NEOADJUVANT CHEMO FOR ENDOMETRIAL CANCER

 In a National Cancer Database analysis reported in JAMA Network Open, Tobias et al found that receipt of neoadjuvant chemotherapy was associated with improved short-term but not long-term survival vs primary debulking surgery in patients with metastatic endometrial cancer.

As stated by the investigators, “Although primary debulking surgery is often considered the criterion standard for treatment of stage IV endometrial cancer, primary debulking surgery is associated with significant morbidity and poor survival. Neoadjuvant chemotherapy has been proposed as an alternative treatment strategy.”

“The results of this cohort study suggest that women treated with primary debulking surgery are at increased risk of early death but have a more favorable long-term prognosis. In contrast, results suggest that women treated with neoadjuvant chemotherapy, particularly if they ultimately undergo surgery, may have superior survival in the short term.”

— Tobias et al

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Study Details

The study involved National Cancer Database data on 4,890 women with stage IV endometrial cancer treated from January 2010 to December 2015. Patients had to be aged ≤ 70 years with minimal comorbidity (comorbidity score = 0). Women were stratified based on receipt of neoadjuvant chemotherapy or primary debulking surgery.

Key Findings

Overall, neoadjuvant chemotherapy was used in 952 women (19.5%), with use increasing from 106 (16.0%) of 661 women in 2010 to 224 (23.9%) of 938 women in 2015 (P < .001).

In multivariate analysis, use of neoadjuvant chemotherapy was associated with more recent year of diagnosis (risk ratio [RR] = 1.42, 95% confidence interval [CI] =1.21–1.79, for 2015 vs 2010), stage IVB vs IVA disease (RR = 1.31, 95% CI = 1.03–1.67), and serous vs endometrioid histology (RR = 1.38, 95% CI = 1.13–1.69).

In a propensity score–balanced cohort, use of neoadjuvant chemotherapy exhibited an association with overall survival that varied over time from diagnosis. In intention-to-treat analysis, neoadjuvant chemotherapy was associated with improved survival vs primary debulking surgery for approximately 3 months (HRs for mortality = 0.56, 95% CI = 0.39–0.80, in month 1 and 0.81, 95% CI = 0.66–0.99 in month 2), with hazard ratios being similar for months 3 and 4; the survival curves crossed after 4 months, and neoadjuvant chemotherapy was associated with worse survival from month 5 onward (HR = 1.17, 95% CI = 1.03–1.33).

Among women who started treatment with surgery, 3,139 (79.7%) ultimately received chemotherapy. Among those who initiated neoadjuvant chemotherapy, 555 (58.3%) underwent surgery. In a per-protocol analysis that included only women who received both chemotherapy and surgery in either sequence, use of neoadjuvant chemotherapy was associated with improved survival for the first 8 months after diagnosis (HR at 6 months = 0.79, 95% CI = 0.63–0.98). The survival curves crossed after 9 months, with neoadjuvant chemotherapy being associated with poorer survival thereafter (HR at 12 months = 1.22, 95% CI = 1.04–1.43).

The investigators concluded, “The results of this cohort study suggest that women treated with primary debulking surgery are at increased risk of early death but have a more favorable long-term prognosis. In contrast, results suggest that women treated with neoadjuvant chemotherapy, particularly if they ultimately undergo surgery, may have superior survival in the short term. Based on these findings, neoadjuvant chemotherapy may be appropriate for select patients with advanced uterine serous carcinoma.”

Jason D. Wright, MD, of the Division of Gynecologic Oncology, Columbia University College of Physicians and Surgeons, is the corresponding author for the JAMA Network Open article.

Disclosure: For full disclosures of the study authors, visit jamanetwork.com.

NOVEL TREATMENTS FOR CERVICAL CANCER

The treatment of recurrent or metastatic cervical cancer has not changed much in recent years, but according to preliminary trials presented at the European Society for Medical Oncology (ESMO) Virtual Congress 2020, checkpoint inhibitors and antibody-drug conjugates may become new options.

In the multicenter phase II innovaTV 204 trial of the antibody-drug conjugate tisotumab vedotin, 24 of 101 patients responded, with 7 being complete responders.1 In two phase II studies also presented at ESMO 2020, the investigative PD-1 inhibitor balstilimab as a single agent and combined with the CTLA-4 inhibitor zalifrelimab also yielded promising response rates, regardless of PD-L1 expression.2

Tisotumab Vedotin in innovaTV 204

Tisotumab vedotin comprises an antibody directed at tissue factor and covalently linked to the microtubule disruptor monomethyl auristatin E (MMAE). Tissue factor is commonly found in cervical cancer and is associated with a poor prognosis.

Robert L. Coleman, MD

“Tisotumab vedotin demonstrated compelling and durable antitumor activity in recurrent or metastatic cervical cancer previously treated with doublet chemotherapy,” reported Robert L. Coleman, MD, of Texas Oncology in the Woodlands, Texas. Thus, the antibody-drug conjugate is “a potential novel treatment” for women with recurrent or metastatic cervical cancer, for whom there is no established second-line option.

In innovaTV 204, single-agent tisotumab vedotin was given to 101 patients (median age of 50) with recurrent or extrapelvic metastatic cervical cancer that had progressed during or after doublet chemotherapy with bevacizumab (if eligible). No more than two prior lines of therapy were allowed; most patients had received cisplatin-containing chemoradiation therapy. The primary endpoint was objective response rate, as determined by independent imaging review.

