Cervical dysplasia is commonly diagnosed in women who have completed childbearing and don’t desire future fertility. While diagnostic and/or definitive therapy for cervical dysplasia can include hysterectomy, there are important considerations to make when offering this procedure to patients.
Dr. Emma C. Rossi
Pitfalls
Hysterectomy is commonly requested by patients upon learning of cervical dysplasia, particularly if they have chronic human papillomavirus (HPV) infection and have experienced years of frequent surveillance and interventions. They may see hysterectomy as an option to avoid this close surveillance and to be free of their dysplasia. There are two main concerns with offering hysterectomy as the primary surgical option for the management of dysplasia. Firstly, it may not be curative, and secondly, it may be an inadequate excisional procedure, particularly if the patient has occult invasive disease that has not been adequately diagnosed with a loop electrosurgical excision procedure (LEEP) or a cone biopsy procedure.
It is important to counsel these patients that surgery is not a treatment for high-risk HPV infection, which is the underlying etiology of their disease. With that etiology, HPV infection is likely to persist after hysterectomy and they may develop vaginal or vulvar dysplasia. Therefore, the American Society for Colposcopy and Cervical Pathology recommends that cytology and/or high-risk HPV surveillance continue following hysterectomy if that surgery was performed for dysplasia.1 Hysterectomy is not a means to avoid years of surveillance testing. Approximately 10% of women who have hysterectomy for cervical dysplasia develop vaginal dysplasia or cancer after surgery.2,3 This is similar to the likelihood of recurrent dysplasia after an alternative excisional procedure. In my experience, this diagnosis is often met with enormous frustration for the patient who thought that her hysterectomy would be the cure of her HPV-related disease. Thorough colposcopic evaluation of the vagina can be technically challenging after hysterectomy because of difficulty adequately visualizing lesions within the vaginal rugations, particularly within the puckered lateral vaginal fornices, the most common location for dysplasia.3 We will explore the diagnosis and treatment options for vaginal dysplasia further in a future column.
It is critical that, if patients are offered hysterectomy for treatment of cervical dysplasia, they are counseled that it may not be curative, that they will require long-term vaginal surveillance, and that they are at continued risk for vaginal and vulvar cancer.
An additional concern with performing hysterectomy for definitive management of cervical dysplasia is the concern that occult cancer may be missed preoperatively, and that the hysterectomy is inadequate surgical clearance of the disease. Approximately 2%-5% of patients with a high-grade squamous intraepithelial lesion or equivocal Pap test have occult cervical cancer.4 A similar proportion of patients with cervical intraepithelial neoplasia stage III or adenocarcinoma in situ on colposcopy biopsy have invasive carcinoma on evaluation of an excisional specimen.5 The traditional surgical approach has dictated that a modified (type II) or extended (type III) radical hysterectomy be performed in the setting of FIGO stage IA2 or greater cervical cancer. Radical hysterectomies remove parametrial tissue, effectively achieving a wider margin around the primary lesion. This is important because cervical cancer primarily spreads via direct extension.
The appropriate radicality of surgery for microscopic lesions is debated. It has been proposed that for very small, low-risk lesions, a traditional extrafascial hysterectomy or trachelectomy, or possibly even a large conization, may be adequate.6 However, this is controversial, and National Comprehensive Cancer Network guidelines still advocate for radical procedures for these lesions.7 Certainly an excisional procedure (LEEP or cone) should first be performed to define the size and histologic features of the lesion, and ideally, evaluation and counseling with a gynecologic oncologist should be performed prior to offering patients with a stage IA2 or greater lesion an extrafascial hysterectomy. Additionally, a separate decision would need to be made regarding the need for lymphadenectomy, as this is typically recommended for patients with stage IA2 or greater lesions.
Patients should be counseled that, if extrafascial (simple) hysterectomy is chosen as the primary excisional procedure, they may require additional therapy (additional surgery, or radiation and possibly chemotherapy) if cancer is found in the specimen and the parametrial margin is inadequate. Additionally, and of more concern, if the lesion is a bulky lesion extending into the parametrium and not recognized preoperatively, a “cut-through” hysterectomy will be inadvertently performed (in which margins are grossly positive). These situations typically feature heavy blood loss with patients at increased risk for immediate surgical complications. Postoperatively, prognosis is substantially worse for patients who have had a cut-through hysterectomy, compared stage for stage with patients who primarily received a radical procedure with negative margins or primary chemotherapy and radiation.8 Otherwise said, their risk for death is higher if this error is made. Therefore a thorough examination is essential prior to performing hysterectomy for dysplasia. Any suspicion of bulky cancer should be considered a contraindication for proceeding.
Preoperative evaluation
As a rule, no patient should transition directly from cytologic evaluation with Pap screening to hysterectomy. A colposcopic evaluation of the cervix and vagina accompanied with a thorough bimanual rectovaginal examination should always be performed first. Biopsies of the ectocervix and ideally the endocervix should be obtained because the accuracy of histology is greater than that of cytology. For patients with cervical intraepithelial neoplasia stage I lesions, hysterectomy is not appropriate, as these patients have an extremely low risk for the development of cervical cancer, and the risks and costs of hysterectomy are not justified in such a population.
Surgeons should wait at least 6 weeks following conization or LEEP before performing hysterectomy in order to minimize the likelihood of perioperative complications.9
Substituting LEEP or cone with hysterectomy
In general, it is the most prudent approach to first perform a diagnostic excision with LEEP or cone biopsy before proceeding with hysterectomy for definitive surgery. However, there may be some situations in which this is not feasible. In patients whose cervix is very small and flush with the vagina, an excisional procedure may not be technically possible without concern for damage to adjacent structures. In these patients, after a thorough exam has evaluated for gross disease, a hysterectomy may be the only way to adequately diagnose and treat high-grade dysplasia through excision. For patients with limited access to resources, transportation, or a concern for noncompliance with follow-up, surgeons may wish to offer patients primary hysterectomy rather than a staged procedure.
Hysterectomy remains a potential option for treatment of cervical dysplasia. However, patients should be made aware of the risks of undertreatment of occult cancers, the need for long-term surveillance testing, and the risk for future vaginal dysplasia or cancer. Ideally a comprehensive, stepwise assessment from cytology to colposcopy and examination to diagnostic excisional procedure will first take place to proceed safely with this approach.
References
1. Saslow D et al. American Cancer Society, American Society for Colposcopy and Cervical Pathology, and American Society for Clinical Pathology screening guidelines for the prevention and early detection of cervical cancer. CA Cancer J Clin. 2012 May-Jun;62(3):147-72.
2. Schockaert S et al. Incidence of vaginal intraepithelial neoplasia after hysterectomy for cervical intraepithelial neoplasia: a retrospective study. Am J Obstet Gynecol. 2008 Aug;199(2):113.e1-5.
3. Kalogirou D et al. Vaginal intraepithelial neoplasia (VAIN) following hysterectomy in patients treated for carcinoma in situ of the cervix. Eur J Gynaecol Oncol. 1997;18(3):188-91.
5. Latif NA et al. Management of adenocarcinoma in situ of the uterine cervix: a comparison of loop electrosurgical excision procedure and cold knife conization. J Low Genit Tract Dis. 2015 Apr;19(2):97-102.
8. Barber HR et al. Operative management of patients previously operated upon for a benign lesion with cervical cancer as a surprise finding. Am J Obstet Gynecol. 1968 Aug 1;101(7):959-65.
9. Sullivan SA et al. Association between timing of cervical excision procedure to minimally invasive hysterectomy and surgical complications. Gynecol Oncol. 2017 Feb;144(2):294-298.
Cervical dysplasia is commonly diagnosed in women who have completed childbearing and don’t desire future fertility. While diagnostic and/or definitive therapy for cervical dysplasia can include hysterectomy, there are important considerations to make when offering this procedure to patients.
Dr. Emma C. Rossi
Pitfalls
Hysterectomy is commonly requested by patients upon learning of cervical dysplasia, particularly if they have chronic human papillomavirus (HPV) infection and have experienced years of frequent surveillance and interventions. They may see hysterectomy as an option to avoid this close surveillance and to be free of their dysplasia. There are two main concerns with offering hysterectomy as the primary surgical option for the management of dysplasia. Firstly, it may not be curative, and secondly, it may be an inadequate excisional procedure, particularly if the patient has occult invasive disease that has not been adequately diagnosed with a loop electrosurgical excision procedure (LEEP) or a cone biopsy procedure.
It is important to counsel these patients that surgery is not a treatment for high-risk HPV infection, which is the underlying etiology of their disease. With that etiology, HPV infection is likely to persist after hysterectomy and they may develop vaginal or vulvar dysplasia. Therefore, the American Society for Colposcopy and Cervical Pathology recommends that cytology and/or high-risk HPV surveillance continue following hysterectomy if that surgery was performed for dysplasia.1 Hysterectomy is not a means to avoid years of surveillance testing. Approximately 10% of women who have hysterectomy for cervical dysplasia develop vaginal dysplasia or cancer after surgery.2,3 This is similar to the likelihood of recurrent dysplasia after an alternative excisional procedure. In my experience, this diagnosis is often met with enormous frustration for the patient who thought that her hysterectomy would be the cure of her HPV-related disease. Thorough colposcopic evaluation of the vagina can be technically challenging after hysterectomy because of difficulty adequately visualizing lesions within the vaginal rugations, particularly within the puckered lateral vaginal fornices, the most common location for dysplasia.3 We will explore the diagnosis and treatment options for vaginal dysplasia further in a future column.
It is critical that, if patients are offered hysterectomy for treatment of cervical dysplasia, they are counseled that it may not be curative, that they will require long-term vaginal surveillance, and that they are at continued risk for vaginal and vulvar cancer.
An additional concern with performing hysterectomy for definitive management of cervical dysplasia is the concern that occult cancer may be missed preoperatively, and that the hysterectomy is inadequate surgical clearance of the disease. Approximately 2%-5% of patients with a high-grade squamous intraepithelial lesion or equivocal Pap test have occult cervical cancer.4 A similar proportion of patients with cervical intraepithelial neoplasia stage III or adenocarcinoma in situ on colposcopy biopsy have invasive carcinoma on evaluation of an excisional specimen.5 The traditional surgical approach has dictated that a modified (type II) or extended (type III) radical hysterectomy be performed in the setting of FIGO stage IA2 or greater cervical cancer. Radical hysterectomies remove parametrial tissue, effectively achieving a wider margin around the primary lesion. This is important because cervical cancer primarily spreads via direct extension.
The appropriate radicality of surgery for microscopic lesions is debated. It has been proposed that for very small, low-risk lesions, a traditional extrafascial hysterectomy or trachelectomy, or possibly even a large conization, may be adequate.6 However, this is controversial, and National Comprehensive Cancer Network guidelines still advocate for radical procedures for these lesions.7 Certainly an excisional procedure (LEEP or cone) should first be performed to define the size and histologic features of the lesion, and ideally, evaluation and counseling with a gynecologic oncologist should be performed prior to offering patients with a stage IA2 or greater lesion an extrafascial hysterectomy. Additionally, a separate decision would need to be made regarding the need for lymphadenectomy, as this is typically recommended for patients with stage IA2 or greater lesions.
Patients should be counseled that, if extrafascial (simple) hysterectomy is chosen as the primary excisional procedure, they may require additional therapy (additional surgery, or radiation and possibly chemotherapy) if cancer is found in the specimen and the parametrial margin is inadequate. Additionally, and of more concern, if the lesion is a bulky lesion extending into the parametrium and not recognized preoperatively, a “cut-through” hysterectomy will be inadvertently performed (in which margins are grossly positive). These situations typically feature heavy blood loss with patients at increased risk for immediate surgical complications. Postoperatively, prognosis is substantially worse for patients who have had a cut-through hysterectomy, compared stage for stage with patients who primarily received a radical procedure with negative margins or primary chemotherapy and radiation.8 Otherwise said, their risk for death is higher if this error is made. Therefore a thorough examination is essential prior to performing hysterectomy for dysplasia. Any suspicion of bulky cancer should be considered a contraindication for proceeding.
Preoperative evaluation
As a rule, no patient should transition directly from cytologic evaluation with Pap screening to hysterectomy. A colposcopic evaluation of the cervix and vagina accompanied with a thorough bimanual rectovaginal examination should always be performed first. Biopsies of the ectocervix and ideally the endocervix should be obtained because the accuracy of histology is greater than that of cytology. For patients with cervical intraepithelial neoplasia stage I lesions, hysterectomy is not appropriate, as these patients have an extremely low risk for the development of cervical cancer, and the risks and costs of hysterectomy are not justified in such a population.
Surgeons should wait at least 6 weeks following conization or LEEP before performing hysterectomy in order to minimize the likelihood of perioperative complications.9
Substituting LEEP or cone with hysterectomy
In general, it is the most prudent approach to first perform a diagnostic excision with LEEP or cone biopsy before proceeding with hysterectomy for definitive surgery. However, there may be some situations in which this is not feasible. In patients whose cervix is very small and flush with the vagina, an excisional procedure may not be technically possible without concern for damage to adjacent structures. In these patients, after a thorough exam has evaluated for gross disease, a hysterectomy may be the only way to adequately diagnose and treat high-grade dysplasia through excision. For patients with limited access to resources, transportation, or a concern for noncompliance with follow-up, surgeons may wish to offer patients primary hysterectomy rather than a staged procedure.
Hysterectomy remains a potential option for treatment of cervical dysplasia. However, patients should be made aware of the risks of undertreatment of occult cancers, the need for long-term surveillance testing, and the risk for future vaginal dysplasia or cancer. Ideally a comprehensive, stepwise assessment from cytology to colposcopy and examination to diagnostic excisional procedure will first take place to proceed safely with this approach.
References
1. Saslow D et al. American Cancer Society, American Society for Colposcopy and Cervical Pathology, and American Society for Clinical Pathology screening guidelines for the prevention and early detection of cervical cancer. CA Cancer J Clin. 2012 May-Jun;62(3):147-72.
2. Schockaert S et al. Incidence of vaginal intraepithelial neoplasia after hysterectomy for cervical intraepithelial neoplasia: a retrospective study. Am J Obstet Gynecol. 2008 Aug;199(2):113.e1-5.
3. Kalogirou D et al. Vaginal intraepithelial neoplasia (VAIN) following hysterectomy in patients treated for carcinoma in situ of the cervix. Eur J Gynaecol Oncol. 1997;18(3):188-91.
5. Latif NA et al. Management of adenocarcinoma in situ of the uterine cervix: a comparison of loop electrosurgical excision procedure and cold knife conization. J Low Genit Tract Dis. 2015 Apr;19(2):97-102.
8. Barber HR et al. Operative management of patients previously operated upon for a benign lesion with cervical cancer as a surprise finding. Am J Obstet Gynecol. 1968 Aug 1;101(7):959-65.
9. Sullivan SA et al. Association between timing of cervical excision procedure to minimally invasive hysterectomy and surgical complications. Gynecol Oncol. 2017 Feb;144(2):294-298.
Cervical dysplasia is commonly diagnosed in women who have completed childbearing and don’t desire future fertility. While diagnostic and/or definitive therapy for cervical dysplasia can include hysterectomy, there are important considerations to make when offering this procedure to patients.
Dr. Emma C. Rossi
Pitfalls
Hysterectomy is commonly requested by patients upon learning of cervical dysplasia, particularly if they have chronic human papillomavirus (HPV) infection and have experienced years of frequent surveillance and interventions. They may see hysterectomy as an option to avoid this close surveillance and to be free of their dysplasia. There are two main concerns with offering hysterectomy as the primary surgical option for the management of dysplasia. Firstly, it may not be curative, and secondly, it may be an inadequate excisional procedure, particularly if the patient has occult invasive disease that has not been adequately diagnosed with a loop electrosurgical excision procedure (LEEP) or a cone biopsy procedure.
It is important to counsel these patients that surgery is not a treatment for high-risk HPV infection, which is the underlying etiology of their disease. With that etiology, HPV infection is likely to persist after hysterectomy and they may develop vaginal or vulvar dysplasia. Therefore, the American Society for Colposcopy and Cervical Pathology recommends that cytology and/or high-risk HPV surveillance continue following hysterectomy if that surgery was performed for dysplasia.1 Hysterectomy is not a means to avoid years of surveillance testing. Approximately 10% of women who have hysterectomy for cervical dysplasia develop vaginal dysplasia or cancer after surgery.2,3 This is similar to the likelihood of recurrent dysplasia after an alternative excisional procedure. In my experience, this diagnosis is often met with enormous frustration for the patient who thought that her hysterectomy would be the cure of her HPV-related disease. Thorough colposcopic evaluation of the vagina can be technically challenging after hysterectomy because of difficulty adequately visualizing lesions within the vaginal rugations, particularly within the puckered lateral vaginal fornices, the most common location for dysplasia.3 We will explore the diagnosis and treatment options for vaginal dysplasia further in a future column.
It is critical that, if patients are offered hysterectomy for treatment of cervical dysplasia, they are counseled that it may not be curative, that they will require long-term vaginal surveillance, and that they are at continued risk for vaginal and vulvar cancer.
