1002/14651858.CD008587.pub2. PMID: 28796882

Access the abstract here.

New slender hand-held pocket colposcope will make cervical cancer screening comfortable and accessible for more women.

courtesy:Duke University 

Uncomfortable speculums and high cost colposcopes can soon be replaced by a simple hand-held device for cervical cancer screening say researchers at Duke University.

Invasive cervical cancer (ICC) affects the lives of 500,000 women worldwide each year, and results in more than 270,000 deaths.Many deaths can be prevented by addressing the barriers to cervical cancer screening which also includes travel distance to the provider, comfort during the procedure  and  adequate assessment of risk.

The “pocket colposcope” is a slender wand that can connect to many devices, including laptops or cell phones. It can be used by woman for self-screening in low resource settings, including some areas in US.

The paper was published on May 31 in the Journal Plos One.

“The mortality rate of cervical cancer should absolutely be zero percent because we have all the tools to see and treat it,” said Nimmi Ramanujam, the Robert W. Carr, Jr., Professor of Biomedical Engineering at Duke. “But it isn’t. That is in part because women do not receive screening or do not follow up on a positive screening to have colposcopy performed at a referral clinic. We need to bring colposcopy to women so that we can reduce this complicated string of actions into a single touch point.”

courtesy: Plos One 

The device has a slender, tubular body just like a tampon with a funnel-like curved tip measuring approximately 2.5 cm in diameter. The inserter has a side channel which a 2 megapixel (MP) mini camera with LED illumination to enable image capture.

The device also includes a channel through which contrast agents used for the cervical cancer screening procedure can be applied. The researchers recruited a group of volunteers to try the new device and  92.3%  said that they would prefer it over a traditional speculum. 80% women got good image and the rest said that they can do it with a better practice.

Dr. Ramanujam and Asiedu, a graduate student in Duke’s Global Women’s Health Technologies Center are working on clinical trials to compare it with traditional speculum and coloscopes.

Asiedu is also working to teach the computer to spot precancerous and cancerous lesions. This involves machine learning so that the screening can be performed by midwives, community health workers and even the women themselves.

Oral contraceptive pill use protects against colorectal, endometrial and ovarian cancer.

 courtesy: Getty images

Women who have ever used the ‘pill’ have a decreased chance of having colorectal cancer, endometrial cancer or ovarian cancer than women who had never used the pill according to a new research from The University of Aberdeen, UK

The study was published in February issue of American Journal of Obstetrics and Gynecology.[1]

The study answers three important questions about safety of the use of OC. (1) What is the duration of benefits for endometrial, ovarian, and colorectal cancer. (2) Does combined oral contraceptive use during the reproductive years led to new cancer risks as we age? (3) What is the risk benefit ratio for cancer among past users as they age and enter old age when the general population risk of cancer increases?[2]

This is the longest running study of its kind  that looked at data from 46,022 women who were recruited by the UK Royal College of General Practitioners' Oral Contraception Study in 1968 -1969 and were followed for up to 44 years. The study looked at risk of specific and general cancer risk for women who have ‘ever’ used the pill against the women who have ‘never’ used the pill.

The pill was first approved for contraceptive use in 1960 and was an instant hit with 2.3 million women using it by 1963. Controversies ranged from its inception and are still rife about the pill causing cancers, blood clots, heart attack and stroke.

Few studies have documented that women are protected against GI malignancies and are at increased risk of breast and cervical cancer while currently using pills or being a recent user.

The current study data showed that the protective effect of pill lasts for 30 years even after the pill is stopped and pill users have a 19% lower risk of GI malignancies, 26% lower chance of lymphatic, and hematopoietic cancer, 34% lower risk of endometrial cancer and a 33% lower risk of ovarian cancer.

The study showed a slight increased chance of breast and cervical cancer while using the pill but this was neutralized and plummeted to the general population risk in 5 years of stopping the pill.

The cohort did not show increased risk of any other malignancy as the women aged.

The authors concluded that “Most women who choose to use oral contraceptives do not expose themselves to long-term cancer harms; instead, with some cancers, many women benefit from important reductions of risk that persist for many years after stopping.”

Professor Helen Stokes-Lampard, Chair of the RCGP, said: “Millions of women worldwide who use the combined oral contraceptive pill should be reassured by this comprehensive research that they are not at increased risk of cancer as a result – and that taking the pill might actually decrease their risk of certain cancers.”[3]

“This is not to advocate that women should be given the pill as a preventative measure against cancer as we know that a minority of women do have adverse health effects as a result of taking the pill. Ultimately decisions to prescribe the pill need to be made on a patient by patient basis, but this research will be useful to inform the conversations we have with our patients when discussing various contraceptive options that are available.”