After a median follow-up of 10 months, objective responses were observed in 24%, and stable disease was seen 49% (four patients were yet to be evaluated). The median duration of response was 8.3 months, and 79% of patients had some tumor shrinkage.

“Most responses were rapid, with activity observed within the first two treatment cycles. Clinically meaningful responses were observed regardless of histology subtype, tissue factor expression level or prior therapy, including use of doublet chemotherapy with bevacizumab as a first-line treatment,” Dr. Coleman said. “Of note, the objective response rates in patients with nonsquamous histology (25%) and in those previously treated with bevacizumab (19%) were encouraging, as only limited data currently exist in these populations.”

Median progression-free survival was 4.2 months, and 30% of patients were alive without disease progression at 6 months. Median overall survival was 12.1 months, with 79% alive at 6 months. One-third of the treatment cohort is still being followed for overall survival.

Safety Profile

Most treatment-related adverse events were grade 1 or 2, most commonly alopecia (38%), epistaxis (30%), nausea (27%), conjunctivitis (26%), fatigue (24%), and dry eyes (23%). Treatment-related adverse events grade ≥ 3 occurred in 28% of patients; one death due to septic shock was considered to related to the study drug.

Prespecified adverse events of interest included ocular toxicities, bleeding, and peripheral neuropathy. Conjunctivitis and dry eye effects were mostly mild to moderate, resolved, and were manageable with an eye care plan. Most bleeding events were grade 1 epistaxis, of which the majority resolved. Most peripheral neuropathy events (a known MMAE-related toxicity) were grade 1 and manageable with dose modifications; resolution was limited by the follow-up period.

New Checkpoint Inhibitors Under Study

Two phase II trials evaluated the novel checkpoint inhibitors balstilimab alone or with the novel anti–CTLA-4 agent zalifrelimab. They included patients with squamous cell carcinoma, adenocarcinoma, or adenosquamous carcinoma with relapse following platinum-based therapy. The single-agent trial included 160 patients, 138 of whom had received at least one prior line of chemotherapy. The combination cohort included 155 patients, of whom 119 had received one line.

“This is, by far, the largest reported study of checkpoint inhibitors in recurrent or metastatic cervical cancer reported to date. We demonstrated responses in both PD-L1–positive and PD-L1–negative tumors in patients treated with single-agent balstilimab and with the combination of balstilimab and zalifrelimab,” said David O’Malley, MD, Professor of Obstetrics and Gynecology at The Ohio State University College of Medicine.

David O’Malley, MD

Single-agent balstilimab elicited a 14% response rate overall; of 20 responses, 3 were complete responses. With the combination of balstilimab and zalifrelimab, response rates increased to 22%; of 23 responses, 8 were complete responses. The median duration of response was 15.4 months with balstilimab and was not reached with the combination, he reported.

In the single-agent cohort, by PD-L1 status, responses were seen in 19%, 10%, and 0% of patients with PD-L1–positive disease (≥ 1%), PD-L1–negative disease, and unknown PD-L1 status, respectively. In the combination study, these rates were 27%, 11%, and 21%, respectively.

Treatment was well tolerated in both studies, and no new safety signals were identified, with all-grade endocrine disorders being more common with the combination than with single-agent balstilimab (20.6% vs 9.3%, respectively). As expected, more immune-related adverse effects were also seen with the combination, but few were grade ≥ 3. 

IMRT NEW STANDARD FOR CERVICAL CANCER

For women who receive radiotherapy after undergoing hysterectomy for high-risk cervical cancer, image-guided intensity-modulated radiotherapy (IG-IMRT) is superior to three-dimensional conformal radiotherapy (3D-CRT) at reducing late gastrointestinal (GI) toxicity and is similarly efficacious, according to new findings.

"IG-IMRT should represent the new standard of care for postoperative pelvic radiation therapy in women with gynecological cancers," said study lead author Supriya Chopra, MD, of the Tata Memorial Center in Mumbai, India.

She noted that the study, known as PARCER, is the first in gynecologic cancer to show the impact of advanced technology in reducing long-term morbidity and thus improving the experience of survivors.

At 4 years, rates of late GI toxicity of grade 2 or higher in the IG-IMRT and 3D-CRT arms were 19.2% and 36.2%, respectively (P = .005). Rates of toxicity of grade 3 or higher were 2.0% and 8.7%, respectively (P < .01).

Chopra presented the results at the American Society for Radiation Oncology (ASTRO) 2020 Annual Meeting, which was held online.

Postoperative radiotherapy is indicated for women with cervical and endometrial cancers who have high-risk features, but long-term follow-up has shown an increase in GI symptom burden and toxicity in long-term survivors after adjuvant radiotherapy.

"The uptake of IMRT has been relatively slow in gynecological cancers," said Chopra. She explained that previous data suggested a benefit with the use of IMRT, but long-term postoperative effects were unclear.

The new data amount to a "practice-change use" of IMRT for this indication, said Sue Yom, MD, PhD, of the University of California, San Francisco, who was not involved with the study. "I see this as having potentially important future impacts on clinical practice."

I see this as having potentially important future impacts on clinical practice. Dr Sue Yom

Yom explained that although there have been studies in the United States on the use of postoperative IMRT for pelvic cancer, "this is the first phase 3 study that has shown definite long-term advantages with the use of IMRT, and I would consider it confirmatory."