An additional concern with performing hysterectomy for definitive management of cervical dysplasia is the concern that occult cancer may be missed preoperatively, and that the hysterectomy is inadequate surgical clearance of the disease. Approximately 2%-5% of patients with a high-grade squamous intraepithelial lesion or equivocal Pap test have occult cervical cancer.4 A similar proportion of patients with cervical intraepithelial neoplasia stage III or adenocarcinoma in situ on colposcopy biopsy have invasive carcinoma on evaluation of an excisional specimen.5 The traditional surgical approach has dictated that a modified (type II) or extended (type III) radical hysterectomy be performed in the setting of FIGO stage IA2 or greater cervical cancer. Radical hysterectomies remove parametrial tissue, effectively achieving a wider margin around the primary lesion. This is important because cervical cancer primarily spreads via direct extension.
The appropriate radicality of surgery for microscopic lesions is debated. It has been proposed that for very small, low-risk lesions, a traditional extrafascial hysterectomy or trachelectomy, or possibly even a large conization, may be adequate.6 However, this is controversial, and National Comprehensive Cancer Network guidelines still advocate for radical procedures for these lesions.7 Certainly an excisional procedure (LEEP or cone) should first be performed to define the size and histologic features of the lesion, and ideally, evaluation and counseling with a gynecologic oncologist should be performed prior to offering patients with a stage IA2 or greater lesion an extrafascial hysterectomy. Additionally, a separate decision would need to be made regarding the need for lymphadenectomy, as this is typically recommended for patients with stage IA2 or greater lesions.
Patients should be counseled that, if extrafascial (simple) hysterectomy is chosen as the primary excisional procedure, they may require additional therapy (additional surgery, or radiation and possibly chemotherapy) if cancer is found in the specimen and the parametrial margin is inadequate. Additionally, and of more concern, if the lesion is a bulky lesion extending into the parametrium and not recognized preoperatively, a “cut-through” hysterectomy will be inadvertently performed (in which margins are grossly positive). These situations typically feature heavy blood loss with patients at increased risk for immediate surgical complications. Postoperatively, prognosis is substantially worse for patients who have had a cut-through hysterectomy, compared stage for stage with patients who primarily received a radical procedure with negative margins or primary chemotherapy and radiation.8 Otherwise said, their risk for death is higher if this error is made. Therefore a thorough examination is essential prior to performing hysterectomy for dysplasia. Any suspicion of bulky cancer should be considered a contraindication for proceeding.
Preoperative evaluation
As a rule, no patient should transition directly from cytologic evaluation with Pap screening to hysterectomy. A colposcopic evaluation of the cervix and vagina accompanied with a thorough bimanual rectovaginal examination should always be performed first. Biopsies of the ectocervix and ideally the endocervix should be obtained because the accuracy of histology is greater than that of cytology. For patients with cervical intraepithelial neoplasia stage I lesions, hysterectomy is not appropriate, as these patients have an extremely low risk for the development of cervical cancer, and the risks and costs of hysterectomy are not justified in such a population.
Surgeons should wait at least 6 weeks following conization or LEEP before performing hysterectomy in order to minimize the likelihood of perioperative complications.9
Substituting LEEP or cone with hysterectomy
In general, it is the most prudent approach to first perform a diagnostic excision with LEEP or cone biopsy before proceeding with hysterectomy for definitive surgery. However, there may be some situations in which this is not feasible. In patients whose cervix is very small and flush with the vagina, an excisional procedure may not be technically possible without concern for damage to adjacent structures. In these patients, after a thorough exam has evaluated for gross disease, a hysterectomy may be the only way to adequately diagnose and treat high-grade dysplasia through excision. For patients with limited access to resources, transportation, or a concern for noncompliance with follow-up, surgeons may wish to offer patients primary hysterectomy rather than a staged procedure.
Hysterectomy remains a potential option for treatment of cervical dysplasia. However, patients should be made aware of the risks of undertreatment of occult cancers, the need for long-term surveillance testing, and the risk for future vaginal dysplasia or cancer. Ideally a comprehensive, stepwise assessment from cytology to colposcopy and examination to diagnostic excisional procedure will first take place to proceed safely with this approach.
References
1. Saslow D et al. American Cancer Society, American Society for Colposcopy and Cervical Pathology, and American Society for Clinical Pathology screening guidelines for the prevention and early detection of cervical cancer. CA Cancer J Clin. 2012 May-Jun;62(3):147-72.
2. Schockaert S et al. Incidence of vaginal intraepithelial neoplasia after hysterectomy for cervical intraepithelial neoplasia: a retrospective study. Am J Obstet Gynecol. 2008 Aug;199(2):113.e1-5.
3. Kalogirou D et al. Vaginal intraepithelial neoplasia (VAIN) following hysterectomy in patients treated for carcinoma in situ of the cervix. Eur J Gynaecol Oncol. 1997;18(3):188-91.
5. Latif NA et al. Management of adenocarcinoma in situ of the uterine cervix: a comparison of loop electrosurgical excision procedure and cold knife conization. J Low Genit Tract Dis. 2015 Apr;19(2):97-102.
8. Barber HR et al. Operative management of patients previously operated upon for a benign lesion with cervical cancer as a surprise finding. Am J Obstet Gynecol. 1968 Aug 1;101(7):959-65.
9. Sullivan SA et al. Association between timing of cervical excision procedure to minimally invasive hysterectomy and surgical complications. Gynecol Oncol. 2017 Feb;144(2):294-298.
Women with platinum-sensitive recurrent ovarian cancer who received maintenance therapy with a poly(ADP-ribose) polymerase (PARP) inhibitor had no significant decreases in health-related quality of life, outcomes data from two randomized clinical trials show.
Health-related quality of life (HRQOL) analyses from the SOLO2/ENGOT-Ov-21 trial comparing olaparib (Lynparza) with placebo and the ENGOT-OV16/NOVA trial comparing niraparib (Zejula) with placebo as maintenance therapy in women with ongoing responses to their last platinum-based chemotherapy showed that neither agent had major detrimental effects on patient-reported outcomes, further supporting the progression-free survival benefits previously seen with each agent in its respective trials.
“These results show the significant benefit of maintenance olaparib to patients beyond the RECIST [Response Evaluation Criteria in Solid Tumors] definition of progression, the primary endpoint of SOLO2, and highlight the importance of including patient-centered outcomes in addition to HRQOL in trials of maintenance therapy, in line with the recommendations of the 5th Ovarian Cancer Consensus Conference,” wrote Michael Friedlander, MD, of the University of New South Wales Clinical School and Prince of Wales Hospital in Randwick, New South Wales, Australia, and his colleagues.
Similarly, Amit M. Oza, MD, of Princess Margaret Cancer Centre in Toronto, and his coinvestigators in the ENGOT-OV16/NOVA trial found that “niraparib has no significant negative effect on QOL in patients with recurrent ovarian cancer. Combined with the evidence of increased progression-free survival with niraparib in the maintenance setting, these findings support the addition of niraparib as a component of standard of care.”
In SOLO2, patients with a germline BRCA1 or BRCA2 mutation and platinum-sensitive ovarian cancer that relapsed after at least two lines of chemotherapy were randomly assigned to receive either oral olaparib 300 mg twice daily (196 patients) or placebo (99 patients).
The prespecified primary HRQOL analysis looked at the change from baseline in the Functional Assessment of Cancer Therapy–Ovarian Cancer (FACT-O) Trial Outcome Index (TOI) score during the first 12 months of the study.
In addition, the investigators examined secondary planned QOL analyses, including duration of good quality of life, defined as time without significant symptoms of toxicity, or TWiST, and quality-adjusted progression-free survival (QAPFS).
The adjusted average mean change from baseline over the first 12 months in TOI was –2.90 with olaparib vs. –2.87 with placebo (nonsignificant).
In contrast, patients treated with olaparib had significantly better mean QAPFS (13.96 vs. 7.28 months) and TWiST (15.03 vs. 7.70 months) results.
“All these predefined endpoints support the benefit to patients of a prolongation of progression-free survival, which is the primary endpoint in maintenance trials in ovarian cancer, and should be routinely included in future trials,” wrote Dr. Friedlander and his associates.
ENGOT-OV16/NOVA QOL summary
Investigators for this trial enrolled patients into two independent cohorts based on germline BRCA mutations or lack thereof. In all, 138 patients were assigned to niraparib and 65 to placebo in the germline BRCA mutation cohort, and 234 to niraparib and 116 to placebo in the nonmutation cohort.
The current study assessed patient-reported outcomes in the intention-to-treat population using different validated instruments from those assessed in SOLO2: the Functional Assessment of Cancer Therapy–Ovarian Symptoms Index (FOSI) and European QOL five-dimension five-level questionnaire (EQ-5D-5L).
The outcomes were reported every 8 weeks for the first 14 treatment cycles and every 12 weeks thereafter.
The investigators looked at the effects of hematologic toxicities on QOL with disutility analyses (measuring the decrement on QOL of a particular symptom or complication) of the most common grade 3-4 adverse events (thrombocytopenia, anemia, and neutropenia) using a mixed model with covariates.
They found that overall QOL scores remained stable during treatment and the preprogression period among patients on niraparib in each cohort, and that there were no significant differences in preprogression EQ-5D-5L scores between niraparib- or placebo-treated patients in either cohort.
In addition, patient-reported lack of energy and pain, two of the most common baseline symptoms, either remained stable or improved during maintenance, although the proportion of patients reporting nausea increased at cycle 2. The incidence of nausea declined over subsequent cycles, and eventually approached baseline levels, the investigators said.
Hematologic toxicities were the most common grade 3 or 4 adverse events seen in patients treated with niraparib, including thrombocytopenia in 34%, anemia in 25%, and neutropenia in 20%. However, disutility analyses showed no significant effects of these toxicities on QOL measures.
“This analysis did not examine integrated measures of duration and QOL such as time without symptoms and toxicity or quality-adjusted progression-free survival. Although these analyses were beyond the scope of this report, these measures are potentially of interest and we plan to assess these as part of future research,” wrote Dr. Oza and his associates.
The QOL analyses of these two trials clearly show that neither olaparib nor niraparib has a detrimental effect on QOL in the maintenance setting of platinum-sensitive recurrent ovarian cancer. Future trials of the maintenance setting of recurrent ovarian cancer should include a predefined patient reported outcome (PRO) hypothesis and a statistical analysis plan including appropriate timing and duration of measurements. The completion of PRO instruments can be a burden to patients; thus, limiting PROs to those that inform a study-specific hypothesis can aid in achieving a high compliance rate. For example, the effect of gastrointestinal symptoms on QOL by EQ-5D-5L [European QOL five-dimension five-level questionnaire] is difficult to assess. As other drug classes are incorporated into treatment regimens for recurrent ovarian cancer, the use of the same PRO measures between trials, such as the Measure of Ovarian Symptoms and Treatment, might help in comparison of the therapeutic regimens.
Daisuke Aoki, MD, and Tatsuyuki Chiyoda, MD, are with the department of obstetrics and gynecology at Keio University, Tokyo. Dr. Aoki disclosed personal fees from AstraZeneca. Dr. Chiyoda reported no conflicts of interest. Their remarks are adapted and condensed from an editorial published online July 16, 2018, in The Lancet Oncology.
The QOL analyses of these two trials clearly show that neither olaparib nor niraparib has a detrimental effect on QOL in the maintenance setting of platinum-sensitive recurrent ovarian cancer. Future trials of the maintenance setting of recurrent ovarian cancer should include a predefined patient reported outcome (PRO) hypothesis and a statistical analysis plan including appropriate timing and duration of measurements. The completion of PRO instruments can be a burden to patients; thus, limiting PROs to those that inform a study-specific hypothesis can aid in achieving a high compliance rate. For example, the effect of gastrointestinal symptoms on QOL by EQ-5D-5L [European QOL five-dimension five-level questionnaire] is difficult to assess. As other drug classes are incorporated into treatment regimens for recurrent ovarian cancer, the use of the same PRO measures between trials, such as the Measure of Ovarian Symptoms and Treatment, might help in comparison of the therapeutic regimens.
Daisuke Aoki, MD, and Tatsuyuki Chiyoda, MD, are with the department of obstetrics and gynecology at Keio University, Tokyo. Dr. Aoki disclosed personal fees from AstraZeneca. Dr. Chiyoda reported no conflicts of interest. Their remarks are adapted and condensed from an editorial published online July 16, 2018, in The Lancet Oncology.
Body
The QOL analyses of these two trials clearly show that neither olaparib nor niraparib has a detrimental effect on QOL in the maintenance setting of platinum-sensitive recurrent ovarian cancer. Future trials of the maintenance setting of recurrent ovarian cancer should include a predefined patient reported outcome (PRO) hypothesis and a statistical analysis plan including appropriate timing and duration of measurements. The completion of PRO instruments can be a burden to patients; thus, limiting PROs to those that inform a study-specific hypothesis can aid in achieving a high compliance rate. For example, the effect of gastrointestinal symptoms on QOL by EQ-5D-5L [European QOL five-dimension five-level questionnaire] is difficult to assess. As other drug classes are incorporated into treatment regimens for recurrent ovarian cancer, the use of the same PRO measures between trials, such as the Measure of Ovarian Symptoms and Treatment, might help in comparison of the therapeutic regimens.
Daisuke Aoki, MD, and Tatsuyuki Chiyoda, MD, are with the department of obstetrics and gynecology at Keio University, Tokyo. Dr. Aoki disclosed personal fees from AstraZeneca. Dr. Chiyoda reported no conflicts of interest. Their remarks are adapted and condensed from an editorial published online July 16, 2018, in The Lancet Oncology.
Title
Patient-reported outcomes should be standard
Patient-reported outcomes should be standard
Women with platinum-sensitive recurrent ovarian cancer who received maintenance therapy with a poly(ADP-ribose) polymerase (PARP) inhibitor had no significant decreases in health-related quality of life, outcomes data from two randomized clinical trials show.
Health-related quality of life (HRQOL) analyses from the SOLO2/ENGOT-Ov-21 trial comparing olaparib (Lynparza) with placebo and the ENGOT-OV16/NOVA trial comparing niraparib (Zejula) with placebo as maintenance therapy in women with ongoing responses to their last platinum-based chemotherapy showed that neither agent had major detrimental effects on patient-reported outcomes, further supporting the progression-free survival benefits previously seen with each agent in its respective trials.
“These results show the significant benefit of maintenance olaparib to patients beyond the RECIST [Response Evaluation Criteria in Solid Tumors] definition of progression, the primary endpoint of SOLO2, and highlight the importance of including patient-centered outcomes in addition to HRQOL in trials of maintenance therapy, in line with the recommendations of the 5th Ovarian Cancer Consensus Conference,” wrote Michael Friedlander, MD, of the University of New South Wales Clinical School and Prince of Wales Hospital in Randwick, New South Wales, Australia, and his colleagues.
Similarly, Amit M. Oza, MD, of Princess Margaret Cancer Centre in Toronto, and his coinvestigators in the ENGOT-OV16/NOVA trial found that “niraparib has no significant negative effect on QOL in patients with recurrent ovarian cancer. Combined with the evidence of increased progression-free survival with niraparib in the maintenance setting, these findings support the addition of niraparib as a component of standard of care.”
In SOLO2, patients with a germline BRCA1 or BRCA2 mutation and platinum-sensitive ovarian cancer that relapsed after at least two lines of chemotherapy were randomly assigned to receive either oral olaparib 300 mg twice daily (196 patients) or placebo (99 patients).
The prespecified primary HRQOL analysis looked at the change from baseline in the Functional Assessment of Cancer Therapy–Ovarian Cancer (FACT-O) Trial Outcome Index (TOI) score during the first 12 months of the study.
In addition, the investigators examined secondary planned QOL analyses, including duration of good quality of life, defined as time without significant symptoms of toxicity, or TWiST, and quality-adjusted progression-free survival (QAPFS).
The adjusted average mean change from baseline over the first 12 months in TOI was –2.90 with olaparib vs. –2.87 with placebo (nonsignificant).
In contrast, patients treated with olaparib had significantly better mean QAPFS (13.96 vs. 7.28 months) and TWiST (15.03 vs. 7.70 months) results.
“All these predefined endpoints support the benefit to patients of a prolongation of progression-free survival, which is the primary endpoint in maintenance trials in ovarian cancer, and should be routinely included in future trials,” wrote Dr. Friedlander and his associates.
ENGOT-OV16/NOVA QOL summary
Investigators for this trial enrolled patients into two independent cohorts based on germline BRCA mutations or lack thereof. In all, 138 patients were assigned to niraparib and 65 to placebo in the germline BRCA mutation cohort, and 234 to niraparib and 116 to placebo in the nonmutation cohort.
The current study assessed patient-reported outcomes in the intention-to-treat population using different validated instruments from those assessed in SOLO2: the Functional Assessment of Cancer Therapy–Ovarian Symptoms Index (FOSI) and European QOL five-dimension five-level questionnaire (EQ-5D-5L).
The outcomes were reported every 8 weeks for the first 14 treatment cycles and every 12 weeks thereafter.
The investigators looked at the effects of hematologic toxicities on QOL with disutility analyses (measuring the decrement on QOL of a particular symptom or complication) of the most common grade 3-4 adverse events (thrombocytopenia, anemia, and neutropenia) using a mixed model with covariates.
They found that overall QOL scores remained stable during treatment and the preprogression period among patients on niraparib in each cohort, and that there were no significant differences in preprogression EQ-5D-5L scores between niraparib- or placebo-treated patients in either cohort.