“Long-term and ongoing research into the health effects of any medication is important in shaping new clinical guidelines around the care we are able to provide to our patients – and it’s encouraging to hear that RCGP research that originated in in the 1960s is still having a positive impact and increasing our knowledge now.”

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[1] Iversen L, Sivasubramaniam S, Lee AJ, et al. Lifetime cancer risk and combined oral contraceptives: the Royal College of General Practitioners’ Oral Contraception Study. Am J Obstet Gynecol 2017

[2] http://www.sciencedirect.com/science/article/pii/S0002937817301795

[3] http://www.rcgp.org.uk/news/2017/march/pill-study-should-reassure-millions-of-women-workdwide-says-rcgp.aspx

ASCO issues new evidence based recommendations for global cervical cancer screening.

AmericanSociety of Clinical Oncology (ASCO)[i]  releases new resource stratified, evidence based global screening guidelines for secondary prevention of cervical cancer. ASCO called upon multidisciplinary, multinational team of cancer control, public health, oncology, epidemiology, primary care and patient advocacy experts to review the earlier guidelines and formulate recommendations according to the resources available.  

The panel of expert identified 7 existing guidelines, reviewed them and formed the evidence base, along with cost effective analysis and four systematic reviews leading to more than 75% agreement.

The basic aim of the guidelines was utilizing the resources available in countries across the globe to screen the maximum number of women to detect precancerous lesions and treatment and follow-up thereafter.

According to Medscape Surendra S. Shastri, MD, MBBS, co-chair of the ASCO expert panel that developed the guideline and professor of preventive oncology at Tata Memorial Center in Mumbai, India said "Every woman ― no matter where she lives ― should have at least one good cervical cancer screen in her lifetime, but unfortunately, we are not even close to that."

The guidelines were published online October 12 in the Journal of Global Oncology.[ii]

The countries around the world are divided into 4 tier based on available healthcare resources- maximal resources, enhanced resources, limited resources and basic resources. Countries with most resources are in the maximal resource group while countries with very limited resources were labelled as into basic resources group.

The panel then evaluated that what type of screening will be suitable for each tier.

Key Recommendations as published in the Journal of Global Oncology:

Primary Screening

• Human papillomavirus (HPV) DNA testing is recommended in all resource settings.
• Visual inspection with acetic acid may be used in basic settings.
• The recommended age ranges and frequencies in each setting are as follows:
• Maximal: 25-65 years, every 5 years
• Enhanced: 30-65 years, if two consecutive negative tests at 5-years intervals, then every 10 years
• Limited: 30-49 years, every 10 years
• Basic: 30-49 years, one to three times per lifetime

Exiting Screening

• Maximal and enhanced: ≥ 65 years with consistently negative results during past ≥ 15 years
• Limited and basic: ≤ 49 years, resource-dependent; see specific recommendations

Triage

• In basic settings, visual assessment for treatment may be used after positive HPV DNA testing results.
• If visual inspection with acetic acid was used as primary screening with abnormal results, women should receive treatment.
• For other settings, HPV genotyping and/or cytology may be used.

After Triage

• Women with negative triage results should receive follow-up in 12 months.
• In basic settings, women should be treated if there are abnormal or positive triage results.
• In limited settings, women with abnormal results from triage should receive colposcopy, if available, or visual assessment for treatment, if colposcopy is not available.
• In maximal and enhanced settings, women with abnormal or positive results from triage should receive colposcopy.

Treatment of Women With Precursor Lesions

• In basic settings, treatment options are cryotherapy or loop electrosurgical excision procedure (LEEP).
• In other settings, LEEP (if high level of quality assurance) or ablation (if medical contraindication to LEEP) is recommended.
• Twelve-month post-treatment follow-up is recommended for all settings.

Special Populations

• Women who are HIV positive or immunosuppressed for other reasons should be screened with HPV as soon as diagnosed and screened twice as many times in a lifetime as the general population.
• The management of abnormal screening results for women with HIV and positive results of triage is the same as in the general population
• Women should be offered primary screening 6 weeks postpartum in basic settings and 6 months postpartum in other settings.
• Screening may be discontinued in women who have received a total hysterectomy for benign causes with no history of cervical dysplasia or HPV. Women who have received a subtotal hysterectomy (with an intact cervix) should continue receiving routine screening.

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[i] https://pilotguidelines.atlassian.net/wiki/display/SPCCRG/Secondary+Prevention+of+Cervical+Cancer+Resource-Stratified+Guideline+Home

[ii] http://jgo.ascopubs.org/content/early/2016/10/08/JGO.2016.006577.full#abstract-1

Cervical cancer screening interval can be extended beyond five years in HPV negative women.