In 2015, the preliminary results of PARCER were presented at the plenary session at ASTRO. The results showed that patients treated with IG-IMRT had fewer late GI toxicities at a median follow-up of 20 months. However, the difference between groups was not statistically significant in this earlier analysis.

Now at 49 Months' Follow-Up

The study was conducted in three clinical sites of Tata Memorial Center and included a total of 300 patients with cervical cancer. The patients had undergone type III hysterectomy and had intermediate- or high-risk features, or they had undergone type I/II hysterectomy necessitating adjuvant chemoradiotherapy. They were randomly assigned to IG-IMRT (n = 151) or 3D-CRT (n = 149). Most patients (117 in the IG-IMRT arm and 114 in the 3D-CRT arm) received concurrent chemotherapy.

The primary endpoint was late GI toxicity of grade 2 or higher. Follow-up included clinical and quality-of-life evaluations, which were conducted every 3 months for 2 years and then every 6 months for years 2 to 5.

Chopra and colleagues evaluated 11 different GI-related side effects. Differences emerged over time between the two groups. Among the group that received IG-IMRT, significantly fewer patients reported moderate to severe acute diarrhea (17% in the IG-IMRT arm, vs 27% in the 3D-CRT arm), late abdominal bloating (14% vs 28%), bowel obstruction (1% vs 7%), and anorexia/appetite loss (1% vs 7%).

Overall, for patients treated with IG-IMRT, grade 2 toxicity-free survival rates were significantly higher (78% with IG-IMRT vs 57% with 3D-CRT; P = .0009), as were grade 3 toxicity-free survival rates (97.6% vs 81.6%; P = .001).

As noted above, rates of disease-free survival were similar for both groups (73% with image-guided IMRT vs 68% with 3D-CRT; P = .30).

Funding for the study was provided by the Department of Science and Technology and the Department of Atomic Energy, Clinical Trials Center, in India, and by Varian International and the Terry Fox Foundation. Chopra and Yom have disclosed no relevant financial relationships.

American Society for Radiation Oncology (ASTRO) 2020 Annual Meeting. Abstract 2, presented October 26, 2020.

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A NOVEL REGIMEN FOR CERVICAL CANCER

In the Chinese phase II CLAP study reported in the Journal of Clinical Oncology, Lan et al found that the combination of the anti–PD-1 antibody camrelizumab and the VEGFR inhibitor apatinib produced high response rates in previously treated women with advanced cervical cancer.

Study Details

The multicenter study included 45 patients (intent-to-treat population) whose disease had progressed after one or more lines of prior systemic treatment. Patients were enrolled between January and August 2019, and received camrelizumab at 200 mg every 2 weeks and apatinib at 250 mg once daily continuously in 4-week cycles up to a maximum of 24 months of camrelizumab treatment. A total of 41 patients were included in the efficacy-evaluable population. The primary endpoint was investigator-assessed objective response rate according to Response Evaluation Criteria in Solid Tumors version 1.1. A total of 57.8% of patients had previously received two or more lines of chemotherapy for recurrent or metastatic disease and 67% had PD-L1–positive disease (defined as having a combined positive score > 1).

Responses

Median follow-up was 11.3 months. Objective response was observed in 25 (55.6%) of 45 patients, including complete response in 2 (4.4%). An additional 12 patients (26.7%) had stable disease, yielding a disease control rate of 82.2%. Objective response was observed in 25 (61.0%) of 41 patients in the efficacy-evaluable population. Median duration of response was not reached (95% confidence interval [CI] = 5.6 months–not estimable). At time of analysis, 16 of 25 responses were ongoing, with 71.5% lasting ≥ 6 months and 66.8% lasting ≥ 12 months.

In the intent-to-treat population, median progression-free survival was 8.8 months (95% CI = 5.6 months–not estimable), with a 6-month rate of 57.0%. Median overall survival was not reached (95% CI = 11.6 months–not estimable), with a 9-month rate of 69.2%.

KEY POINTS

• Objective response was observed in 55.6% of patients.
• Median duration of response was not reached after median follow-up of 11.3 months.

Objective response rates were 69.0% vs 50.0% (P = .281) among patients with PD-L1–positive vs PD-L1–negative tumors. Median progression-free survival was not reached vs 5.2 months (P = .034). Objective response rates were 77.8% in 30 patients with squamous cell carcinoma and 28.6% in 15 patients with adenocarcinoma.

Adverse Events

Treatment-related grade 3 or 4 adverse events occurred in 71.1% of patients, with the most common being hypertension (24.4%), anemia (20.0%), and fatigue (15.6%). Serious treatment- related adverse events were observed in four patients (8.9%) and consisted of rash in two patients; pneumonitis in one; and neutropenia, anemia, and thrombocytopenia in one patient. Adverse events led to discontinuation of treatment in three patients (6.7%). No treatment-related deaths were observed.

The most common potential immune-related adverse events included grade 1 or 2 hypothyroidism (22.2%) and reactive cutaneous capillary endothelial proliferation (8.9%).

The investigators concluded, “Camrelizumab plus apatinib had promising antitumor activity and manageable toxicities in patients with advanced cervical cancer. Larger randomized controlled trials are warranted to validate our findings.”

Xin Huang, MD, of the Department of Gynecologic Oncology, Sun Yat-sen University Cancer Centre, Collaborative Innovation Center for Cancer Medicine, Guangdong, is the corresponding author for the Journal of Clinical Oncology article.

Disclosure: The study was supported by the Chinese National Natural Science Foundation. For full disclosures of the study authors, visit ascopubs.org.