In addition, patient-reported lack of energy and pain, two of the most common baseline symptoms, either remained stable or improved during maintenance, although the proportion of patients reporting nausea increased at cycle 2. The incidence of nausea declined over subsequent cycles, and eventually approached baseline levels, the investigators said.
Hematologic toxicities were the most common grade 3 or 4 adverse events seen in patients treated with niraparib, including thrombocytopenia in 34%, anemia in 25%, and neutropenia in 20%. However, disutility analyses showed no significant effects of these toxicities on QOL measures.
“This analysis did not examine integrated measures of duration and QOL such as time without symptoms and toxicity or quality-adjusted progression-free survival. Although these analyses were beyond the scope of this report, these measures are potentially of interest and we plan to assess these as part of future research,” wrote Dr. Oza and his associates.
Women with platinum-sensitive recurrent ovarian cancer who received maintenance therapy with a poly(ADP-ribose) polymerase (PARP) inhibitor had no significant decreases in health-related quality of life, outcomes data from two randomized clinical trials show.
Health-related quality of life (HRQOL) analyses from the SOLO2/ENGOT-Ov-21 trial comparing olaparib (Lynparza) with placebo and the ENGOT-OV16/NOVA trial comparing niraparib (Zejula) with placebo as maintenance therapy in women with ongoing responses to their last platinum-based chemotherapy showed that neither agent had major detrimental effects on patient-reported outcomes, further supporting the progression-free survival benefits previously seen with each agent in its respective trials.
“These results show the significant benefit of maintenance olaparib to patients beyond the RECIST [Response Evaluation Criteria in Solid Tumors] definition of progression, the primary endpoint of SOLO2, and highlight the importance of including patient-centered outcomes in addition to HRQOL in trials of maintenance therapy, in line with the recommendations of the 5th Ovarian Cancer Consensus Conference,” wrote Michael Friedlander, MD, of the University of New South Wales Clinical School and Prince of Wales Hospital in Randwick, New South Wales, Australia, and his colleagues.
Similarly, Amit M. Oza, MD, of Princess Margaret Cancer Centre in Toronto, and his coinvestigators in the ENGOT-OV16/NOVA trial found that “niraparib has no significant negative effect on QOL in patients with recurrent ovarian cancer. Combined with the evidence of increased progression-free survival with niraparib in the maintenance setting, these findings support the addition of niraparib as a component of standard of care.”
In SOLO2, patients with a germline BRCA1 or BRCA2 mutation and platinum-sensitive ovarian cancer that relapsed after at least two lines of chemotherapy were randomly assigned to receive either oral olaparib 300 mg twice daily (196 patients) or placebo (99 patients).
The prespecified primary HRQOL analysis looked at the change from baseline in the Functional Assessment of Cancer Therapy–Ovarian Cancer (FACT-O) Trial Outcome Index (TOI) score during the first 12 months of the study.
In addition, the investigators examined secondary planned QOL analyses, including duration of good quality of life, defined as time without significant symptoms of toxicity, or TWiST, and quality-adjusted progression-free survival (QAPFS).
The adjusted average mean change from baseline over the first 12 months in TOI was –2.90 with olaparib vs. –2.87 with placebo (nonsignificant).
In contrast, patients treated with olaparib had significantly better mean QAPFS (13.96 vs. 7.28 months) and TWiST (15.03 vs. 7.70 months) results.
“All these predefined endpoints support the benefit to patients of a prolongation of progression-free survival, which is the primary endpoint in maintenance trials in ovarian cancer, and should be routinely included in future trials,” wrote Dr. Friedlander and his associates.
ENGOT-OV16/NOVA QOL summary
Investigators for this trial enrolled patients into two independent cohorts based on germline BRCA mutations or lack thereof. In all, 138 patients were assigned to niraparib and 65 to placebo in the germline BRCA mutation cohort, and 234 to niraparib and 116 to placebo in the nonmutation cohort.
The current study assessed patient-reported outcomes in the intention-to-treat population using different validated instruments from those assessed in SOLO2: the Functional Assessment of Cancer Therapy–Ovarian Symptoms Index (FOSI) and European QOL five-dimension five-level questionnaire (EQ-5D-5L).
The outcomes were reported every 8 weeks for the first 14 treatment cycles and every 12 weeks thereafter.
The investigators looked at the effects of hematologic toxicities on QOL with disutility analyses (measuring the decrement on QOL of a particular symptom or complication) of the most common grade 3-4 adverse events (thrombocytopenia, anemia, and neutropenia) using a mixed model with covariates.
They found that overall QOL scores remained stable during treatment and the preprogression period among patients on niraparib in each cohort, and that there were no significant differences in preprogression EQ-5D-5L scores between niraparib- or placebo-treated patients in either cohort.
In addition, patient-reported lack of energy and pain, two of the most common baseline symptoms, either remained stable or improved during maintenance, although the proportion of patients reporting nausea increased at cycle 2. The incidence of nausea declined over subsequent cycles, and eventually approached baseline levels, the investigators said.
Hematologic toxicities were the most common grade 3 or 4 adverse events seen in patients treated with niraparib, including thrombocytopenia in 34%, anemia in 25%, and neutropenia in 20%. However, disutility analyses showed no significant effects of these toxicities on QOL measures.
“This analysis did not examine integrated measures of duration and QOL such as time without symptoms and toxicity or quality-adjusted progression-free survival. Although these analyses were beyond the scope of this report, these measures are potentially of interest and we plan to assess these as part of future research,” wrote Dr. Oza and his associates.
Key clinical point: Poly (ADP-ribose) polymerase (PARP) inhibitors do not adversely affect quality of life when used as maintenance therapy for platinum-sensitive recurrent ovarian cancer.
Major finding: Neither olaparib nor niraparib was associated with significant decrements in health related quality of life measures.
Study details: Quality-of-life analyses from two randomized phase 3 trials comparing a PARP inhibitor with placebo for maintenance in women with platinum-sensitive relapsed or recurrent ovarian cancer.
Disclosures: Solo 2/ENGOT Ov-21 was funded by AstraZeneca. Dr. Friedland reported personal fees from the company during the conduct of the study. Coauthors reported fees or other consideration from the company. ENGOT-OV16/NOVA was funded by Tesaro. Dr. Oza reported personal fees from Clovis Oncology, WebRx, and Intas Oncology. One coauthor was a Tesaro employee and stockholder at the time the study was completed, and others reported serving on advisory boards and/or receiving fees from Tesaro and other companies.
Source: Friedlander M et al. Lancet Oncol 2018 Jul 16 doi: 10.1016/S1470-2045(18)30343-7. Oza AM et al. Lancet Oncol 2018 Jul 16 doi: 10.1016/S1470-2045(18)30333-4.
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Young women are more likely to be insured and diagnosed with gynecologic cancers at an early stage after the Affordable Care Act’s dependent coverage mandate than before the mandate went into effect, according to a new study from Johns Hopkins University School of Medicine.
“We know if these women are identified early and treated early, they are much more likely to live longer and have their cancer go into remission,” Anna Jo Bodurtha Smith, MD, MPH, of Johns Hopkins University, Baltimore, stated in a press release.
Dr. Smith and her colleague, Amanda N. Fader, MD, evaluated 1,912 gynecologic cancer cases before the Affordable Care Act (ACA) and 2,059 cases after the ACA in women who were aged 21-26 years. They also analyzed 9,782 and 10,456 pre-ACA and post-ACA cases in women aged 27-35 years. The researchers obtained the pre-ACA data, which included cases of uterine, cervical, vaginal and vulvar cancer, from the 2006-2009 surveys in the National Cancer Database; post-ACA data were obtained from the 2011-2014 surveys in the same database. Using a difference-in-differences study design to compare both age groups, they assessed factors such as diagnosis stage, insurance status, and whether the patients received fertility-sparing treatment. The study results were published in Obstetrics & Gynecology.
The researchers found post-ACA insurance coverage increased (difference in differences, 2.2%; 95% confidence interval, −4.0 to 0.1; P = .04) in women aged 21-26 years, compared with women aged 27-35 years, with a significant increase in cases of gynecological cancer being detected early (difference in differences, 3.6%; 95% CI, 0.4-6.9; P = .03) in the women aged 21-26 years, compared with women aged 27-35 years. While both groups showed an increase in fertility-sparing treatments post ACA, there was no significant difference in differences between the two groups.
Insurance status affected whether women were diagnosed with gynecologic cancer early or received fertility-sparing treatment, as women who were privately insured had a greater likelihood of early diagnoses of gynecologic cancer and receiving fertility-sparing treatment, compared with women who were publicly insured or did not have insurance.
“As the debate on how we insure women goes on, reminding ourselves that these insurance gains have huge impacts on people’s lives is the big takeaway here,” Dr. Smith stated in the release.
Researchers noted limitations to the study included its 80% power to detect overall pre-post differences of 4% due to its design, lack of power due to the small sample size for women with gynecologic cancer in the younger cohort, and change in coverage status due to external economic factors.
The authors reported no relevant financial disclosures.
Young women are more likely to be insured and diagnosed with gynecologic cancers at an early stage after the Affordable Care Act’s dependent coverage mandate than before the mandate went into effect, according to a new study from Johns Hopkins University School of Medicine.
“We know if these women are identified early and treated early, they are much more likely to live longer and have their cancer go into remission,” Anna Jo Bodurtha Smith, MD, MPH, of Johns Hopkins University, Baltimore, stated in a press release.
Dr. Smith and her colleague, Amanda N. Fader, MD, evaluated 1,912 gynecologic cancer cases before the Affordable Care Act (ACA) and 2,059 cases after the ACA in women who were aged 21-26 years. They also analyzed 9,782 and 10,456 pre-ACA and post-ACA cases in women aged 27-35 years. The researchers obtained the pre-ACA data, which included cases of uterine, cervical, vaginal and vulvar cancer, from the 2006-2009 surveys in the National Cancer Database; post-ACA data were obtained from the 2011-2014 surveys in the same database. Using a difference-in-differences study design to compare both age groups, they assessed factors such as diagnosis stage, insurance status, and whether the patients received fertility-sparing treatment. The study results were published in Obstetrics & Gynecology.
The researchers found post-ACA insurance coverage increased (difference in differences, 2.2%; 95% confidence interval, −4.0 to 0.1; P = .04) in women aged 21-26 years, compared with women aged 27-35 years, with a significant increase in cases of gynecological cancer being detected early (difference in differences, 3.6%; 95% CI, 0.4-6.9; P = .03) in the women aged 21-26 years, compared with women aged 27-35 years. While both groups showed an increase in fertility-sparing treatments post ACA, there was no significant difference in differences between the two groups.
Insurance status affected whether women were diagnosed with gynecologic cancer early or received fertility-sparing treatment, as women who were privately insured had a greater likelihood of early diagnoses of gynecologic cancer and receiving fertility-sparing treatment, compared with women who were publicly insured or did not have insurance.
“As the debate on how we insure women goes on, reminding ourselves that these insurance gains have huge impacts on people’s lives is the big takeaway here,” Dr. Smith stated in the release.
Researchers noted limitations to the study included its 80% power to detect overall pre-post differences of 4% due to its design, lack of power due to the small sample size for women with gynecologic cancer in the younger cohort, and change in coverage status due to external economic factors.
The authors reported no relevant financial disclosures.
Young women are more likely to be insured and diagnosed with gynecologic cancers at an early stage after the Affordable Care Act’s dependent coverage mandate than before the mandate went into effect, according to a new study from Johns Hopkins University School of Medicine.
“We know if these women are identified early and treated early, they are much more likely to live longer and have their cancer go into remission,” Anna Jo Bodurtha Smith, MD, MPH, of Johns Hopkins University, Baltimore, stated in a press release.
Dr. Smith and her colleague, Amanda N. Fader, MD, evaluated 1,912 gynecologic cancer cases before the Affordable Care Act (ACA) and 2,059 cases after the ACA in women who were aged 21-26 years. They also analyzed 9,782 and 10,456 pre-ACA and post-ACA cases in women aged 27-35 years. The researchers obtained the pre-ACA data, which included cases of uterine, cervical, vaginal and vulvar cancer, from the 2006-2009 surveys in the National Cancer Database; post-ACA data were obtained from the 2011-2014 surveys in the same database. Using a difference-in-differences study design to compare both age groups, they assessed factors such as diagnosis stage, insurance status, and whether the patients received fertility-sparing treatment. The study results were published in Obstetrics & Gynecology.
The researchers found post-ACA insurance coverage increased (difference in differences, 2.2%; 95% confidence interval, −4.0 to 0.1; P = .04) in women aged 21-26 years, compared with women aged 27-35 years, with a significant increase in cases of gynecological cancer being detected early (difference in differences, 3.6%; 95% CI, 0.4-6.9; P = .03) in the women aged 21-26 years, compared with women aged 27-35 years. While both groups showed an increase in fertility-sparing treatments post ACA, there was no significant difference in differences between the two groups.
Insurance status affected whether women were diagnosed with gynecologic cancer early or received fertility-sparing treatment, as women who were privately insured had a greater likelihood of early diagnoses of gynecologic cancer and receiving fertility-sparing treatment, compared with women who were publicly insured or did not have insurance.
“As the debate on how we insure women goes on, reminding ourselves that these insurance gains have huge impacts on people’s lives is the big takeaway here,” Dr. Smith stated in the release.
Researchers noted limitations to the study included its 80% power to detect overall pre-post differences of 4% due to its design, lack of power due to the small sample size for women with gynecologic cancer in the younger cohort, and change in coverage status due to external economic factors.
The authors reported no relevant financial disclosures.
Key clinical point: Under the Affordable Care Act dependent coverage mandate, more young women are likely to be insured and receive early gynecological cancer diagnoses than before the law was passed.
Major finding: There was a 2.2% increase in insured young women and a 3.6% increase in early cancer diagnoses, according to a difference-in-differences model.
Data source: An analysis of 1,912 pre-ACA and 2,059 post-ACA gynecologic cancer cases in women aged 21-26 years and 9,782 pre-ACA and 10,456 post-ACA cases in women aged 27-35 years obtained from the National Cancer Center Database in a study with a difference-in-differences design.
Disclosures: The authors reported no relevant financial disclosures.
Source: Smith AJB, Fader AN. Obstet Gynecol. 2018 Jun. doi: 10.1097/AOG.0000000000002592.
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MALMO, SWEDEN – Robust human papillomavirus antibody responses persist through 36 months in boys and girls who received two doses of the 9-valent HPV vaccine known as Gardasil 9 at age 9-14 years, according to an open-label randomized immunogenicity study conducted in 15 countries.
luiscar/Thinkstock
This is reassuring news supportive of regulatory decisions made in 2016/2017 to license the more convenient two-dose schedule in the United States, European Union, Canada, and other countries, Rosybel Drury, PhD, observed in reporting the results at the annual meeting of the European Society for Paediatric Infectious Diseases.
Moreover, HPV type-specific antibody levels at 36 months post vaccination in boys and girls who received two doses were similar to or greater than in the 36-month follow-up of adolescent and young adult females who received three doses at ages 16-26 years.
“This result supports the bridging of efficacy findings in young women receiving three doses to girls and boys receiving two doses,” according to Dr. Drury, a vaccine scientist at Merck Sharp & Dohme in Lyon, France.
Bruce Jancin/MDedge News
Dr. Rosybel Drury
She presented an update of a five-cohort study including roughly 1,500 recipients of either two doses of the 9-valent HPV vaccine given 6 or 12 months apart or three doses administered at 0, 2, and 6 months. Four cohorts were composed of 9- to 14-year-olds. The fifth consisted of adolescent girls and young women who got three doses of Gardasil 9 over the course of 6 months at ages 16-26 years. The previous report from this major study provided only short-term data based upon measurements of immunogenicity obtained 1 month after the last dose of vaccine (JAMA. 2016 Dec. 13;316(22):2411-21).
Anti-HPV geometric mean titers were highest 1 month after completing a two- or three-dose series, dropped off sharply during the next 6-12 months, then declined more slowly through 36 months.
While the demonstration of persistent immunogenicity over 3 years of follow-up was reassuring overall, there was a potential hitch: Significantly lower antibody levels for some HPV types were observed in girls who received two doses of the vaccine than in those who got three. Specifically, levels of anti-HPV antibodies to HPV types 18, 31, 45, and 52 were significantly lower in the girls who got two doses of the 9-valent HPV vaccine than in those who got three doses at the same age. Antibody levels directed against HPV types 6, 11, 16, 33, and 58 were similar in the two patient populations.
“The clinical significance of this finding remains unknown,” Dr. Drury said.
Challenged as to why the study didn’t include a single-dose vaccine arm, which would be the preferred preventive strategy in low-income countries where the burden of anogenital cancers and warts due to HPV is greatest, she replied that while there is great interest in this approach, and some modeling studies suggest it would be beneficial, the study she presented was designed to evaluate immunogenicity over time, not clinical efficacy, which needs to be assessed before single-dose public health programs are implemented.
The study was funded by Merck and presented by a company employee.
MALMO, SWEDEN – Robust human papillomavirus antibody responses persist through 36 months in boys and girls who received two doses of the 9-valent HPV vaccine known as Gardasil 9 at age 9-14 years, according to an open-label randomized immunogenicity study conducted in 15 countries.
luiscar/Thinkstock
This is reassuring news supportive of regulatory decisions made in 2016/2017 to license the more convenient two-dose schedule in the United States, European Union, Canada, and other countries, Rosybel Drury, PhD, observed in reporting the results at the annual meeting of the European Society for Paediatric Infectious Diseases.