 Clinical pearls:

• Primary HPV testing provides better protection against cervical cancer than cytology screening tests.
• HPV negative women who are at-least 40 years of age have a very low risk of cervical pathology and the screening interval can be increased to 10 years in Netherlands. All other women continued to be screened every 5 years.
• HPV positive women, who are triage negative, or negative for HPV 16/18 genotyping have a very high risk of developing CIN3+ or cervical cancer, and the screening intervals cannot be extended beyond 5 years.
• The use of HPV testing and age of the patient is the first step towards risk based screening.

Randomized control trials in the past have shown that HPV based screening provides a better protection against CIN3 than only cytology based screening.  Dutch researchers have reported the results of large population based study that confirms the findings from earlier studies. They suggest that cervical cancer screening interval for those women who test negative for HPV and are older (40+ years) can be safely extended from 5 to 10 years. All other women can get the screening at 5 years’ interval.

Separate screening intervals are defined for women who are HPV negative and those who were initially HPV positive but subsequent HPV negative after the triage test, because they face different risks for CIN3.[1]

Many countries (Australia, Italy, Netherlands, New Zealand, Sweden, and the UK) around the world have adopted or recommended HPV screening as the primary screening procedure and US still combines it with cytology.  When advocating for change in policies, the risk of interval cancer should also be taken into account. So longitudinal studies are required to document the incidence of long term cervical cancer.

New data analysis from the Netherlands was published in British Medical Journal, published 04 October 2016, suggest that the interval for cervical screening for HPV-negative individuals, older than 40 years) could be extended from 5 years to 10 years; all other women should continue to be screened every 5 years.[2]

The study is a population based 14 years follow up of cohorts from earlier POBASCAM randomized trial. (population based screening study Amsterdam). The follow up of 14 years comprised of three screening rounds first at baseline, then at five years and 10 years.

A total of 44 938 women aged between 29 and 61 were enrolled, 22 420 were randomized to the intervention group (cytology and HPV co-testing) and 22 518 to the control group (cytology with blinded HPV testing).

Follow up data was collected till year 2013, till that point of time every woman had the opportunity to undergo three rounds of 5-year screening.

Study results showed that the cumulative incidence of cervical cancer and CIN3+ among HPV negative women in the intervention group was similar to negative cytology in control group after two rounds of screening.

Cervical cancer and CIN risk ratios were .97 and .82 respectively.

In women with HPV negative and in the age range of 40+ years, the CIN3+ incidence was 72% lower as compared to younger women. (P < .001). 

Women who were   HPV-positive but had negative results on HPV 16/18 genotyping and negative results on baseline and repeat cytology testing had 10.4 times the cumulative risk of developing CIN3 than HPV-negative women.

Similarly, HPV-positive women with negative cytology triage had 11.9-fold higher risk for developing cervical cancer than among HPV-negative women. After adding HPV 16/18 genotyping or repeat cytology as a triage test, only one cancer case was observed.

The study results show that HPV based screening programme provides a better protection as compared to cytology results. Long term incidences of cervical cancer and CIN3+ were low among HPV negative women in this study cohort, and supports an extension of the cervical screening interval beyond five years for women aged 40 years and older. 

HPV positive women with negative repeat cytology, HPV16/18 genotyping, and/or repeat cytology have at least a fivefold higher risk of CIN3+ than HPV negative women, indicating that HPV based screening programmes with long intervals (>five years) should be implemented with risk stratification according to the age of the patients. 

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[1] Bulkmans NWJ, Berkhof J, Rozendaal L, et al. Human papillomavirus DNA testing for the detection of cervical intraepithelial neoplasia grade 3 and cancer: 5-year follow-up of a randomised controlled implementation trial. Lancet2007;370:1764-72.doi:10.1016/S0140-6736(07)61450-0 pmid:17919718.

[2] http://www.bmj.com/content/355/bmj.i4924

ASCO issues evidence based, global guidelines for managing invasive cervical cancer.

The American Society of Clinical Oncology (ASCO) has issued recommendation on managing invasive cervical cancer.  There exist wide disparities in screening, diagnosing and treatment of patient diagnosed with invasive cervical cancer across the globe. Economic disparity and lack of resources make it impossible to adopt the same guidelines universally. 

ASCO has first time published ‘resource stratified’ guidelines that are tailored according to the resources available in a specific region.

The guidelines were published online before print on May 25, 2016, in Journal of Global Oncology.

According to WHO statistics, an estimated one million-plus women worldwide are currently living with cervical cancer of which about 84 per cent occur in less developed countries.