HPV VACCINATION REDUCES CERVICAL CANCER RISK

Quadrivalent human papillomavirus (HPV) vaccination was associated with a substantial reduction in the incidence of cervical cancer in a Swedish review of more than 1 million girls and women vaccinated from 2006–2017.

It's been shown that the vaccine (Gardasil) helps prevent genital warts and high-grade cervical lesions, but until now, data on the ability of the vaccine to prevent cervical cancer, although widely assumed, had been lacking.

"Our results extend [the] knowledge base by showing that quadrivalent HPV vaccination is also associated with a substantially reduced risk of invasive cervical cancer, which is the ultimate intent of HPV vaccination program," said investigators led by Jiayao Lei, PhD, a researcher in the Department of Medical Epidemiology and Biostatistics at the Karolinska Institute, Stockholm, Sweden.

The study was published online October 1 in The New England Journal of Medicine.

"This work provides evidence of actual cancer prevention," commented Diane Harper, MD, an HPV expert and professor in the Departments of Family Medicine and Obstetrics & Gynecology at the University of Michigan, Ann Arbor, Michigan. She was the principal investigator on the original Gardasil trial.

This study "shows that the quadrivalent HPV vaccine provides prevention from the sexually transmitted HPV infection that actually reduces the incidence of cervical cancer in young women up to 30 years of age," she said when approached for comment.

However, she also added a note of caution. These new results show "that vaccinated women still develop cervical cancer, but at a slower rate. This makes the connection between early-age vaccination and continued adult life screening incredibly important," Harper told Medscape Medical News

Cervical cancer was diagnosed in 19 of the 527,871 women (0.004%) who had received at least one dose of the vaccine, vs 538 among the 1,145,112 women (0.05%) who had not.

The cumulative incidence was 47 cases per 100,000 vaccinated women and 94 cases per 100,000 unvaccinated women. The cervical cancer incidence rate ratio for the comparison of vaccinated vs unvaccinated women was 0.37 (95% CI, 0.21 – 0.57).

The risk reduction was even greater among women who had been vaccinated before the age of 17, with a cumulative incidence of four vs 54 cases per 100,000 for women vaccinated after age 17. The incidence rate ratio was 0.12 (95% CI, 0.00 – 0.34) for women who had been vaccinated before age 17, vs 0.47 (95% CI, 0.27 – 0.75) among those vaccinated from age of 17 to 30 years.

Overall, "the risk of cervical cancer among participants who had initiated vaccination before the age of 17 years was 88% lower than among those who had never been vaccinated," the investigators noted.

These results "support the recommendation to administer quadrivalent HPV vaccine before exposure to HPV infection to achieve the most substantial benefit," the investigators said.

Details of the Swedish Review

For their review, Lei and colleagues used several Swedish demographic and health registries to connect vaccination status to incident cervical cancers, using the personal identification numbers Sweden issues to residents.

Participants were followed starting either on their 10th birthday or on January 1, 2006, whichever came later. They were followed until, among other things, diagnosis of invasive cervical cancer; their 31st birthday; or until December 31, 2017, whichever came first.

The quadrivalent HPV vaccine, approved in Sweden 2006, was used almost exclusively during the study period. Participants were considered vaccinated if they had received only one shot, but the investigators set out to analyze a relationship between the incidence of invasive cervical cancer and the number of shots given.

Among other things, the team controlled for age at follow-up, calendar year, county of residence, maternal disease history, and parental characteristics, including education and household income.

The investigators comment that it's possible that HPV-vaccinated women could have been generally healthier than unvaccinated women and so would have been at lower risk for cervical cancer.

"Confounding by lifestyle and health factors in the women (such as smoking status, sexual activity, oral contraceptive use, and obesity) cannot be excluded; these factors are known to be associated with a risk of cervical cancer," they say.

HPV is also associated with other types of cancer, including anal and oropharyngeal cancers. But these cancers develop over a longer period than cervical cancer.

Harper noted that the "probability of HPV 16 cancer by time since infection peaks at 40 years after infection for anal cancers and nearly 50 years after infection for oropharyngeal cancers. This means that registries, such as in Sweden, for the next 40 years will record the evidence to say whether HPV vaccination lasts long enough to prevent [these] other HPV 16–associated cancers occurring at a much later time in life."

The work was funded by the Swedish Foundation for Strategic Research, the Swedish Cancer Society, and the Swedish Research Council and by the China Scholarship Council. Lei and two other investigators report HPV vaccine research funding from Merck, the maker of Gardasil. Harper has disclosed no relevant financial relationships.

N Engl J Med. Published online October 1, 2020. Abstract

HPV SCREENING

The American Cancer Society (ACS) has released updated guidelines for cervical cancer screening. The key recommendation is that primary human papillomavirus (HPV) testing is the preferred screening method, starting at the age of 25 and repeated every 5 years.

In the past, guidelines for cervical cancer screening recommended cytology (the Pap test) starting at 21 years of age and repeated every 3 years. In more recent years, cotesting (with both Pap and HPV tests) has been recommended.

Since the last ACS guidelines on cervical cancer screening were published in 2012, two HPV tests have been approved by the US Food and Drug Administration (FDA) for use in primary HPV screening.

The new "streamlined recommendations can improve compliance and reduce potential harms," commented Debbie Saslow, PhD, managing director, HPV/GYN Cancers, American Cancer Society.