Moreover, HPV type-specific antibody levels at 36 months post vaccination in boys and girls who received two doses were similar to or greater than in the 36-month follow-up of adolescent and young adult females who received three doses at ages 16-26 years.
“This result supports the bridging of efficacy findings in young women receiving three doses to girls and boys receiving two doses,” according to Dr. Drury, a vaccine scientist at Merck Sharp & Dohme in Lyon, France.
Bruce Jancin/MDedge News
Dr. Rosybel Drury
She presented an update of a five-cohort study including roughly 1,500 recipients of either two doses of the 9-valent HPV vaccine given 6 or 12 months apart or three doses administered at 0, 2, and 6 months. Four cohorts were composed of 9- to 14-year-olds. The fifth consisted of adolescent girls and young women who got three doses of Gardasil 9 over the course of 6 months at ages 16-26 years. The previous report from this major study provided only short-term data based upon measurements of immunogenicity obtained 1 month after the last dose of vaccine (JAMA. 2016 Dec. 13;316(22):2411-21).
Anti-HPV geometric mean titers were highest 1 month after completing a two- or three-dose series, dropped off sharply during the next 6-12 months, then declined more slowly through 36 months.
While the demonstration of persistent immunogenicity over 3 years of follow-up was reassuring overall, there was a potential hitch: Significantly lower antibody levels for some HPV types were observed in girls who received two doses of the vaccine than in those who got three. Specifically, levels of anti-HPV antibodies to HPV types 18, 31, 45, and 52 were significantly lower in the girls who got two doses of the 9-valent HPV vaccine than in those who got three doses at the same age. Antibody levels directed against HPV types 6, 11, 16, 33, and 58 were similar in the two patient populations.
“The clinical significance of this finding remains unknown,” Dr. Drury said.
Challenged as to why the study didn’t include a single-dose vaccine arm, which would be the preferred preventive strategy in low-income countries where the burden of anogenital cancers and warts due to HPV is greatest, she replied that while there is great interest in this approach, and some modeling studies suggest it would be beneficial, the study she presented was designed to evaluate immunogenicity over time, not clinical efficacy, which needs to be assessed before single-dose public health programs are implemented.
The study was funded by Merck and presented by a company employee.
MALMO, SWEDEN – Robust human papillomavirus antibody responses persist through 36 months in boys and girls who received two doses of the 9-valent HPV vaccine known as Gardasil 9 at age 9-14 years, according to an open-label randomized immunogenicity study conducted in 15 countries.
luiscar/Thinkstock
This is reassuring news supportive of regulatory decisions made in 2016/2017 to license the more convenient two-dose schedule in the United States, European Union, Canada, and other countries, Rosybel Drury, PhD, observed in reporting the results at the annual meeting of the European Society for Paediatric Infectious Diseases.
Moreover, HPV type-specific antibody levels at 36 months post vaccination in boys and girls who received two doses were similar to or greater than in the 36-month follow-up of adolescent and young adult females who received three doses at ages 16-26 years.
“This result supports the bridging of efficacy findings in young women receiving three doses to girls and boys receiving two doses,” according to Dr. Drury, a vaccine scientist at Merck Sharp & Dohme in Lyon, France.
Bruce Jancin/MDedge News
Dr. Rosybel Drury
She presented an update of a five-cohort study including roughly 1,500 recipients of either two doses of the 9-valent HPV vaccine given 6 or 12 months apart or three doses administered at 0, 2, and 6 months. Four cohorts were composed of 9- to 14-year-olds. The fifth consisted of adolescent girls and young women who got three doses of Gardasil 9 over the course of 6 months at ages 16-26 years. The previous report from this major study provided only short-term data based upon measurements of immunogenicity obtained 1 month after the last dose of vaccine (JAMA. 2016 Dec. 13;316(22):2411-21).
Anti-HPV geometric mean titers were highest 1 month after completing a two- or three-dose series, dropped off sharply during the next 6-12 months, then declined more slowly through 36 months.
While the demonstration of persistent immunogenicity over 3 years of follow-up was reassuring overall, there was a potential hitch: Significantly lower antibody levels for some HPV types were observed in girls who received two doses of the vaccine than in those who got three. Specifically, levels of anti-HPV antibodies to HPV types 18, 31, 45, and 52 were significantly lower in the girls who got two doses of the 9-valent HPV vaccine than in those who got three doses at the same age. Antibody levels directed against HPV types 6, 11, 16, 33, and 58 were similar in the two patient populations.
“The clinical significance of this finding remains unknown,” Dr. Drury said.
Challenged as to why the study didn’t include a single-dose vaccine arm, which would be the preferred preventive strategy in low-income countries where the burden of anogenital cancers and warts due to HPV is greatest, she replied that while there is great interest in this approach, and some modeling studies suggest it would be beneficial, the study she presented was designed to evaluate immunogenicity over time, not clinical efficacy, which needs to be assessed before single-dose public health programs are implemented.
The study was funded by Merck and presented by a company employee.
Key clinical point: Immunogenicity of two doses of Gardasil 9 given at age 9-14 years persists for at least 36 months.
Major finding: HPV type-specific antibody responses to two doses given at age 9-14 years were as good as or better than in 16- to 26-year-olds who got three doses.
Study details: This prospective open-label immunogenicity study included roughly 1,500 subjects in 15 countries who received either two or three doses of the 9-valent HPV vaccine.
Disclosures: The study was funded by Merck and presented by a company employee.
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A large observational study from Great Britain paints a mixed picture of cancer risks associated with assisted reproduction technologies such as in vitro fertilization (IVF).
Among nearly 256,000 women who had assisted reproduction over a 2-decade period and were followed for more than 2.25 million person-years, there was no significant increase in risk of uterine cancers or invasive breast cancers.
However, these women were at slight but significantly increased risk for in situ breast cancers and invasive or borderline ovarian cancers, although the ovarian tumors may be related more to patient factors than to the assisted reproduction technology itself, reported Alastair Sutcliffe, MD, PhD, from University College London, and his colleagues.
“We were not able to distinguish between a genuine increase in risk of borderline ovarian tumors and other explanations including surveillance bias. Further investigation of this and longer follow-up is warranted to continue monitoring these important outcomes in this ever-growing population,” they wrote in BMJ.
Women who undergo IVF and related procedures are typically exposed to high levels of estradiol, luteinizing hormone, follicle-stimulating hormone, and multiple ovarian punctures, all of which are potentially carcinogenic, the authors noted.
Previous studies of cancer risk in women who undergo assisted reproduction treatment have had conflicting or inconsistent results and lacked information on potential confounders, they pointed out.
To get a better sense of the potential risks, the investigators looked at linked data from the United Kingdom’s Human Fertilization and Embryology Authority and national cancer registries. They identified a total of 255,786 women treated from 1991 through 2010. Total follow-up was for 2,257,789 person-years.
They found that, during an average 8.8 years of follow-up, women had no significant increase in risk of tumors of the uterine corpus, with 164 cancers observed vs. 146.9 expected, for a standardized incidence ratio (SIR) of 1.12 (95% confidence interval, 0.95-1.30).
Similarly, there was no significant increase in risk of either breast cancer overall (2,578 observed vs. 2,641.2 expected; SIR, 0.98; 95% CI, 0.94-1.01) or invasive breast cancer (2,272 observed vs. 2,371.4 expected; SIR, 0.96; 95% CI, 0.92-1.00).
As noted, however, there was an increased risk of in situ breast cancer with 291 vs. 253.5 cases, respectively, translating into a SIR of 1.15 (95% CI, 1.02-1.29), for an absolute excess risk (AER) of 1.7 cases per 100,000 person-years, associated with an increasing number of treatment cycles (P = .03).
Additionally, the women in the study had an increased risk of ovarian cancer with an observed incidence of 405 vs. 291.82 expected, for an SIR of 1.39 (95% CI, 1.26-1.53) and an AER of 5.0 cases per 100,000 person-years.
There was a significantly increased risk for both invasive tumors, with 264 cases vs. 188.1 expected, for an SIR of 1.40 (95% CI, 1.24-1.58) and an AER of 3.4 cases per 100,000 person-years, and borderline ovarian cancers, with 141 vs. 103.7, for an SIR of 1.36 (95% CI, 1.15-1.60) and an AER of 1.7 cases per 100,000 person-years.
Increased risks of ovarian tumors were limited to women with endometriosis, low parity, or both. This study found no increased risk of any ovarian tumor in women treated because of only male-factor or unexplained infertility.
Women who had previously given birth and did not have a diagnosis of endometriosis had no increase in risk for ovarian cancer. Instead, increased risk appeared to be limited to women with endometriosis, few or no births (low parity), or both.
The authors emphasized that ongoing monitoring of outcomes for women who have undergone assisted reproduction is essential.
The study was funded by Cancer Research UK and the National Institute for Health Research, and supported by the NIHR Biomedical Research Centre at Great Ormond Street Hospital for Children NHS Foundation Trust and University College London. Three authors reported personal fees or royalties from entities not involved in the study.
A large observational study from Great Britain paints a mixed picture of cancer risks associated with assisted reproduction technologies such as in vitro fertilization (IVF).
Among nearly 256,000 women who had assisted reproduction over a 2-decade period and were followed for more than 2.25 million person-years, there was no significant increase in risk of uterine cancers or invasive breast cancers.
However, these women were at slight but significantly increased risk for in situ breast cancers and invasive or borderline ovarian cancers, although the ovarian tumors may be related more to patient factors than to the assisted reproduction technology itself, reported Alastair Sutcliffe, MD, PhD, from University College London, and his colleagues.
“We were not able to distinguish between a genuine increase in risk of borderline ovarian tumors and other explanations including surveillance bias. Further investigation of this and longer follow-up is warranted to continue monitoring these important outcomes in this ever-growing population,” they wrote in BMJ.
Women who undergo IVF and related procedures are typically exposed to high levels of estradiol, luteinizing hormone, follicle-stimulating hormone, and multiple ovarian punctures, all of which are potentially carcinogenic, the authors noted.
Previous studies of cancer risk in women who undergo assisted reproduction treatment have had conflicting or inconsistent results and lacked information on potential confounders, they pointed out.
To get a better sense of the potential risks, the investigators looked at linked data from the United Kingdom’s Human Fertilization and Embryology Authority and national cancer registries. They identified a total of 255,786 women treated from 1991 through 2010. Total follow-up was for 2,257,789 person-years.
They found that, during an average 8.8 years of follow-up, women had no significant increase in risk of tumors of the uterine corpus, with 164 cancers observed vs. 146.9 expected, for a standardized incidence ratio (SIR) of 1.12 (95% confidence interval, 0.95-1.30).
Similarly, there was no significant increase in risk of either breast cancer overall (2,578 observed vs. 2,641.2 expected; SIR, 0.98; 95% CI, 0.94-1.01) or invasive breast cancer (2,272 observed vs. 2,371.4 expected; SIR, 0.96; 95% CI, 0.92-1.00).
As noted, however, there was an increased risk of in situ breast cancer with 291 vs. 253.5 cases, respectively, translating into a SIR of 1.15 (95% CI, 1.02-1.29), for an absolute excess risk (AER) of 1.7 cases per 100,000 person-years, associated with an increasing number of treatment cycles (P = .03).
Additionally, the women in the study had an increased risk of ovarian cancer with an observed incidence of 405 vs. 291.82 expected, for an SIR of 1.39 (95% CI, 1.26-1.53) and an AER of 5.0 cases per 100,000 person-years.
There was a significantly increased risk for both invasive tumors, with 264 cases vs. 188.1 expected, for an SIR of 1.40 (95% CI, 1.24-1.58) and an AER of 3.4 cases per 100,000 person-years, and borderline ovarian cancers, with 141 vs. 103.7, for an SIR of 1.36 (95% CI, 1.15-1.60) and an AER of 1.7 cases per 100,000 person-years.
Increased risks of ovarian tumors were limited to women with endometriosis, low parity, or both. This study found no increased risk of any ovarian tumor in women treated because of only male-factor or unexplained infertility.
Women who had previously given birth and did not have a diagnosis of endometriosis had no increase in risk for ovarian cancer. Instead, increased risk appeared to be limited to women with endometriosis, few or no births (low parity), or both.
The authors emphasized that ongoing monitoring of outcomes for women who have undergone assisted reproduction is essential.
The study was funded by Cancer Research UK and the National Institute for Health Research, and supported by the NIHR Biomedical Research Centre at Great Ormond Street Hospital for Children NHS Foundation Trust and University College London. Three authors reported personal fees or royalties from entities not involved in the study.
A large observational study from Great Britain paints a mixed picture of cancer risks associated with assisted reproduction technologies such as in vitro fertilization (IVF).
Among nearly 256,000 women who had assisted reproduction over a 2-decade period and were followed for more than 2.25 million person-years, there was no significant increase in risk of uterine cancers or invasive breast cancers.
However, these women were at slight but significantly increased risk for in situ breast cancers and invasive or borderline ovarian cancers, although the ovarian tumors may be related more to patient factors than to the assisted reproduction technology itself, reported Alastair Sutcliffe, MD, PhD, from University College London, and his colleagues.
“We were not able to distinguish between a genuine increase in risk of borderline ovarian tumors and other explanations including surveillance bias. Further investigation of this and longer follow-up is warranted to continue monitoring these important outcomes in this ever-growing population,” they wrote in BMJ.
Women who undergo IVF and related procedures are typically exposed to high levels of estradiol, luteinizing hormone, follicle-stimulating hormone, and multiple ovarian punctures, all of which are potentially carcinogenic, the authors noted.
Previous studies of cancer risk in women who undergo assisted reproduction treatment have had conflicting or inconsistent results and lacked information on potential confounders, they pointed out.
To get a better sense of the potential risks, the investigators looked at linked data from the United Kingdom’s Human Fertilization and Embryology Authority and national cancer registries. They identified a total of 255,786 women treated from 1991 through 2010. Total follow-up was for 2,257,789 person-years.
They found that, during an average 8.8 years of follow-up, women had no significant increase in risk of tumors of the uterine corpus, with 164 cancers observed vs. 146.9 expected, for a standardized incidence ratio (SIR) of 1.12 (95% confidence interval, 0.95-1.30).
Similarly, there was no significant increase in risk of either breast cancer overall (2,578 observed vs. 2,641.2 expected; SIR, 0.98; 95% CI, 0.94-1.01) or invasive breast cancer (2,272 observed vs. 2,371.4 expected; SIR, 0.96; 95% CI, 0.92-1.00).
As noted, however, there was an increased risk of in situ breast cancer with 291 vs. 253.5 cases, respectively, translating into a SIR of 1.15 (95% CI, 1.02-1.29), for an absolute excess risk (AER) of 1.7 cases per 100,000 person-years, associated with an increasing number of treatment cycles (P = .03).
Additionally, the women in the study had an increased risk of ovarian cancer with an observed incidence of 405 vs. 291.82 expected, for an SIR of 1.39 (95% CI, 1.26-1.53) and an AER of 5.0 cases per 100,000 person-years.
There was a significantly increased risk for both invasive tumors, with 264 cases vs. 188.1 expected, for an SIR of 1.40 (95% CI, 1.24-1.58) and an AER of 3.4 cases per 100,000 person-years, and borderline ovarian cancers, with 141 vs. 103.7, for an SIR of 1.36 (95% CI, 1.15-1.60) and an AER of 1.7 cases per 100,000 person-years.
Increased risks of ovarian tumors were limited to women with endometriosis, low parity, or both. This study found no increased risk of any ovarian tumor in women treated because of only male-factor or unexplained infertility.
Women who had previously given birth and did not have a diagnosis of endometriosis had no increase in risk for ovarian cancer. Instead, increased risk appeared to be limited to women with endometriosis, few or no births (low parity), or both.
The authors emphasized that ongoing monitoring of outcomes for women who have undergone assisted reproduction is essential.
The study was funded by Cancer Research UK and the National Institute for Health Research, and supported by the NIHR Biomedical Research Centre at Great Ormond Street Hospital for Children NHS Foundation Trust and University College London. Three authors reported personal fees or royalties from entities not involved in the study.
Key clinical point: Assisted reproductive technologies may be linked to increased risk for in situ breast and ovarian cancers.
Major finding: The standardized incidence ratios (observed vs. expected cases) for invasive and borderline ovarian tumors were 1.40 and 1.41, respectively, both statistically significant.
Study details: Observational study with linked fertility clinic and cancer registry data on 255,786 women with total follow-up of 2,257,789 person-years.
Disclosures: The study was funded by Cancer Research UK and the National Institute for Health Research, and supported by the NIHR Biomedical Research Centre at Great Ormond Street Hospital for Children NHS Foundation Trust and University College London. Three authors reported personal fees or royalties from entities not involved in the study.
Source: Williams CL et al. BMJ. 2018;362:k2644.
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Intensive use of nonaspirin nonsteroidal anti-inflammatory drugs (NSAIDs) was associated with improved survival of patients with serous ovarian cancer in a recent population-based study.
By contrast, any use of nonaspirin NSAIDs was not associated with survival benefit, according to the authors of the study, which was based on records for more than 4,000 patients in the Danish Cancer Registry.