Dr. Linus Chuang, MD, MS, professor of obstetrics, gynecology, and reproductive science at the Icahn School of Medicine at Mount Sinai in New York City, who is cochair of the ASCO expert panel that developed the guideline said "In those regions, access to pathology services, skilled surgeons, radiation machines, brachytherapy, chemotherapy, and palliative care may all be constrained." 

Dr. Jonathan S. Berek, MD, MMS, professor and chair of obstetrics, gynecology, and gynecologic oncology at the Stanford University School of Medicine in California, and who is also cochair of the ASCO expert panel opined that At least two-thirds of the women who die from cervical cancer have not had regular screening, "If we improved screening and HPV vaccination around the world, we might be able to substantially decrease the mortality from cervical cancer." 

ASCO called upon a multidisciplinary, multinational panel of cancer specialist, medical and radiation oncology, health economic, obstetric and gynecologic, and palliative care experts to develop   guidelines that encompasses resource tiered settings.  A systemic review of literature from the year 1966 to 2015 could not yield sufficiently strong evidence to develop tailored guidelines across the different region globally, so a formal strategy of developing consensus based guidelines was adopted.

Five sets of guidelines from different bodies and societies were reviewed in current context and recommendations were formed into 4 tier that is basic, limited, enhanced, and maximal. For surgery, chemotherapy and radiotherapy treatment combinations and modalities available were formed according to the 4 tier.

1. Surgery: In basic tier Simple (extrafascial) hysterectomy or more extensive hysterectomy can be performed while in maximal  tier facilities Radical hysterectomy, radical trachelectomy, pelvic and paraaortic LN sampling, sentinel node biopsy, and pelvic exenteration; radiation therapy, chemotherapy, interventional radiology, palliative care service, and bevacizumab are all available.
2. Chemotherapy:  In basic tier availability of chemotherapy drugs were unpredictable, while in maximal capacity Chemotherapy available; bevacizumab is also available.
3. Radiotherapy: In basic tier no radiation therapy available while RT including external beam and brachytherapy and interventional radiology available in maximal capacity.

The societies were the National Comprehensive Cancer Network (NCCN) in the United States, and the World Health Organization (WHO), Cancer Care Ontario (CCO) in Canada, the European Society of Medical Oncology (ESMO), the Japan Society of Gynecologic Oncology (JSGO).

Workup, Optimal therapy, follow up and post treatment surveillance and palliative care were earmarked for each of these tiers and stage of cancer.

ASCO emphasized that health care providers and health care administrators should be guided by the recommendations from the highest stratum of resource available to provide women with the best evidence based treatment modality and palliative care.

Some of the key recommendations in treatment for invasive cervical cancer are:

• In Basic setting where radio therapy is not available, extrafascial hysterectomy, either alone or after chemotherapy, can be an option for women with stage IA1 to IVA cervical cancer.
•  In Enhanced and Maximal settings, concurrent radiotherapy and chemotherapy is the standard of care for women with stage IB to IVA disease.
• Adding  Low dose chemotherapy to Radiotherapy is  ideal, but if chemotherapy is not available the radiotherapy should not be delayed for it.
• In limited resource settings where brachytherapy is not available, extrafascial hysterectomy or its modification in patients who still have residual tumor of 2-3 months after concurrent radio and chemotherapy.
• Those patients with stage IV or recurrent cervical cancer in basic settings can be treated with single agent chemotherapy using carboplatin or cisplatin.
• In patients who have disseminated disease and cannot be cured should be given palliative radiotherapy to relieve pain and bleeding.
• In areas with very poor resources, multiple short courses of radiotherapy can be used for retreatment of recurrent or residual diseases.
• In settings where good follow up care can be provided, cone biopsy in basic resources settings and cone biopsy and lymphadenectomy in limited resource setting is the treatment of choice for 1A2 disease. 
• For patients in enhanced and maximal settings, to preserve the fertility in reproductive age group of women radical trachelectomy is recommended for those with stage IB1 disease with tumor size up to 2 cm.
• ASCO also noted that the current guidelines are intended to complement the existing guidelines and not necessary replace it.
• ASCO also provided future directions and stressed the need for prospective comparative research. Radical versus simple hysterectomy (the feasibility and safety of performing cone biopsy or simple hysterectomy) is an active area of investigation in limited resource settings, with stage IA2 versus 1B1 disease.

References:

http://www.wcrf.org/int/cancer-facts-figures/data-specific-cancers/cervical-cancer-statistics

http://www.who.int/reproductivehealth/topics/cancers/en/

http://www.asco.org/sites/new-www.asco.org/files/content-files/practice-and-guidelines/documents/2016-RS-Cervical-Cancer-Treatment-Summary-Table.pdf

http://jgo.ascopubs.org/content/early/2016/05/21/JGO.2016.003954.full