The updated guidelines were published online July 30 in CA: A Cancer Journal for Clinicians.

"We now have stronger evidence to support starting cervical cancer screening at a later age and to recommend screening with the HPV test as the preferred test," Saslow told Medscape Medical News. This also reflects the phasing out of cytology and cotesting, she added.

"This update is based on decades of studies comparing the effectiveness of HPV testing to cytology and is bolstered by evidence of the impact of HPV vaccination, including a dramatic decline in cervical precancers and, more recently, cervical cancers among young women," she said.

The American Society for Colposcopy and Cervical Pathology (ASCCP) said that it was preparing a response to these new guidelines, as is the American College of Obstetricians and Gynecologists (ACOG).

Cotesting or Cytology Alone

The updated guidelines recommend primary HPV testing as the preferred screening method for all women with a cervix. If primary HPV testing is not available, women should be screened with cotesting, which should also be performed every 5 years.

If only cytology is available, then women should be screened every 3 years.

The ACS authors point out that cotesting or cytology testing alone is still an acceptable option for cervical cancer screening, insofar as primary HPV testing using FDA-approved tests may not be available in some settings.

As more laboratories in the United States transition to FDA-approved tests for primary HPV testing, it is expected that the use of cotesting or cytology alone will be phased out.

The new guidelines also emphasize that women may discontinue screening at the age of 65 if they have not had cervical intraepitheal neoplasia of grade 2 or higher within the past 25 years and if they have tested negative over the past 10 years on all past screens.

The authors caution that past screens should only be considered negative if the patient has had two consecutive negative HPV tests or two consecutive negative cotests or three consecutive negative cytology tests within the past 10 years."These criteria do not apply to individuals who are currently under surveillance for abnormal screening results," the authors state.

Women older than 65 for whom adequate documentation of prior screening is not available should continue to be screened until criteria for screening discontinuation are met, they add.

Screening may be discontinued among women with a limited life expectancy.

HPV Vaccination

The authors note that HPV vaccination is expected to substantially change cervical cancer screening strategies.

In 2018, the National Immunization Survey–Teen, involving adolescents aged 13 to 17 years, showed that 68.1% of female patients were up to date on HPV vaccine recommendations, as were 51.1% of male patients.

"Cytology-based screening is much less efficient in vaccinated populations, as abnormal cytology disproportionately identifies minor abnormalities resulting from HPV types that are associated with lower cancer risk," the reports' authors point out.

As the prevalence of high-grade cervical abnormalities as well as the incidence of cervical cancer continue to decline, "the proportion of false-positive findings [on cytology alone] is expected to increase significantly," they caution.

As a result, the ACS suggests that physicians will likely have to consider a patient's vaccination status in tandem with cervical cancer screening results to arrive at an accurate assessment.

Raising Starting Age to 25 Years

Saslow also noted that there were several reasons why it is now recommended that screening begin at the age of 25 instead of the age of 21, as in earlier guidelines.

"Firstly, less than 1% of cervical cancers are diagnosed before the age of 25 — so this is about 130 cases per year," she explained.

Thanks to HPV vaccination, this percentage is further declining, "so screening is just not beneficial at this age," Saslow emphasized.

Furthermore, the rate of false positives is much higher in younger patients, and a false positive result can have a negative impact on pregnancy outcomes, she added.

Saslow also dismissed an article in favor of cotesting instead of HPV testing alone. That study, carried out by researchers at Quest Diagnostics and the University of Pittsburgh Medical Center, recommended cotesting, claiming that primary HPV testing is significantly less likely to detect cervical precancers or cervical cancer than cotesting.

"These data come from parties with a vested interest in preserving cytology as a screening test," Saslow told Medscape Medical News. She noted that "these findings are not at all credible as judged by the scientific community."

On the basis of their own modeling, ACS researchers estimate that "starting with primary HPV testing at age 25 will prevent 13% more cervical cancers and 7% more cervical cancer deaths" in comparison with cytology (Pap testing alone) beginning at the age of 21, then cotesting at the age of 30, Saslow said in a statement.

"Our model showed we could do that with a 9% increase in follow-up procedures but with 45% fewer tests required overall," she added.

The new recommendations are not expected to create any change in the type or amount of care required by providers, and patients will not notice any difference, inasmuch as cotesting and primary HPV testing are performed the same way in the examination room, she added.

"Resistance [to the changes] is expected — and is already occurring — from laboratories and manufacturers of tests that will no longer be used once we transition from cotesting and, less commonly, Pap testing to primary HPV testing," Saslow said.

However, providers need to be aware that HPV infection, as with any sexually transmitted disease, is associated with a certain stigma, and they need to take care in discussing potential HPV infection with their patients

Good Method

Medscape Medical News approached Mark Einstein, MD, president of the ASCCP and professor and chair of obstetrics, gynecology, and reproductive health at Rutgers Biomedical and Health Sciences, Newark, New Jersey, to comment on the new guidelines.

"First and foremost," he said, "everything we want to do when it comes to screening is to maximize the identification of picking up a cancer and minimize the risk or potential harm of not only screening itself but of missing cancers, so any strategy that improves on the sensitivity of picking up a cancer is a good method."

Nevertheless, inasmuch as the ASCCP is one of the foremost organizations involved in cervical cancer screening and management, its members need more time to take a closer look at the updated ACS guidelines before they, together with sister organizations, such as the ACOG, release an official statement as to whether or not they fully endorse the new guidelines.