“More intensive use of nonaspirin NSAIDs appears necessary to obtain a prognostic benefit,” wrote Freija Verdoodt, PhD, postdoctoral researcher with the Danish Cancer Society Research Center, Copenhagen and her coauthors. The report was published in Gynecologic Oncology.
In addition, there was a suggestion that use of these drugs was associated with increased mortality in patients that with nonserous ovarian cancer, Dr. Verdoodt and her colleagues noted.
The study population comprised 4,117 women who were alive 1 year after a diagnosis of epithelial ovarian cancer. Ovarian cancer–specific mortality, the primary outcome of the analysis, was evaluated in relation to postdiagnosis use of nonaspirin NSAIDs.
The investigators found that any postdiagnosis use of nonaspirin NSAIDs was not associated with a difference in mortality, with a hazard ratio of 0.97 (95% confidence interval, 0.87-1.08) after adjusting for factors such as age, clinical stage, and year of diagnosis.
“Nonaspirin NSAIDs are typically used sporadically, and thus limited use among a substantial proportion of the postdiagnosis users may have attenuated the mortality risk estimates of our main analysis,” Dr. Verdoodt and her coauthors wrote.
However, increasing cumulative dose was associated with decreases in mortality, with hazard ratios of 1.03, 0.96, and 0.75 for low, medium, and high cumulative doses, respectively.
Likewise, the intensity of use, defined as cumulative dose divided by the number of days between the first and most recent postdiagnosis NSAID prescription, was associated with decreased mortality, with hazard ratios of 1.04, 0.98, and 0.86 for low, medium, and high use intensity, the reported data show.
When stratified by tumor histology, the data showed an association between reduced ovarian cancer–specific mortality and serous ovarian tumors (hazard ratio, 0.87; 95% CI, 0.77-0.99), and post hoc analyses confirmed further reductions in mortality based on high cumulative doses, with a hazard ratio of 0.62, and high intensity of use, with a hazard ratio of 0.79.
Conversely, other histologies were associated with increases in ovarian cancer mortality, though the numbers of patients in these subgroups were small, limiting interpretation of the results, investigators said.
Prior to this study, there were few epidemiologic investigations of the impact of nonaspirin NSAIDs on ovarian cancer prognosis, and of those, most did not include separate estimates based on histological subtypes, according to the investigators.
Although this study suggests intensive nonaspirin NSAID use comes with a potential prognostic benefit, these drugs also have potential adverse effects, including serious cardiovascular adverse events, the investigators said.
“A consideration of such risks in the light of a survival benefit among poor-prognosis serous ovarian cancer patients should guide further research,” they wrote.
The study was supported by the Sapere Aude program of the Independent Research Fund Denmark and the Mermaid project. The authors declared no conflicts of interest.
Intensive use of nonaspirin nonsteroidal anti-inflammatory drugs (NSAIDs) was associated with improved survival of patients with serous ovarian cancer in a recent population-based study.
By contrast, any use of nonaspirin NSAIDs was not associated with survival benefit, according to the authors of the study, which was based on records for more than 4,000 patients in the Danish Cancer Registry.
“More intensive use of nonaspirin NSAIDs appears necessary to obtain a prognostic benefit,” wrote Freija Verdoodt, PhD, postdoctoral researcher with the Danish Cancer Society Research Center, Copenhagen and her coauthors. The report was published in Gynecologic Oncology.
In addition, there was a suggestion that use of these drugs was associated with increased mortality in patients that with nonserous ovarian cancer, Dr. Verdoodt and her colleagues noted.
The study population comprised 4,117 women who were alive 1 year after a diagnosis of epithelial ovarian cancer. Ovarian cancer–specific mortality, the primary outcome of the analysis, was evaluated in relation to postdiagnosis use of nonaspirin NSAIDs.
The investigators found that any postdiagnosis use of nonaspirin NSAIDs was not associated with a difference in mortality, with a hazard ratio of 0.97 (95% confidence interval, 0.87-1.08) after adjusting for factors such as age, clinical stage, and year of diagnosis.
“Nonaspirin NSAIDs are typically used sporadically, and thus limited use among a substantial proportion of the postdiagnosis users may have attenuated the mortality risk estimates of our main analysis,” Dr. Verdoodt and her coauthors wrote.
However, increasing cumulative dose was associated with decreases in mortality, with hazard ratios of 1.03, 0.96, and 0.75 for low, medium, and high cumulative doses, respectively.
Likewise, the intensity of use, defined as cumulative dose divided by the number of days between the first and most recent postdiagnosis NSAID prescription, was associated with decreased mortality, with hazard ratios of 1.04, 0.98, and 0.86 for low, medium, and high use intensity, the reported data show.
When stratified by tumor histology, the data showed an association between reduced ovarian cancer–specific mortality and serous ovarian tumors (hazard ratio, 0.87; 95% CI, 0.77-0.99), and post hoc analyses confirmed further reductions in mortality based on high cumulative doses, with a hazard ratio of 0.62, and high intensity of use, with a hazard ratio of 0.79.
Conversely, other histologies were associated with increases in ovarian cancer mortality, though the numbers of patients in these subgroups were small, limiting interpretation of the results, investigators said.
Prior to this study, there were few epidemiologic investigations of the impact of nonaspirin NSAIDs on ovarian cancer prognosis, and of those, most did not include separate estimates based on histological subtypes, according to the investigators.
Although this study suggests intensive nonaspirin NSAID use comes with a potential prognostic benefit, these drugs also have potential adverse effects, including serious cardiovascular adverse events, the investigators said.
“A consideration of such risks in the light of a survival benefit among poor-prognosis serous ovarian cancer patients should guide further research,” they wrote.
The study was supported by the Sapere Aude program of the Independent Research Fund Denmark and the Mermaid project. The authors declared no conflicts of interest.
Intensive use of nonaspirin nonsteroidal anti-inflammatory drugs (NSAIDs) was associated with improved survival of patients with serous ovarian cancer in a recent population-based study.
By contrast, any use of nonaspirin NSAIDs was not associated with survival benefit, according to the authors of the study, which was based on records for more than 4,000 patients in the Danish Cancer Registry.
“More intensive use of nonaspirin NSAIDs appears necessary to obtain a prognostic benefit,” wrote Freija Verdoodt, PhD, postdoctoral researcher with the Danish Cancer Society Research Center, Copenhagen and her coauthors. The report was published in Gynecologic Oncology.
In addition, there was a suggestion that use of these drugs was associated with increased mortality in patients that with nonserous ovarian cancer, Dr. Verdoodt and her colleagues noted.
The study population comprised 4,117 women who were alive 1 year after a diagnosis of epithelial ovarian cancer. Ovarian cancer–specific mortality, the primary outcome of the analysis, was evaluated in relation to postdiagnosis use of nonaspirin NSAIDs.
The investigators found that any postdiagnosis use of nonaspirin NSAIDs was not associated with a difference in mortality, with a hazard ratio of 0.97 (95% confidence interval, 0.87-1.08) after adjusting for factors such as age, clinical stage, and year of diagnosis.
“Nonaspirin NSAIDs are typically used sporadically, and thus limited use among a substantial proportion of the postdiagnosis users may have attenuated the mortality risk estimates of our main analysis,” Dr. Verdoodt and her coauthors wrote.
However, increasing cumulative dose was associated with decreases in mortality, with hazard ratios of 1.03, 0.96, and 0.75 for low, medium, and high cumulative doses, respectively.
Likewise, the intensity of use, defined as cumulative dose divided by the number of days between the first and most recent postdiagnosis NSAID prescription, was associated with decreased mortality, with hazard ratios of 1.04, 0.98, and 0.86 for low, medium, and high use intensity, the reported data show.
When stratified by tumor histology, the data showed an association between reduced ovarian cancer–specific mortality and serous ovarian tumors (hazard ratio, 0.87; 95% CI, 0.77-0.99), and post hoc analyses confirmed further reductions in mortality based on high cumulative doses, with a hazard ratio of 0.62, and high intensity of use, with a hazard ratio of 0.79.
Conversely, other histologies were associated with increases in ovarian cancer mortality, though the numbers of patients in these subgroups were small, limiting interpretation of the results, investigators said.
Prior to this study, there were few epidemiologic investigations of the impact of nonaspirin NSAIDs on ovarian cancer prognosis, and of those, most did not include separate estimates based on histological subtypes, according to the investigators.
Although this study suggests intensive nonaspirin NSAID use comes with a potential prognostic benefit, these drugs also have potential adverse effects, including serious cardiovascular adverse events, the investigators said.
“A consideration of such risks in the light of a survival benefit among poor-prognosis serous ovarian cancer patients should guide further research,” they wrote.
The study was supported by the Sapere Aude program of the Independent Research Fund Denmark and the Mermaid project. The authors declared no conflicts of interest.
Key clinical point: Intensive use of nonaspirin nonsteroidal anti-inflammatory drugs (NSAIDs) was associated with improved survival of patients with serous ovarian cancer
Major finding: Serous ovarian tumors were associated with reduced ovarian cancer-specific mortality (HR, 0.87; 95% CI, 0.77-0.99), while post hoc analyses confirmed further reductions in mortality based on high cumulative doses (HR, 0.62), and high use intensity (HR, 0.79).
Study details: A population-based study of the Danish Cancer Registry including 4,117 women alive at least 1 year after an ovarian cancer diagnosis.
Disclosures: The study was supported by the Sapere Aude program of the Independent Research Fund Denmark and the Mermaid project. The authors declared no conflicts of interest.
Source: Verdoodt F et al. Gynecol Oncol. 2018 Jun 27. doi: 10.1016/j.ygyno.2018.06.018.
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Women who received only a primary human papillomavirus test were 58% less likely to develop grade 3 or worse cervical intraepithelial neoplasia (CIN3+) by 48 months than women who had the traditional Pap cytology screen.
The primary HPV test also reduced the 2-year risk of CIN2+ neoplasia, compared with Pap smear alone, Gina Suzanne Ogilvie, MD, and her colleagues reported in JAMA.
“These results have demonstrated that primary HPV testing detects cervical neoplasia earlier and more accurately than cytology,” wrote Dr. Ogilvie of the University of British Columbia, Vancouver, and her colleagues.
HPV FOCAL (the Human Papilloma Virus For Cervical Cancers Screening trial) enrolled 19,009 Canadian women aged 25-65 years and randomized them to two cervical cancer screening paradigms: Pap liquid-based cytology (LBC) or primary HPV testing.
The intervention group (9,552) had cervical cancer screening with a high-risk HPV DNA test that detects types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, and 68. If either test was positive, they were referred for colposcopy. If both tests were negative, they returned for their final screen with both tests at 48 months.
The control group underwent primary LBC testing, followed by HPV testing for women with atypical squamous cells of unknown significance (ASCUS). If these tests were both positive, they were referred for colposcopy. Women who were positive for ASCUS and HPV negative returned in 12 months and were referred for colposcopy if they had ASCUS or any higher-grade abnormality. At 48 months, they also returned and underwent both screening tests.
The primary outcome was the rate of CIN3+ at 48 months. Secondary endpoints included the 48-month rate of CIN2+, the threshold for colposcopy referral, and the effect of primary HPV testing on colposcopy.
In the first round of screening, HPV testing detected significantly more cases of CIN3+ than did LBC (risk ratio, 1.61). This was an absolute difference of 2.67 more cases per 1,000 screened women.
At 48 months, the rate of CIN3+ was significantly lower in the intervention group than in the control group (2.3 vs. 5.5 per 1,000; RR, 0.42). This represents an absolute difference of 3.2 fewer cases per 1,000, the investigators said.
Overall, however, the two methods detected about the same number of cases by 48 months, the investigators said.
“Cumulative CIN3+ incidence curves show no significantly different disease detection across trial groups in the intervention group. The cumulative incidence was higher earlier in the trial at 18 months and 42 months, compared with the control group. ... By the end of trial follow-up (72 months), incidence was similar across both groups.”
Women who were HPV negative at baseline reaped the biggest benefit. The 48-month HPV incidence rate among them was 1.4 per 1,000, compared with 5.4 per 1,000 in the control group. This 75% risk reduction (RR, 0.25) represents an absolute reduction of 4 cases per 1,000 women.
The intervention group was 61% more likely to have a CIN2+ result by 12 months (RR, 1.61), but 53% less likely to have it at 48 months (RR, 0.47).
“By 48 months, significantly fewer CIN2+ cases were detected overall and across all age groups in the intervention group, compared with the control group,” the team said. At 48 months, the CIN2+ rate was 5 per 1,000 vs. 10.6 per 1,000 – a 53% reduced risk (RR, 0.47) and an absolute reduction of 5.6 cases per 1,000.
Again, the benefit accrued early and mostly in women who were negative by HPV or cytology at baseline. Among these, the CIN2+ risk for the intervention, compared with the control group, was 64% lower (RR, 0.36), and the absolute difference in incidence was 6.38 per 1,000.
This early detection came at a cost, however. Colposcopies were significantly more common in the intervention group in the first screening round (57 vs. 30.8). However, by 48 months, colposcopy rates were lower in the intervention group, compared with the control group (49.2 vs. 70.5). By the end of the study, cumulative colposcopy referral rates were similar (106.2 vs. 101.5).
Dr. Ogilvie and her colleagues suggested that this ultimate similarity in colposcopy rate shows that fears about overdiagnosis with HPV testing are unfounded.
“One of the concerns for adopting HPV-based screening is the lower CIN2+ specificity of HPV testing, compared with cytology, leading to higher screen positive rates and the resulting need for more colposcopies and biopsies. Unnecessary colposcopies potentially cause unintended harm for women and increased costs to health care systems. In this trial, round 1 colposcopy rates in the HPV-tested group were significantly higher than the cytology-tested group. However, by 48 months, the colposcopy rate in the intervention group was reduced while the control group rate increased.
“This increase is partly a result of HPV and cytology co-testing at trial end. Of the 513 control-group women referred for colposcopy at exit, 304 (59%) were cytology negative and HPV positive. In the HPV-tested group, the colposcopy rate decreased in the second round of screening, which more accurately reflects the ongoing impact of HPV-based screening on a colposcopy program. The baseline colposcopy referral rate reflects what happens when HPV-based screening is first implemented, when both prevalent and incident infections will be detected,” the investigators said.
The Canadian Institute of Health Research funded the study. Dr. Ogilvie was a coinvestigator on adjunct studies funded by Hologic and Roche, designed to compare the performance of different HPV assays. Funding for the adjunct studies was not applied to the main HPV FOCAL trial.
Primary HPV testing has been available since 2014 in the United States, but has yet to replace Pap smears, L. Stewart Massad, MD, said in an accompanying editorial (JAMA. 2018;320:35-37).
The reasons are complex and numerous, beginning with the probability that the more sensitive HPV test can run up alarming, but unnecessary, red flags, especially for younger women.
“Adoption of primary HPV screening has been delayed by the suboptimal specificity of this approach, estimated at 85%-95%, especially among populations of young women who often carry HPV infections that regress without oncogenic consequence. These HPV infections represent true-positive HPV assays, but are false-positive cancer screens.”
Lack of patient education is another factor.
“HPV is almost universally acquired by sexually active adults. The virus usually clears in response to immune recognition, although clearance of this intraepithelial virus may take more than a year, and yet HPV may recur and first be detected decades later in the context of long-term monogamy or abstinence.
“Communicating a positive HPV test result requires sensitivity by the clinician and may entail lengthy counseling about the natural history of HPV, the lack of curative therapy, and the low absolute risk of progression to cancer. The clinical implications of an HPV diagnosis for sexual partners and offspring are marginal yet may be quite distressing for an affected woman.”
The HPV vaccine is already affecting cervical cancer rates and will complicate the picture even more. HPV FOCAL completed recruitment in 2012. Since then, rates of HPV 16 and 18, the most cervically carcinogenic serotypes, have fallen in the wake of the 2006 vaccine approval.
This reduction is becoming more apparent as women who were adolescents at vaccination and at the time the study was launched are now aging into screening cohorts. Lower prevalence of cervical precancer has changed the accuracy of screening tests in ways that are only now being appreciated, but that will further favor adoption of primary HPV screening by lowering its false-positive rate.”
The HPV test used in the FOCAL study was also suboptimal, compared with newer versions. The test incorporated all carcinogenic HPV serotypes in a single positive or negative result.
“More recent assays provide HPV genotyping that allows nuanced risk stratification, especially immediate referral to colposcopy for women who screen positive for HPV 16 or HPV 18. Triage for women who test positive for HPV was by cytology, which may not be the optimal triage test because other assays that do not depend on cytotechnologists’ vigilance are becoming available for this purpose. However, these advances should result in fewer false-positive results, further favoring HPV screening over cytology.”
The future of the Pap test remains unclear. Organizations that develop cancer screening guidelines continue to debate the issue.
“A draft recommendation on cervical screening from the U.S. Preventive Services Task Force recommended either cytology testing at 3-year intervals or primary HPV testing at 5-year intervals for women 30-65 years of age, but the final recommendation statement has not yet been released. Fortunately for women, both modalities are so effective for cancer screening that an adequately powered comparative effectiveness trial is likely impossible.”
Dr. Massad is a gynecologic oncology surgeon at Washington University, St. Louis. He has consulted with malpractice attorneys in cases alleging missed cervical cancer but has no financial ties with pharmaceutical companies.
Primary HPV testing has been available since 2014 in the United States, but has yet to replace Pap smears, L. Stewart Massad, MD, said in an accompanying editorial (JAMA. 2018;320:35-37).
The reasons are complex and numerous, beginning with the probability that the more sensitive HPV test can run up alarming, but unnecessary, red flags, especially for younger women.
“Adoption of primary HPV screening has been delayed by the suboptimal specificity of this approach, estimated at 85%-95%, especially among populations of young women who often carry HPV infections that regress without oncogenic consequence. These HPV infections represent true-positive HPV assays, but are false-positive cancer screens.”
Lack of patient education is another factor.
“HPV is almost universally acquired by sexually active adults. The virus usually clears in response to immune recognition, although clearance of this intraepithelial virus may take more than a year, and yet HPV may recur and first be detected decades later in the context of long-term monogamy or abstinence.
“Communicating a positive HPV test result requires sensitivity by the clinician and may entail lengthy counseling about the natural history of HPV, the lack of curative therapy, and the low absolute risk of progression to cancer. The clinical implications of an HPV diagnosis for sexual partners and offspring are marginal yet may be quite distressing for an affected woman.”
The HPV vaccine is already affecting cervical cancer rates and will complicate the picture even more. HPV FOCAL completed recruitment in 2012. Since then, rates of HPV 16 and 18, the most cervically carcinogenic serotypes, have fallen in the wake of the 2006 vaccine approval.
This reduction is becoming more apparent as women who were adolescents at vaccination and at the time the study was launched are now aging into screening cohorts. Lower prevalence of cervical precancer has changed the accuracy of screening tests in ways that are only now being appreciated, but that will further favor adoption of primary HPV screening by lowering its false-positive rate.”
The HPV test used in the FOCAL study was also suboptimal, compared with newer versions. The test incorporated all carcinogenic HPV serotypes in a single positive or negative result.
“More recent assays provide HPV genotyping that allows nuanced risk stratification, especially immediate referral to colposcopy for women who screen positive for HPV 16 or HPV 18. Triage for women who test positive for HPV was by cytology, which may not be the optimal triage test because other assays that do not depend on cytotechnologists’ vigilance are becoming available for this purpose. However, these advances should result in fewer false-positive results, further favoring HPV screening over cytology.”
The future of the Pap test remains unclear. Organizations that develop cancer screening guidelines continue to debate the issue.
“A draft recommendation on cervical screening from the U.S. Preventive Services Task Force recommended either cytology testing at 3-year intervals or primary HPV testing at 5-year intervals for women 30-65 years of age, but the final recommendation statement has not yet been released. Fortunately for women, both modalities are so effective for cancer screening that an adequately powered comparative effectiveness trial is likely impossible.”
Dr. Massad is a gynecologic oncology surgeon at Washington University, St. Louis. He has consulted with malpractice attorneys in cases alleging missed cervical cancer but has no financial ties with pharmaceutical companies.
Body
Primary HPV testing has been available since 2014 in the United States, but has yet to replace Pap smears, L. Stewart Massad, MD, said in an accompanying editorial (JAMA. 2018;320:35-37).
The reasons are complex and numerous, beginning with the probability that the more sensitive HPV test can run up alarming, but unnecessary, red flags, especially for younger women.
“Adoption of primary HPV screening has been delayed by the suboptimal specificity of this approach, estimated at 85%-95%, especially among populations of young women who often carry HPV infections that regress without oncogenic consequence. These HPV infections represent true-positive HPV assays, but are false-positive cancer screens.”
Lack of patient education is another factor.
“HPV is almost universally acquired by sexually active adults. The virus usually clears in response to immune recognition, although clearance of this intraepithelial virus may take more than a year, and yet HPV may recur and first be detected decades later in the context of long-term monogamy or abstinence.
“Communicating a positive HPV test result requires sensitivity by the clinician and may entail lengthy counseling about the natural history of HPV, the lack of curative therapy, and the low absolute risk of progression to cancer. The clinical implications of an HPV diagnosis for sexual partners and offspring are marginal yet may be quite distressing for an affected woman.”
The HPV vaccine is already affecting cervical cancer rates and will complicate the picture even more. HPV FOCAL completed recruitment in 2012. Since then, rates of HPV 16 and 18, the most cervically carcinogenic serotypes, have fallen in the wake of the 2006 vaccine approval.
This reduction is becoming more apparent as women who were adolescents at vaccination and at the time the study was launched are now aging into screening cohorts. Lower prevalence of cervical precancer has changed the accuracy of screening tests in ways that are only now being appreciated, but that will further favor adoption of primary HPV screening by lowering its false-positive rate.”
The HPV test used in the FOCAL study was also suboptimal, compared with newer versions. The test incorporated all carcinogenic HPV serotypes in a single positive or negative result.
“More recent assays provide HPV genotyping that allows nuanced risk stratification, especially immediate referral to colposcopy for women who screen positive for HPV 16 or HPV 18. Triage for women who test positive for HPV was by cytology, which may not be the optimal triage test because other assays that do not depend on cytotechnologists’ vigilance are becoming available for this purpose. However, these advances should result in fewer false-positive results, further favoring HPV screening over cytology.”
The future of the Pap test remains unclear. Organizations that develop cancer screening guidelines continue to debate the issue.
“A draft recommendation on cervical screening from the U.S. Preventive Services Task Force recommended either cytology testing at 3-year intervals or primary HPV testing at 5-year intervals for women 30-65 years of age, but the final recommendation statement has not yet been released. Fortunately for women, both modalities are so effective for cancer screening that an adequately powered comparative effectiveness trial is likely impossible.”
Dr. Massad is a gynecologic oncology surgeon at Washington University, St. Louis. He has consulted with malpractice attorneys in cases alleging missed cervical cancer but has no financial ties with pharmaceutical companies.
Title
Fortunately for women, both modalities are effective
Fortunately for women, both modalities are effective
Women who received only a primary human papillomavirus test were 58% less likely to develop grade 3 or worse cervical intraepithelial neoplasia (CIN3+) by 48 months than women who had the traditional Pap cytology screen.
The primary HPV test also reduced the 2-year risk of CIN2+ neoplasia, compared with Pap smear alone, Gina Suzanne Ogilvie, MD, and her colleagues reported in JAMA.
“These results have demonstrated that primary HPV testing detects cervical neoplasia earlier and more accurately than cytology,” wrote Dr. Ogilvie of the University of British Columbia, Vancouver, and her colleagues.
HPV FOCAL (the Human Papilloma Virus For Cervical Cancers Screening trial) enrolled 19,009 Canadian women aged 25-65 years and randomized them to two cervical cancer screening paradigms: Pap liquid-based cytology (LBC) or primary HPV testing.
The intervention group (9,552) had cervical cancer screening with a high-risk HPV DNA test that detects types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, and 68. If either test was positive, they were referred for colposcopy. If both tests were negative, they returned for their final screen with both tests at 48 months.
The control group underwent primary LBC testing, followed by HPV testing for women with atypical squamous cells of unknown significance (ASCUS). If these tests were both positive, they were referred for colposcopy. Women who were positive for ASCUS and HPV negative returned in 12 months and were referred for colposcopy if they had ASCUS or any higher-grade abnormality. At 48 months, they also returned and underwent both screening tests.
The primary outcome was the rate of CIN3+ at 48 months. Secondary endpoints included the 48-month rate of CIN2+, the threshold for colposcopy referral, and the effect of primary HPV testing on colposcopy.
In the first round of screening, HPV testing detected significantly more cases of CIN3+ than did LBC (risk ratio, 1.61). This was an absolute difference of 2.67 more cases per 1,000 screened women.
At 48 months, the rate of CIN3+ was significantly lower in the intervention group than in the control group (2.3 vs. 5.5 per 1,000; RR, 0.42). This represents an absolute difference of 3.2 fewer cases per 1,000, the investigators said.
Overall, however, the two methods detected about the same number of cases by 48 months, the investigators said.
“Cumulative CIN3+ incidence curves show no significantly different disease detection across trial groups in the intervention group. The cumulative incidence was higher earlier in the trial at 18 months and 42 months, compared with the control group. ... By the end of trial follow-up (72 months), incidence was similar across both groups.”
Women who were HPV negative at baseline reaped the biggest benefit. The 48-month HPV incidence rate among them was 1.4 per 1,000, compared with 5.4 per 1,000 in the control group. This 75% risk reduction (RR, 0.25) represents an absolute reduction of 4 cases per 1,000 women.
The intervention group was 61% more likely to have a CIN2+ result by 12 months (RR, 1.61), but 53% less likely to have it at 48 months (RR, 0.47).
“By 48 months, significantly fewer CIN2+ cases were detected overall and across all age groups in the intervention group, compared with the control group,” the team said. At 48 months, the CIN2+ rate was 5 per 1,000 vs. 10.6 per 1,000 – a 53% reduced risk (RR, 0.47) and an absolute reduction of 5.6 cases per 1,000.
Again, the benefit accrued early and mostly in women who were negative by HPV or cytology at baseline. Among these, the CIN2+ risk for the intervention, compared with the control group, was 64% lower (RR, 0.36), and the absolute difference in incidence was 6.38 per 1,000.
This early detection came at a cost, however. Colposcopies were significantly more common in the intervention group in the first screening round (57 vs. 30.8). However, by 48 months, colposcopy rates were lower in the intervention group, compared with the control group (49.2 vs. 70.5). By the end of the study, cumulative colposcopy referral rates were similar (106.2 vs. 101.5).
Dr. Ogilvie and her colleagues suggested that this ultimate similarity in colposcopy rate shows that fears about overdiagnosis with HPV testing are unfounded.
“One of the concerns for adopting HPV-based screening is the lower CIN2+ specificity of HPV testing, compared with cytology, leading to higher screen positive rates and the resulting need for more colposcopies and biopsies. Unnecessary colposcopies potentially cause unintended harm for women and increased costs to health care systems. In this trial, round 1 colposcopy rates in the HPV-tested group were significantly higher than the cytology-tested group. However, by 48 months, the colposcopy rate in the intervention group was reduced while the control group rate increased.
“This increase is partly a result of HPV and cytology co-testing at trial end. Of the 513 control-group women referred for colposcopy at exit, 304 (59%) were cytology negative and HPV positive. In the HPV-tested group, the colposcopy rate decreased in the second round of screening, which more accurately reflects the ongoing impact of HPV-based screening on a colposcopy program. The baseline colposcopy referral rate reflects what happens when HPV-based screening is first implemented, when both prevalent and incident infections will be detected,” the investigators said.
The Canadian Institute of Health Research funded the study. Dr. Ogilvie was a coinvestigator on adjunct studies funded by Hologic and Roche, designed to compare the performance of different HPV assays. Funding for the adjunct studies was not applied to the main HPV FOCAL trial.
Women who received only a primary human papillomavirus test were 58% less likely to develop grade 3 or worse cervical intraepithelial neoplasia (CIN3+) by 48 months than women who had the traditional Pap cytology screen.
The primary HPV test also reduced the 2-year risk of CIN2+ neoplasia, compared with Pap smear alone, Gina Suzanne Ogilvie, MD, and her colleagues reported in JAMA.
“These results have demonstrated that primary HPV testing detects cervical neoplasia earlier and more accurately than cytology,” wrote Dr. Ogilvie of the University of British Columbia, Vancouver, and her colleagues.
HPV FOCAL (the Human Papilloma Virus For Cervical Cancers Screening trial) enrolled 19,009 Canadian women aged 25-65 years and randomized them to two cervical cancer screening paradigms: Pap liquid-based cytology (LBC) or primary HPV testing.
The intervention group (9,552) had cervical cancer screening with a high-risk HPV DNA test that detects types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, and 68. If either test was positive, they were referred for colposcopy. If both tests were negative, they returned for their final screen with both tests at 48 months.
The control group underwent primary LBC testing, followed by HPV testing for women with atypical squamous cells of unknown significance (ASCUS). If these tests were both positive, they were referred for colposcopy. Women who were positive for ASCUS and HPV negative returned in 12 months and were referred for colposcopy if they had ASCUS or any higher-grade abnormality. At 48 months, they also returned and underwent both screening tests.
The primary outcome was the rate of CIN3+ at 48 months. Secondary endpoints included the 48-month rate of CIN2+, the threshold for colposcopy referral, and the effect of primary HPV testing on colposcopy.
In the first round of screening, HPV testing detected significantly more cases of CIN3+ than did LBC (risk ratio, 1.61). This was an absolute difference of 2.67 more cases per 1,000 screened women.
At 48 months, the rate of CIN3+ was significantly lower in the intervention group than in the control group (2.3 vs. 5.5 per 1,000; RR, 0.42). This represents an absolute difference of 3.2 fewer cases per 1,000, the investigators said.
Overall, however, the two methods detected about the same number of cases by 48 months, the investigators said.
“Cumulative CIN3+ incidence curves show no significantly different disease detection across trial groups in the intervention group. The cumulative incidence was higher earlier in the trial at 18 months and 42 months, compared with the control group. ... By the end of trial follow-up (72 months), incidence was similar across both groups.”
Women who were HPV negative at baseline reaped the biggest benefit. The 48-month HPV incidence rate among them was 1.4 per 1,000, compared with 5.4 per 1,000 in the control group. This 75% risk reduction (RR, 0.25) represents an absolute reduction of 4 cases per 1,000 women.
The intervention group was 61% more likely to have a CIN2+ result by 12 months (RR, 1.61), but 53% less likely to have it at 48 months (RR, 0.47).
“By 48 months, significantly fewer CIN2+ cases were detected overall and across all age groups in the intervention group, compared with the control group,” the team said. At 48 months, the CIN2+ rate was 5 per 1,000 vs. 10.6 per 1,000 – a 53% reduced risk (RR, 0.47) and an absolute reduction of 5.6 cases per 1,000.
Again, the benefit accrued early and mostly in women who were negative by HPV or cytology at baseline. Among these, the CIN2+ risk for the intervention, compared with the control group, was 64% lower (RR, 0.36), and the absolute difference in incidence was 6.38 per 1,000.
This early detection came at a cost, however. Colposcopies were significantly more common in the intervention group in the first screening round (57 vs. 30.8). However, by 48 months, colposcopy rates were lower in the intervention group, compared with the control group (49.2 vs. 70.5). By the end of the study, cumulative colposcopy referral rates were similar (106.2 vs. 101.5).
Dr. Ogilvie and her colleagues suggested that this ultimate similarity in colposcopy rate shows that fears about overdiagnosis with HPV testing are unfounded.
“One of the concerns for adopting HPV-based screening is the lower CIN2+ specificity of HPV testing, compared with cytology, leading to higher screen positive rates and the resulting need for more colposcopies and biopsies. Unnecessary colposcopies potentially cause unintended harm for women and increased costs to health care systems. In this trial, round 1 colposcopy rates in the HPV-tested group were significantly higher than the cytology-tested group. However, by 48 months, the colposcopy rate in the intervention group was reduced while the control group rate increased.
“This increase is partly a result of HPV and cytology co-testing at trial end. Of the 513 control-group women referred for colposcopy at exit, 304 (59%) were cytology negative and HPV positive. In the HPV-tested group, the colposcopy rate decreased in the second round of screening, which more accurately reflects the ongoing impact of HPV-based screening on a colposcopy program. The baseline colposcopy referral rate reflects what happens when HPV-based screening is first implemented, when both prevalent and incident infections will be detected,” the investigators said.
The Canadian Institute of Health Research funded the study. Dr. Ogilvie was a coinvestigator on adjunct studies funded by Hologic and Roche, designed to compare the performance of different HPV assays. Funding for the adjunct studies was not applied to the main HPV FOCAL trial.
Key clinical point: Compared with a Pap smear, HPV testing detected CIN3+ more often and earlier.
Major finding: Women who had HPV testing were 58% less likely to be CIN3+ 48 months later.
Study details: The prospective randomized trial comprised 19,009 women.
Disclosures: The Canadian Institute of Health Research funded the study, Dr. Ogilvie was a coinvestigator on adjunct studies funded by Hologic and Roche, designed to compare the performance of different HPV assays. Funding for the adjunct studies was not applied to the main HPV FOCAL trial.
Source: Ogilvie GS et al. JAMA. 2018;320:43-52.
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Cervical cancer screening represents one of the great public health successes of the 20th Century. Two physician-scientists, George Papanicolaou, MD, PhD (1883–1962), and Harald zur Hausen, MD (1936–), made extraordinary contributions to the evolution of effective cervical cancer screening programs. Dr. Papanicolaou led development of the iconic Pap smear, creating techniques for collecting specimens and using cytologic techniques to identify cervical cancer and its precursors, and Dr. zur Hausen discovered the association of human papillomavirus (HPV) infection with cervical cancer.1,2
Although it is but a distant memory, in the 1930s cervical and uterine cancer caused more deaths among women than breast, lung, or ovarian cancer.The successful deployment of Pap smear screening resulted in a decrease in cervical cancer rates in developed countries. Cervical cancer deaths remain common in many parts of the world, however. Cervical cancer screening programs can reduce cervical cancer incidence by greater than 80%.3 In the United States between 1973 and 2006, the invasive cervical cancer age-adjusted incidence rates dropped from 10.28 to 3.97 per 100,000 women.4
HPV causes cervical cancer
Dr. zur Hausen dedicated his career to identifying viral causes of human cancer. In his Nobel Laureate autobiography, he reported that during his 2-year rotating residency, he loved his obstetrics and gynecology experience, but found it “physically highly demanding” and decided to focus his career in microbiology and immunology.5 After proving that herpes simplex virus did not cause cervical cancer he began to explore the role of HPV in the disease process. He first identified HPV types 6 and 11 and showed that these agents caused genital warts. He then used low-stringency hybridization techniques to identify HPV types 16 and 18 in specimens of cervical cancer. Later, he and his colleagues proved that two HPV proteins, E6 and E7, interfere with the function of cell cycle control proteins p53 and retinoblastoma protein, resulting in dysregulated cell growth and cancer.2 These findings permitted the development of both HPV vaccines and nucleic acid–based tests to identify high-risk oncogenic HPV (hrHPV) in cells and tissue specimens.