The United States Preventive Services Task Force recently endorsed primary HPV testing (starting at age 30), but it also said that an alternative strategy is cotesting for women between 30 and 65 years of age, Einstein observed.

Asked to comment on the article from Quest Diagnostics and the University of Pittsburgh that recommended cotesting instead of primary HPV testing, Einstein said that that suggestion should not be dismissed out of hand.

The ASCCP has asked the authors of that study for their data in order conduct an independent assessment of it, largely because the study was retrospective in nature. Because of that, "there may have been a few pieces of information that were missing in true real-time fashion," he said. "Not having [both the primary HPV testing and the cytology results] in front of me might change the next thing I might recommend to the patient," Einstein explained.

The bottom line is that when comparing primary HPV testing alone, cytology alone, and cotesting and rates of cervical cancer at 5 years, "the biggest driver for true performance of positive predictive value is HPV," Einstein said.

Nevertheless, cotesting does bring more information into the equation compared with primary HPV testing alone, although it also increases the potential for harm, including the harm of overtesting and conducting needless colposcopies, he added.

That said, starting primary HPV testing at the age of 25 rather than the age of 30, as was previously recommended, is very likely to lead to detection of spurious HPV infections, because HPV infections are very common among women in their 20s, Einstein pointed out.

"This, too, could potentially lead to more colposcopies, which may cause harm from the procedure itself but also create a certain amount of anxiety and concern, so there is some harm in testing for HPV at an earlier age as well," Einstein said.

Saslow and Einstein have disclosed no relevant financial relationships. 

CA Cancer J Clin. Published online July 30, 2020. Full text

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HAPV VACCINATION GUIDELINES

The American Cancer Society's new guidance on human papillomavirusvaccination diverges from the Centers for Disease Control and Prevention's recommendations.

The ACS has endorsed two recommendations made by the CDC's Advisory Committee on Immunization Practices, but the ACS does not agree with a third recommendation for older adults.

The ACIP recommends shared clinical decision-making regarding human papillomavirus (HPV) vaccination in some adults aged 27-45 years who are not adequately vaccinated. The ACS does not endorse this recommendation "because of the low effectiveness and low cancer prevention potential of vaccination in this age group, the burden of decision-making on patients and clinicians, and the lack of sufficient guidance on the selection of individuals who might benefit," wrote Debbie Saslow, PhD, of the ACS's section on human papillomavirus and gynecologic cancers, and colleagues.

Dr. Saslow and colleagues detailed the ACS recommendations in CA: A Cancer Journal for Clinicians.

The HPV vaccine protects against the virus that can cause cervical, oropharyngeal, anal, vaginal, vulvar, and penile cancers. For younger people, the ACIP recommends routine HPV vaccination of boys and girls aged 9-12 years and catch-up vaccination in everyone up to age 26 who has not been fully immunized against HPV.

The ACS endorses both of these recommendations. It also advises clinicians to tell patients aged 22-26 years who haven't received the HPV vaccine or completed the series that the vaccine is less effective at reducing the risk of cancer at older ages.

After the Food and Drug Administration approved the HPV vaccine for adults aged 27-45 years, the ACIP updated its recommendations to state that routine catch-up vaccination is not recommended for anyone aged over 26 years. However, the ACIP recommended that these older adults talk with their providers about the risks and benefits of the vaccine to determine whether to get it.

The ACS subsequently conducted a methodological review of the ACIP's recommendations and published its own adapted guidance, stating that the ACS does not endorse the shared decision-making. Administering the HPV vaccine to adults aged over 26 years would only prevent an estimated 0.5% of additional cancer cases, 0.4% additional cases of cervical precancer, and 0.3% additional cases of genital warts over the next 100 years, compared with vaccination under age 26.A"In addition to the low effectiveness and low cancer prevention potential of vaccination in this age group, other considerations included the burden of decision-making on patients and clinicians and the lack of sufficient guidance on the selection of individuals who might benefit," according to the guidance. The ACS also expressed concern that these provider-patient discussions could interfere with the public health goal of increasing HPV vaccination in younger peopleHPV vaccination rates have lagged substantially behind other routinely recommended childhood vaccinations. Just over half (51%) of U.S. teens aged 13-17 years were up to date with HPV vaccination, and 68% had received one dose of the vaccine in 2018, according to the National Immunization Survey.

It's very uncommon for a professional medical organization to not endorse recommendations from the CDC, particularly with vaccines, according to Robert A. Bednarczyk, PhD, an assistant professor of public health at Emory University, Atlanta, who specializes in HPV vaccination research but was not involved with the ACS statement or the ACIP recommendations.

"Often, for vaccination recommendations, there is a harmonization between health care provider organizations, such as the American Academy of Pediatrics, American Academy of Family Physicians, etc., when new vaccination schedules are released," Dr. Bednarczyk said.

He acknowledged the ACS's reasons for not endorsing the ACIP's HPV recommendations in older adults: the burden of shared decision-making given the communication issues, the vaccine's lower effectiveness in this population, and the ongoing HPV vaccine shortage.

But Dr. Bednarczyk also pointed out that the ACIP's recommendation opens the door to these discussions when they may actually be needed, such as in adults at greater risk for HPV. He cited data suggesting that, in 2015, divorces occurred in 24 out of 1,000 married people aged 25-39 years and 21 out of 1,000 people aged 40-49.