HPV vaccination
Dr. zur Hausen was an energetic and vocal advocate for the development and widescale deployment of HPV vaccines, including vaccination of males and females.6 Initially his ideas were rejected by the pharmaceutical industry, but eventually, with advances in virology and vaccine development, multiple companies pursued the development of HPV vaccines, the first cancer prevention vaccines. The best approach to cervical cancer prevention is intensive population-wide HPV vaccination of both boys and girls before exposure to the HPV virus. Beyond its beneficial effect on the incidence of cervical cancer, HPV vaccination also reduces the population incidence of anal, vulvar, and oropharyngeal cancer.7 Prevention of oropharyngeal cancer is especially important for men, supporting the recommendation for vaccination of all boys.8
Population-wide HPV vaccination will result in a lower prevalence of cervical cancer precursors and reduce the sensitivity of cytology, thereby making primary HPV screening more attractive.9 Based on one modelling study, universal HPV vaccination can reduce cervical cancer rates by greater than 50% over current levels, and introduction of primary HPV screening will reduce cervical cancer rates by an additional 20%.10 In an era of widespread vaccination for HPV, screening for cervical cancer should be intensified for nonvaccinated women.10
Primary screening with cervical cytology alone remains an option supported by many authorities and professional society guidelines.11 Most studies report that HPV testing has greater sensitivity than cervical cytology alone, especially for the detection of adenocarcinoma of the cervix.12 In one Canadian study, 10,154 women were randomly assigned to HPV or cervical cytology testing. The sensitivity of HPV testing and cervical cytology for detecting cervical intraepithelial neoplasia grade 2 or 3 was 95% and 55%, respectively, with a specificity of 94% and 97%, respectively.13 When used together the sensitivity and specificity of cotesting was 100% and 93%, respectively, but resulted in an increased number of colposcopies, which may be costly and add stress for the patient. Many countries are beginning to move away from cervical cancer screening with cytology or cotesting to programs built upon a foundation of primary HPV testing.
Primary cervical cancer screening with HPV testing
The knowledge that hrHPV is a more sensitive test for cervical cancer and its precursors, as well as the relatively lower sensitivity of cytology, is the foundation for transitioning from primary screening with cervical cytology to primary screening with HPV testing. In the Netherlands14 and Australia15,16 HPV testing with reflex cytology is the nationwide approach to cervical cancer screening. The basic components of the Dutch primary HPV screening program, as explained by Dr. Lai van Zulyan Mandres, are14:
Samples are collected by a general practitioner and sent to one of 5 central testing facilities for DNA testing for hrHPV.
If all previous samples tested negative, the screening occurs at ages 30, 35, 40, 50, and 60 years, a minimum of 5 screens per woman.
If there is a history of a previously positive hrHPV, the screening is intensified, with additional specimens collected at ages 45, 55, and 60 years.
If the sample is hrHPV negative, the patient continues screening at the standard intervals. No cytology testing is performed.
If the sample is hrHPV positive, reflex cytology is performed using the original collected sample. If the cytology shows no intraepithelial lesion or malignancy (NILM), another specimen is obtained for cytology within 6 months. If the second cytology specimen shows atypical squamous cells of undetermined significance (ASCUS) or a more worrisome cytology finding, the patient is sent for colposcopy. If two NILM cytology specimens have been obtained, the patient resumes primary hrHPV screening every 5 years.
If the specimen is hrHPV positive and cytology is ASCUS or more worrisome the patient is referred for colposcopy (FIGURE).14 The Dutch estimate that primary hrHPV screening will reduce the number of cervical cytology specimens by 90% annually.
Australia also has implemented nationwide primary HPV testing for cervical cancer screening. This change was implemented following a 10-year program of universal school-based vaccination of girls and boys, and biennial cytology screening for all women. The Australian screening program initiates hrHPV testing at age 25 years and thereafter every 5 years until age 74. If the hrHPV test is positive, reflex testing for HPV types 16 and 18 are performed on the original specimen along with cervical cytology. Women who test positive for HPV 16 or 18 are immediately referred for colposcopy. If the hrHPV test is positive and reflex testing for HPV 16 and 18 is negative, cervical cytology demonstrating ASCUS, low- or high-grade squamous intraepithelial lesions, or more worrisome results trigger a referral for colposcopy. The Australian program supports testing of self-collected vaginal samples for women who are underscreened or have never been screened.15,16
Deployment of new technology often yields benefits and challenges. A putative benefit of primary HPV screening is a reduction in health care costs without an increase in cervical cancer deaths. Another benefit of primary HPV screening is that it may enable self-collection of specimens for analysis, thereby increasing access to cervical cancer screening for underserved and marginalized populations of women who are not currently participating in cervical cancer screening programs.17 One challenge is that many women are unaware that hrHPV is the cause of most invasive cervical cancers. The detection of hrHPV in a woman in a long-term relationship who was previously negative for hrHPV may cause the emotions of surprise, fear, anxiety, and anger, thereby stressing the relationship.18
Another concern is that many women are worried about no longer receiving the familiar “Pap smear” cancer screening test in which they have tremendous faith. When Australia transitioned to primary HPV screening, more than 70,000 women signed a petition to “save women’s lives” by permitting continued access to the cervical cytology testing.19 Primary HPV testing may result in a transient increase in the number of women referred for colposcopy, potentially overwhelming the capacity of the health care system to deliver this vital service.20,21 The HPV types that most often cause cervical cancer may vary among countries. For example, in Thailand, HPV 52 and 58 are frequently detected in women with high-grade squamous lesions, and including these subtypes in reflex genotyping may be of regional benefit.22
Primary cervical cancer screening with HPV testing: When will it be used widely in the United States?
In contrast to the United States, the Netherlands is a small, densely populated country that has a highly integrated health system with centralized laboratory centers, a nationwide electronic health record, and clinicians organized to perform as an integrated team. These features ensure that all lifetime tests results are available in one record, that HPV testing is highly standardized, and that clinicians will follow a prescribed care pathway. The Netherlands’ health system is organized to support the successful transition, in a single step, to primary HPV testing. The United States is the third most populous country in the world, following China and India, with a diverse approach to health care, a highly mobile population, no single interoperable electronic health record, and minimal central control of clinical practice. The United States is not organized to make a “big bang” transition to primary HPV cervical cancer screening. It is likely that the introduction of primary HPV screening will occur first in highly integrated health systems that control the clinical, laboratory, and electronic records of a large population.
The results of the ATHENA study provide a clear clinical algorithm for implementing a primary HPV screening program for cervical cancer in the United States.23–25 Samples are collected for hrHPV testing at a specified interval, 3 or 5 years, beginning at age 25 years. Women younger than age 25 years should be screened with cytology alone. Detection of hrHPV results in reflex viral typing for HPV 16 and 18. Women with samples positive for HPV 16 and 18 are immediately referred for colposcopy. Samples positive for hrHPV and negative for HPV 16 and 18 have reflex cytology testing performed on the original HPV specimen. If cytology testing reports NILM, repeat cotesting is performed in one year. If cytology testing reports ASCUS or a more concerning result, the woman is referred for colposcopy.
Malcolm Gladwell, in his book The Tipping Point, identified 3 processes that help push an innovative new approach from obscurity into widespread use.26 First, authoritative voices that can catalyze change need to consistently communicate their shared vision for the future. Second, there must be a clear message that galvanizes the many to change their approach. Third, the historical context must be supportive of the change. Over the next decade we are likely to hit a tipping point and transition from cervical cancer screening that relies on cervical cytology to an approach that prioritizes hrHPV testing. When that change will occur in the United States is unclear. But our colleagues in other countries already have transitioned to primary hrHPV testing for cervical cancer screening.
Share your thoughts! Send your Letter to the Editor to rbarbieri@mdedge.com. Please include your name and the city and state in which you practice.
References
Hinsey JC. George Nicholas Papanicolaou, May 13, 1883–February 19, 1962. Acta Cytol. 1962;6:483–486.
zur Hausen H. Papillomaviruses in human cancers. Proc Assoc Am Physicians. 1999;111(6):581–587.
International Agency for Research on Cancer. IARC Handbooks of Cancer Prevention, Vol 10: Cervix Cancer Screening. Lyon, France: IARC Press; 2005.
Adegoke O, Kulasingam S, Virnig B. Cervical cancer trends in the United States: a 35-year population-based analysis. J Women’s Health (Larchmt). 2012;21(10):1031–1037.
Michels KB, zur Hausen H. HPV vaccine for all. Lancet. 2009;374(9686):268–270.
Hansen BT, Campbell S, Nygaard M. Long-term incidence of HPV-related cancers, and cases preventable by HPV vaccination: a registry-based study in Norway. BMJ Open. 2018;8(2):e019005.
Barbieri RL. Advances in protection against oncogenic human papillomaviruses: the 9-valent vaccine. OBG Manag. 2015;27(5):6–8.
Massad LS. Anticipating the impact of human papillomavirus vaccination on US cervical cancer prevention strategies. J Low Genit Tract Dis. 2018;22(2):123–125.
Castanon A, Landy R, Pesola F, Windridge P, Sasieni P. Prediction of cervical cancer incidence in England, UK, up to 2040, under four scenarios: a modeling study. Lancet Public Health. 2018;3(1):e34–e43.
Moyer VA; U.S. Preventive Services Task Force. Screening for cervical cancer: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med. 2012;156(12):880–891.
Moukarzel LA, Angarita AM, VandenBussche C, et al. Preinvasive and invasive cervical adenocarcinoma: preceding low-risk or negative Pap result increases time to diagnosis. J Low Genital Tract Dis. 2017;21(2):91–96.
Mayrand MH, Duarte-Franco E, Rodrigues I, et al; Canadian Cervical Cancer Screening Trial Study Group. Human papillomavirus DNA versus Papanicolaou screening tests for cervical cancer. N Engl J Med. 2007;357(16):1579–1588.
Hammond I, Canfell K, Saville M. A new era for cervical cancer screening in Australia: watch this space! Aust N Z J Obstet Gynaecol. 2017;57(5):499–501.
Canfell K, Saville M, Caruana M, et al. Protocol for Compass: a randomised controlled trial of primary HPV testing versus cytology screening for cervical cancer in HPV-unvaccinated and vaccinated women aged 25-69 years living in Australia. BMJ Open. 2018;8(1):e016700.
Wood B, Lofters A, Vahabi M. Strategies to reach marginalized women for cervical cancer screening: a qualitative study of stakeholder perspectives. Curr Oncol. 2018;25(1):e8–e16.
Patel H, Moss EL, Sherman SM. HPV primary cervical cancer screening in England: women’s awareness and attitudes. Psychooncology. 2018;27(6):1559–1564.
Obermair HM, Dodd RH, Bonner C, Jansen J, McCaffery K. “It has saved thousands of lives, so why change it?” Content analysis of objections to cervical cancer screening programme changes in Australia. BMJ Open. 2018;8(2):e019171.
Hall MT, Simms KT, Lew JB, Smith MA, Saville M, Canfell K. Projected future impact of HPV vaccination and primary HPV screening on cervical cancer rates from 2017-2035: Example from Australia. PLoS One. 2018;13(2):e0185332.
Rebolj M, Bonde J, Preisler S, Ejegod D, Rygaard C, Lynge E. Human papillomavirus assays and cytology in primary cervical screening of women aged 30 years and above. PLoS One. 2016;11(1):e0147326.
Khunamornpong S, Settakorn J, Sukpan K, Suprasert P, Srisomboon J, Intaraphet S, Siriaunkgul S. Genotyping for human papillomavirus (HPV) 16/18/52/58 has a higher performance than HPV16/18 genotyping in triaging women with positive high-risk HPV test in Northern Thailand. PLoS One. 2016;11(6):e0158184.
Wright TC, Stoler MH, Behrens CM, Sharma A, Zhang G, Wright TL. Primary cervical cancer screening with human papillomavirus: end of study results from the ATHENA study using HPV as the first-line screening test. Gynecol Oncol. 2015;136(2):189–197.
Huh WK, Ault KA, Chelmow D, et al. Use of primary high-risk human papillomavirus testing for cervical cancer screening: interim clinical guidance. Obstet Gynecol. 2015;125(2):330–337.
American College of Obstetricians and Gynecologists Committee on Practice Bulletins–Gynecology. Practice Bulletin No. 168: cervical cancer screening and prevention. Obstet Gynecol. 2016;128(4):e111–e130.
Gladwell M. The Tipping Point: How Little Things Can Make a Big Difference. New York, New York: Little Brown; 2000.
Dr. Feldman is Director, Pap Smear Evaluation Center, and Associate Professor, Obstetrics, Gynecology and Reproductive Biology, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts.
Dr. Barbieri is Editor in Chief, OBG Management, and Chair, Obstetrics and Gynecology, Brigham and Women's Hospital, Boston, Massachusetts, and Kate Macy Ladd Professor of Obstetrics, Gynecology and Reproductive Biology, Harvard Medical School, Boston.
The authors report no financial relationships relevant to this article.
Dr. Feldman is Director, Pap Smear Evaluation Center, and Associate Professor, Obstetrics, Gynecology and Reproductive Biology, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts.
Dr. Barbieri is Editor in Chief, OBG Management, and Chair, Obstetrics and Gynecology, Brigham and Women's Hospital, Boston, Massachusetts, and Kate Macy Ladd Professor of Obstetrics, Gynecology and Reproductive Biology, Harvard Medical School, Boston.
The authors report no financial relationships relevant to this article.
Author and Disclosure Information
Dr. Feldman is Director, Pap Smear Evaluation Center, and Associate Professor, Obstetrics, Gynecology and Reproductive Biology, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts.
Dr. Barbieri is Editor in Chief, OBG Management, and Chair, Obstetrics and Gynecology, Brigham and Women's Hospital, Boston, Massachusetts, and Kate Macy Ladd Professor of Obstetrics, Gynecology and Reproductive Biology, Harvard Medical School, Boston.
The authors report no financial relationships relevant to this article.
Cervical cancer screening represents one of the great public health successes of the 20th Century. Two physician-scientists, George Papanicolaou, MD, PhD (1883–1962), and Harald zur Hausen, MD (1936–), made extraordinary contributions to the evolution of effective cervical cancer screening programs. Dr. Papanicolaou led development of the iconic Pap smear, creating techniques for collecting specimens and using cytologic techniques to identify cervical cancer and its precursors, and Dr. zur Hausen discovered the association of human papillomavirus (HPV) infection with cervical cancer.1,2
Although it is but a distant memory, in the 1930s cervical and uterine cancer caused more deaths among women than breast, lung, or ovarian cancer.The successful deployment of Pap smear screening resulted in a decrease in cervical cancer rates in developed countries. Cervical cancer deaths remain common in many parts of the world, however. Cervical cancer screening programs can reduce cervical cancer incidence by greater than 80%.3 In the United States between 1973 and 2006, the invasive cervical cancer age-adjusted incidence rates dropped from 10.28 to 3.97 per 100,000 women.4
HPV causes cervical cancer
Dr. zur Hausen dedicated his career to identifying viral causes of human cancer. In his Nobel Laureate autobiography, he reported that during his 2-year rotating residency, he loved his obstetrics and gynecology experience, but found it “physically highly demanding” and decided to focus his career in microbiology and immunology.5 After proving that herpes simplex virus did not cause cervical cancer he began to explore the role of HPV in the disease process. He first identified HPV types 6 and 11 and showed that these agents caused genital warts. He then used low-stringency hybridization techniques to identify HPV types 16 and 18 in specimens of cervical cancer. Later, he and his colleagues proved that two HPV proteins, E6 and E7, interfere with the function of cell cycle control proteins p53 and retinoblastoma protein, resulting in dysregulated cell growth and cancer.2 These findings permitted the development of both HPV vaccines and nucleic acid–based tests to identify high-risk oncogenic HPV (hrHPV) in cells and tissue specimens.