"When you consider these marriages that end, in addition to marriages that end when one spouse dies, there is a potential for individuals who previously had a low risk of HPV acquisition now entering into new potential sexual relationships," Dr. Bednarczyk said. "Additionally, it has been estimated that approximately 4% of the U.S. population are in open or consensually nonmonogamous relationships, where exposure to more sexual partners may increase their risk for HPV. These are just some examples of where conversations with health care providers, and shared clinical decision-making, can help with a targeted reduction of HPV risk."

The ACIP recommendation regarding adults aged 27-45 years also provides people in this age group with insurance coverage for the HPV vaccine if they choose to get it, Dr. Bednarczyk pointed out. Insurance companies may not be required to cover HPV vaccination in people aged over 26 years without the CDC's recommendation, even if it's not for routine immunization.

Dr. Bednarczyk agreed, however, with how the ACS adapted the CDC's recommendation for routine vaccination in youth. The CDC's routine recommendation is at ages 11-12 but can begin at 9 years, according to the ACIP. The ACS guidance qualifies this statement to place more emphasis on encouraging the vaccine earlier.

"Routine HPV vaccination between ages 9-12 is expected to achieve higher on-time vaccination rates, resulting in increased numbers of cancers prevented," according to the ACS. "Health care providers are encouraged to start offering the HPV vaccine at age 9 or 10."

Dr. Bednarczyk pointed to some of his past research finding low proportions of teens fully vaccinated against HPV by age 13 years (J Infect Dis. 2019 Jul 31;220[5]:730-4). Therefore, "any efforts to encourage vaccination, including starting the series at ages 9-10 years may help," he said.

He also agreed that there may be diminished effectiveness with vaccinating adults aged 22-26, "but this should also be considered relative to an individual's risk of acquiring HPV."

While an HPV vaccine shortage is a major concern and HPV vaccination efforts should remain most focused on young teens, adults should not necessarily be neglected, Dr. Bednarczyk noted.

"Given how common HPV infection is in the population, open discussion between patients and health care providers can help identify those adults for whom HPV vaccination can be effective," he said.

The development of the ACS guideline was supported by ACS operational funds. The ACS has received an independent educational grant from Merck Sharp & Dohme for a project intended to increase HPV vaccination rates. Dr. Saslow is the principal investigator for a cooperative agreement between the ACS and the CDC to support the National HPV Vaccination Roundtable and is coprincipal investigator of a cooperative agreement between the ACS and CDC to support initiatives to increase HPV vaccination. The remaining authors and Dr. Bednarczyk reported no relevant disclosures.

SOURCE: Saslow D et al. CA Cancer J Clin. 2020 Jul 8. doi: 10.3322/caac.21616.

This article originally appeared on MDedge.com.

TRASTUZUMAB IN HER2+ SEROUS ENDOMETRIAL CANCER

Combining the HER2-targeted therapy trastuzumab with carboplatin and paclitaxel improved survival rates for women with a rare, aggressive type of endometrial cancer, according to findings published by Fader et al in Clinical Cancer Research.

Each year, more than 65,650 women in the United States are diagnosed with endometrial cancer, and over 12,590 die of the disease.

“As this country’s population ages and obesity climbs, these numbers are likely to double in the next decade,” said senior study author Alessandro Santin, MD, Professor of Gynecology, Obstetrics & Reproductive Sciences and Leader of the Disease Aligned Research Team of the Gynecologic Oncology Program at Smilow Cancer Hospital and Yale Cancer Center, in a statement. “Uterine serous carcinoma accounts for only 3% to 10% of all these cases of endometrial cancer, but it kills over 40% of the patients because it’s so aggressive.”

Study Methods

“The randomized, multi-institutional phase II trial studied 58 women with uterine serous carcinoma whose tumors expressed high levels of the HER2 protein, which is known to drive several forms of cancer in women,” said Dr. Santin.

After surgery, women with either stage III or IV disease were randomly assigned to treatment with chemotherapy regimen of carboplatin and paclitaxel for six cycles, or the same combination chemotherapy regimen followed by trastuzumab. The primary study endpoint was progression-free survival.

Results

“Addition of trastuzumab to carboplatin/paclitaxel increased progression-free survival and overall survival in women with advanced/recurrent HER2-positive uterine serous carcinoma, with the greatest benefit seen for the treatment of stage III to IV disease.”

— Alessandro Santin, MD, and colleagues

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Average progression-free survival almost doubled: from 9.3 months in the control arm to 17.7 months in the trastuzumab arm among 41 patients with stage III to IV disease undergoing primary treatment, and from 7.0 months to 9.2 months among 17 patients with recurrent disease.

Overall survival benefit was most notable in women with stage III to IV disease, with survival median not reached in those given trastuzumab vs 24.4 months in the control group.

“Importantly, the trial showed no difference in toxicity between the two groups,” added Dr. Santin.

Among the 17 women in the study whose cancer recurred, the combination treatment prolonged the disease-free interval but did not significantly improve survival when compared to the standard chemotherapy regimen.

“These are patients who return with large amounts of metastatic cancer,” said Dr. Santin said. “Most likely their tumor burden is so high and heterogenous that the tumor becomes resistant also to trastuzumab.”

The study authors concluded, “Addition of trastuzumab to carboplatin/paclitaxel increased progression-free survival and overall survival in women with advanced/recurrent HER2-positive uterine serous carcinoma, with the greatest benefit seen for the treatment of stage III to IV disease.”

GUIDELINES FOR CERVICAL CANCER RT

A new clinical guideline from the American Society for Radiation Oncology (ASTRO) provides recommendations for radiation therapy to treat patients with nonmetastatic cervical cancer. The guideline—ASTRO's first for cervical cancer—outlines indications and best practices for external-beam radiation therapy (EBRT) and brachytherapy in the postoperative and definitive settings. Recommendations also address other treatments, including chemotherapy and surgery when used in combination with radiation. The guideline was published by Chino et al in Practical Radiation Oncology.

Photo credit: Getty

“[Treatment for] cervical cancer has advanced dramatically over the last 20 years. Increased use of intensity-modulated radiation therapy (IMRT) and image-guided brachytherapy, in particular, have resulted in better patient outcomes and fewer treatment complications. Our intention in developing this guideline is to encourage physicians to make these approaches part of their daily practice,” said Akila N. Viswanathan, MD, MPH, Chair of the guideline task force and Professor and Interim Director of Radiation Oncology and Molecular Radiation Sciences at the Johns Hopkins Sidney Kimmel Cancer Center.

Radiation is an integral part of cervical cancer treatment, either following surgery for patients at risk of recurrence or as a primary definitive treatment. The regimen involves pelvic EBRT, often combined with chemotherapy and a brachytherapy boost.

“We've moved from 2D and 3D treatments for the pelvis into IMRT, a highly focused form of radiation that reduces a patient's risk of treatment complications. We also have seen significant improvements in outcomes with image guidance for brachytherapy. Treatment teams use the most advanced imaging modalities available, and that allows us to treat exactly what we need to treat and avoid normal tissues,” said Junzo Chino, MD, Vice Chair of the guideline task force and Associate Professor of Radiation Oncology at Duke University Cancer Center.

The guideline was based on a systematic literature review of articles published from January 1993 through October 2018; rare histologies, noninvasive disease, and palliative treatment were outside the scope of the current guideline. The multidisciplinary panel included radiation oncologists, a gynecologic oncologist, a medical oncologist, a radiation oncology resident, a medical physicist, and a patient representative. The guideline was endorsed by the American Brachytherapy Society, Canadian Association of Radiation Oncology, European Society for Radiotherapy and Oncology, Royal Australian and New Zealand College of Radiologists, and the Society of Gynecologic Oncology.

The guideline's recommendations address the indications for postoperative and definitive radiation therapy, the use of chemotherapy in combination with radiation, the use of IMRT, and the indications and techniques of brachytherapy. Key recommendations are reproduced below.

Recommendations: Radiation Therapy for Locally Advanced Cervical Cancer

• In the postoperative setting following radical hysterectomy, radiation with concurrent platinum-based chemotherapy (chemoradiation) is recommended for patients with high-risk factors, such as positive margins. Postoperative radiation therapy is recommended for patients with intermediate-risk factors, such as larger tumors. Risk criteria are defined in the guideline.
• In the definitive setting, chemoradiation therapy is recommended for patients with International Federation of Gynecology and Obstetrics stage IB3–IVA disease. Definitive radiation or chemoradiation is conditionally recommended for patients with stage IA1–IB2 disease who are medically inoperable.
• IMRT is recommended for postoperative EBRT and conditionally recommended for definitive EBRT to reduce short- and long-term toxicity.
• Brachytherapy is strongly recommended for patients receiving definitive radiation or chemoradiation. Neither SBRT nor IMRT is a suitable substitute for brachytherapy. In the postoperative setting, brachytherapy is conditionally recommended with the presence of positive margin(s).
• The guideline also addresses optimal dosing, fractionation, and technique for EBRT and brachytherapy, including recommendations for image guidance, volume-based treatment planning, and strategies to limit radiation spread to organs at risk.

Treatment-Related Side Effects

Treatment for cervical cancer can be a challenging experience for patients, given the proximity of the cervix to other critical organs in the pelvis and the combination of multiple therapies.

“Irrespective of the techniques used, radiation therapy for cervical cancer causes side effects for many patients—most commonly, fatigue and complications in the bowel and bladder. Newer radiation technologies can significantly reduce these complications, however. The hallmark of [guided] brachytherapy, for example, is fewer bowel or bladder side effects than with traditional brachytherapy techniques. Medications to manage side effects have also improved considerably,” said Dr. Viswanathan.

“The issues facing women with cervical cancer are unique,” said Dr. Chino. “Doing everything we can to eliminate the tumor is only part of our job. The other part is to make sure that patients are doing well throughout the treatment process.”

COVID-19 and Cervical Cancer

The guideline was completed before the pandemic and therefore does not address the role of COVID-19 in the treatment of cervical cancer. Dr. Viswanathan and Dr. Chino also expressed concern about the effects of the coronavirus pandemic on patients with cervical cancer.

“Cervical cancer is one of those cancers where you just can't wait. You need to treat it right away in order to have the greatest chance of cure,” said Dr. Viswanathan.

“I worry about women not coming in at a time when earlier treatment could be exceedingly beneficial to them,” added Dr. Chino. "I hope that women who have symptoms will continue to be identified early and come in for treatment. We are also preparing for a potential surge of cases where, for understandable reasons, they did not seek screening or treatment as early as they may have before the pandemic. I fear that we will see more patients with more advanced disease.”

Both doctors noted that their clinics implemented a series of safety enhancements and process upgrades that have allowed them to continue cervical cancer treatments safely during the pandemic.

Disclosure: For full disclosures of the guideline authors, visit practicalradonc.org.