HPV vaccination
Dr. zur Hausen was an energetic and vocal advocate for the development and widescale deployment of HPV vaccines, including vaccination of males and females.6 Initially his ideas were rejected by the pharmaceutical industry, but eventually, with advances in virology and vaccine development, multiple companies pursued the development of HPV vaccines, the first cancer prevention vaccines. The best approach to cervical cancer prevention is intensive population-wide HPV vaccination of both boys and girls before exposure to the HPV virus. Beyond its beneficial effect on the incidence of cervical cancer, HPV vaccination also reduces the population incidence of anal, vulvar, and oropharyngeal cancer.7 Prevention of oropharyngeal cancer is especially important for men, supporting the recommendation for vaccination of all boys.8
Population-wide HPV vaccination will result in a lower prevalence of cervical cancer precursors and reduce the sensitivity of cytology, thereby making primary HPV screening more attractive.9 Based on one modelling study, universal HPV vaccination can reduce cervical cancer rates by greater than 50% over current levels, and introduction of primary HPV screening will reduce cervical cancer rates by an additional 20%.10 In an era of widespread vaccination for HPV, screening for cervical cancer should be intensified for nonvaccinated women.10
Primary screening with cervical cytology alone remains an option supported by many authorities and professional society guidelines.11 Most studies report that HPV testing has greater sensitivity than cervical cytology alone, especially for the detection of adenocarcinoma of the cervix.12 In one Canadian study, 10,154 women were randomly assigned to HPV or cervical cytology testing. The sensitivity of HPV testing and cervical cytology for detecting cervical intraepithelial neoplasia grade 2 or 3 was 95% and 55%, respectively, with a specificity of 94% and 97%, respectively.13 When used together the sensitivity and specificity of cotesting was 100% and 93%, respectively, but resulted in an increased number of colposcopies, which may be costly and add stress for the patient. Many countries are beginning to move away from cervical cancer screening with cytology or cotesting to programs built upon a foundation of primary HPV testing.
Primary cervical cancer screening with HPV testing
The knowledge that hrHPV is a more sensitive test for cervical cancer and its precursors, as well as the relatively lower sensitivity of cytology, is the foundation for transitioning from primary screening with cervical cytology to primary screening with HPV testing. In the Netherlands14 and Australia15,16 HPV testing with reflex cytology is the nationwide approach to cervical cancer screening. The basic components of the Dutch primary HPV screening program, as explained by Dr. Lai van Zulyan Mandres, are14:
Samples are collected by a general practitioner and sent to one of 5 central testing facilities for DNA testing for hrHPV.
If all previous samples tested negative, the screening occurs at ages 30, 35, 40, 50, and 60 years, a minimum of 5 screens per woman.
If there is a history of a previously positive hrHPV, the screening is intensified, with additional specimens collected at ages 45, 55, and 60 years.
If the sample is hrHPV negative, the patient continues screening at the standard intervals. No cytology testing is performed.
If the sample is hrHPV positive, reflex cytology is performed using the original collected sample. If the cytology shows no intraepithelial lesion or malignancy (NILM), another specimen is obtained for cytology within 6 months. If the second cytology specimen shows atypical squamous cells of undetermined significance (ASCUS) or a more worrisome cytology finding, the patient is sent for colposcopy. If two NILM cytology specimens have been obtained, the patient resumes primary hrHPV screening every 5 years.
If the specimen is hrHPV positive and cytology is ASCUS or more worrisome the patient is referred for colposcopy (FIGURE).14 The Dutch estimate that primary hrHPV screening will reduce the number of cervical cytology specimens by 90% annually.
Australia also has implemented nationwide primary HPV testing for cervical cancer screening. This change was implemented following a 10-year program of universal school-based vaccination of girls and boys, and biennial cytology screening for all women. The Australian screening program initiates hrHPV testing at age 25 years and thereafter every 5 years until age 74. If the hrHPV test is positive, reflex testing for HPV types 16 and 18 are performed on the original specimen along with cervical cytology. Women who test positive for HPV 16 or 18 are immediately referred for colposcopy. If the hrHPV test is positive and reflex testing for HPV 16 and 18 is negative, cervical cytology demonstrating ASCUS, low- or high-grade squamous intraepithelial lesions, or more worrisome results trigger a referral for colposcopy. The Australian program supports testing of self-collected vaginal samples for women who are underscreened or have never been screened.15,16
Deployment of new technology often yields benefits and challenges. A putative benefit of primary HPV screening is a reduction in health care costs without an increase in cervical cancer deaths. Another benefit of primary HPV screening is that it may enable self-collection of specimens for analysis, thereby increasing access to cervical cancer screening for underserved and marginalized populations of women who are not currently participating in cervical cancer screening programs.17 One challenge is that many women are unaware that hrHPV is the cause of most invasive cervical cancers. The detection of hrHPV in a woman in a long-term relationship who was previously negative for hrHPV may cause the emotions of surprise, fear, anxiety, and anger, thereby stressing the relationship.18
Another concern is that many women are worried about no longer receiving the familiar “Pap smear” cancer screening test in which they have tremendous faith. When Australia transitioned to primary HPV screening, more than 70,000 women signed a petition to “save women’s lives” by permitting continued access to the cervical cytology testing.19 Primary HPV testing may result in a transient increase in the number of women referred for colposcopy, potentially overwhelming the capacity of the health care system to deliver this vital service.20,21 The HPV types that most often cause cervical cancer may vary among countries. For example, in Thailand, HPV 52 and 58 are frequently detected in women with high-grade squamous lesions, and including these subtypes in reflex genotyping may be of regional benefit.22
Primary cervical cancer screening with HPV testing: When will it be used widely in the United States?
In contrast to the United States, the Netherlands is a small, densely populated country that has a highly integrated health system with centralized laboratory centers, a nationwide electronic health record, and clinicians organized to perform as an integrated team. These features ensure that all lifetime tests results are available in one record, that HPV testing is highly standardized, and that clinicians will follow a prescribed care pathway. The Netherlands’ health system is organized to support the successful transition, in a single step, to primary HPV testing. The United States is the third most populous country in the world, following China and India, with a diverse approach to health care, a highly mobile population, no single interoperable electronic health record, and minimal central control of clinical practice. The United States is not organized to make a “big bang” transition to primary HPV cervical cancer screening. It is likely that the introduction of primary HPV screening will occur first in highly integrated health systems that control the clinical, laboratory, and electronic records of a large population.
The results of the ATHENA study provide a clear clinical algorithm for implementing a primary HPV screening program for cervical cancer in the United States.23–25 Samples are collected for hrHPV testing at a specified interval, 3 or 5 years, beginning at age 25 years. Women younger than age 25 years should be screened with cytology alone. Detection of hrHPV results in reflex viral typing for HPV 16 and 18. Women with samples positive for HPV 16 and 18 are immediately referred for colposcopy. Samples positive for hrHPV and negative for HPV 16 and 18 have reflex cytology testing performed on the original HPV specimen. If cytology testing reports NILM, repeat cotesting is performed in one year. If cytology testing reports ASCUS or a more concerning result, the woman is referred for colposcopy.
Malcolm Gladwell, in his book The Tipping Point, identified 3 processes that help push an innovative new approach from obscurity into widespread use.26 First, authoritative voices that can catalyze change need to consistently communicate their shared vision for the future. Second, there must be a clear message that galvanizes the many to change their approach. Third, the historical context must be supportive of the change. Over the next decade we are likely to hit a tipping point and transition from cervical cancer screening that relies on cervical cytology to an approach that prioritizes hrHPV testing. When that change will occur in the United States is unclear. But our colleagues in other countries already have transitioned to primary hrHPV testing for cervical cancer screening.
Share your thoughts! Send your Letter to the Editor to rbarbieri@mdedge.com. Please include your name and the city and state in which you practice.
Cervical cancer screening represents one of the great public health successes of the 20th Century. Two physician-scientists, George Papanicolaou, MD, PhD (1883–1962), and Harald zur Hausen, MD (1936–), made extraordinary contributions to the evolution of effective cervical cancer screening programs. Dr. Papanicolaou led development of the iconic Pap smear, creating techniques for collecting specimens and using cytologic techniques to identify cervical cancer and its precursors, and Dr. zur Hausen discovered the association of human papillomavirus (HPV) infection with cervical cancer.1,2
Although it is but a distant memory, in the 1930s cervical and uterine cancer caused more deaths among women than breast, lung, or ovarian cancer.The successful deployment of Pap smear screening resulted in a decrease in cervical cancer rates in developed countries. Cervical cancer deaths remain common in many parts of the world, however. Cervical cancer screening programs can reduce cervical cancer incidence by greater than 80%.3 In the United States between 1973 and 2006, the invasive cervical cancer age-adjusted incidence rates dropped from 10.28 to 3.97 per 100,000 women.4
HPV causes cervical cancer
Dr. zur Hausen dedicated his career to identifying viral causes of human cancer. In his Nobel Laureate autobiography, he reported that during his 2-year rotating residency, he loved his obstetrics and gynecology experience, but found it “physically highly demanding” and decided to focus his career in microbiology and immunology.5 After proving that herpes simplex virus did not cause cervical cancer he began to explore the role of HPV in the disease process. He first identified HPV types 6 and 11 and showed that these agents caused genital warts. He then used low-stringency hybridization techniques to identify HPV types 16 and 18 in specimens of cervical cancer. Later, he and his colleagues proved that two HPV proteins, E6 and E7, interfere with the function of cell cycle control proteins p53 and retinoblastoma protein, resulting in dysregulated cell growth and cancer.2 These findings permitted the development of both HPV vaccines and nucleic acid–based tests to identify high-risk oncogenic HPV (hrHPV) in cells and tissue specimens.
HPV vaccination
Dr. zur Hausen was an energetic and vocal advocate for the development and widescale deployment of HPV vaccines, including vaccination of males and females.6 Initially his ideas were rejected by the pharmaceutical industry, but eventually, with advances in virology and vaccine development, multiple companies pursued the development of HPV vaccines, the first cancer prevention vaccines. The best approach to cervical cancer prevention is intensive population-wide HPV vaccination of both boys and girls before exposure to the HPV virus. Beyond its beneficial effect on the incidence of cervical cancer, HPV vaccination also reduces the population incidence of anal, vulvar, and oropharyngeal cancer.7 Prevention of oropharyngeal cancer is especially important for men, supporting the recommendation for vaccination of all boys.8
Population-wide HPV vaccination will result in a lower prevalence of cervical cancer precursors and reduce the sensitivity of cytology, thereby making primary HPV screening more attractive.9 Based on one modelling study, universal HPV vaccination can reduce cervical cancer rates by greater than 50% over current levels, and introduction of primary HPV screening will reduce cervical cancer rates by an additional 20%.10 In an era of widespread vaccination for HPV, screening for cervical cancer should be intensified for nonvaccinated women.10
Primary screening with cervical cytology alone remains an option supported by many authorities and professional society guidelines.11 Most studies report that HPV testing has greater sensitivity than cervical cytology alone, especially for the detection of adenocarcinoma of the cervix.12 In one Canadian study, 10,154 women were randomly assigned to HPV or cervical cytology testing. The sensitivity of HPV testing and cervical cytology for detecting cervical intraepithelial neoplasia grade 2 or 3 was 95% and 55%, respectively, with a specificity of 94% and 97%, respectively.13 When used together the sensitivity and specificity of cotesting was 100% and 93%, respectively, but resulted in an increased number of colposcopies, which may be costly and add stress for the patient. Many countries are beginning to move away from cervical cancer screening with cytology or cotesting to programs built upon a foundation of primary HPV testing.
Primary cervical cancer screening with HPV testing
The knowledge that hrHPV is a more sensitive test for cervical cancer and its precursors, as well as the relatively lower sensitivity of cytology, is the foundation for transitioning from primary screening with cervical cytology to primary screening with HPV testing. In the Netherlands14 and Australia15,16 HPV testing with reflex cytology is the nationwide approach to cervical cancer screening. The basic components of the Dutch primary HPV screening program, as explained by Dr. Lai van Zulyan Mandres, are14:
Samples are collected by a general practitioner and sent to one of 5 central testing facilities for DNA testing for hrHPV.
If all previous samples tested negative, the screening occurs at ages 30, 35, 40, 50, and 60 years, a minimum of 5 screens per woman.
If there is a history of a previously positive hrHPV, the screening is intensified, with additional specimens collected at ages 45, 55, and 60 years.
If the sample is hrHPV negative, the patient continues screening at the standard intervals. No cytology testing is performed.
If the sample is hrHPV positive, reflex cytology is performed using the original collected sample. If the cytology shows no intraepithelial lesion or malignancy (NILM), another specimen is obtained for cytology within 6 months. If the second cytology specimen shows atypical squamous cells of undetermined significance (ASCUS) or a more worrisome cytology finding, the patient is sent for colposcopy. If two NILM cytology specimens have been obtained, the patient resumes primary hrHPV screening every 5 years.
If the specimen is hrHPV positive and cytology is ASCUS or more worrisome the patient is referred for colposcopy (FIGURE).14 The Dutch estimate that primary hrHPV screening will reduce the number of cervical cytology specimens by 90% annually.
Australia also has implemented nationwide primary HPV testing for cervical cancer screening. This change was implemented following a 10-year program of universal school-based vaccination of girls and boys, and biennial cytology screening for all women. The Australian screening program initiates hrHPV testing at age 25 years and thereafter every 5 years until age 74. If the hrHPV test is positive, reflex testing for HPV types 16 and 18 are performed on the original specimen along with cervical cytology. Women who test positive for HPV 16 or 18 are immediately referred for colposcopy. If the hrHPV test is positive and reflex testing for HPV 16 and 18 is negative, cervical cytology demonstrating ASCUS, low- or high-grade squamous intraepithelial lesions, or more worrisome results trigger a referral for colposcopy. The Australian program supports testing of self-collected vaginal samples for women who are underscreened or have never been screened.15,16
Deployment of new technology often yields benefits and challenges. A putative benefit of primary HPV screening is a reduction in health care costs without an increase in cervical cancer deaths. Another benefit of primary HPV screening is that it may enable self-collection of specimens for analysis, thereby increasing access to cervical cancer screening for underserved and marginalized populations of women who are not currently participating in cervical cancer screening programs.17 One challenge is that many women are unaware that hrHPV is the cause of most invasive cervical cancers. The detection of hrHPV in a woman in a long-term relationship who was previously negative for hrHPV may cause the emotions of surprise, fear, anxiety, and anger, thereby stressing the relationship.18
Another concern is that many women are worried about no longer receiving the familiar “Pap smear” cancer screening test in which they have tremendous faith. When Australia transitioned to primary HPV screening, more than 70,000 women signed a petition to “save women’s lives” by permitting continued access to the cervical cytology testing.19 Primary HPV testing may result in a transient increase in the number of women referred for colposcopy, potentially overwhelming the capacity of the health care system to deliver this vital service.20,21 The HPV types that most often cause cervical cancer may vary among countries. For example, in Thailand, HPV 52 and 58 are frequently detected in women with high-grade squamous lesions, and including these subtypes in reflex genotyping may be of regional benefit.22
Primary cervical cancer screening with HPV testing: When will it be used widely in the United States?
In contrast to the United States, the Netherlands is a small, densely populated country that has a highly integrated health system with centralized laboratory centers, a nationwide electronic health record, and clinicians organized to perform as an integrated team. These features ensure that all lifetime tests results are available in one record, that HPV testing is highly standardized, and that clinicians will follow a prescribed care pathway. The Netherlands’ health system is organized to support the successful transition, in a single step, to primary HPV testing. The United States is the third most populous country in the world, following China and India, with a diverse approach to health care, a highly mobile population, no single interoperable electronic health record, and minimal central control of clinical practice. The United States is not organized to make a “big bang” transition to primary HPV cervical cancer screening. It is likely that the introduction of primary HPV screening will occur first in highly integrated health systems that control the clinical, laboratory, and electronic records of a large population.
The results of the ATHENA study provide a clear clinical algorithm for implementing a primary HPV screening program for cervical cancer in the United States.23–25 Samples are collected for hrHPV testing at a specified interval, 3 or 5 years, beginning at age 25 years. Women younger than age 25 years should be screened with cytology alone. Detection of hrHPV results in reflex viral typing for HPV 16 and 18. Women with samples positive for HPV 16 and 18 are immediately referred for colposcopy. Samples positive for hrHPV and negative for HPV 16 and 18 have reflex cytology testing performed on the original HPV specimen. If cytology testing reports NILM, repeat cotesting is performed in one year. If cytology testing reports ASCUS or a more concerning result, the woman is referred for colposcopy.
Malcolm Gladwell, in his book The Tipping Point, identified 3 processes that help push an innovative new approach from obscurity into widespread use.26 First, authoritative voices that can catalyze change need to consistently communicate their shared vision for the future. Second, there must be a clear message that galvanizes the many to change their approach. Third, the historical context must be supportive of the change. Over the next decade we are likely to hit a tipping point and transition from cervical cancer screening that relies on cervical cytology to an approach that prioritizes hrHPV testing. When that change will occur in the United States is unclear. But our colleagues in other countries already have transitioned to primary hrHPV testing for cervical cancer screening.
Share your thoughts! Send your Letter to the Editor to rbarbieri@mdedge.com. Please include your name and the city and state in which you practice.
References
Hinsey JC. George Nicholas Papanicolaou, May 13, 1883–February 19, 1962. Acta Cytol. 1962;6:483–486.
zur Hausen H. Papillomaviruses in human cancers. Proc Assoc Am Physicians. 1999;111(6):581–587.
International Agency for Research on Cancer. IARC Handbooks of Cancer Prevention, Vol 10: Cervix Cancer Screening. Lyon, France: IARC Press; 2005.
Adegoke O, Kulasingam S, Virnig B. Cervical cancer trends in the United States: a 35-year population-based analysis. J Women’s Health (Larchmt). 2012;21(10):1031–1037.
Michels KB, zur Hausen H. HPV vaccine for all. Lancet. 2009;374(9686):268–270.
Hansen BT, Campbell S, Nygaard M. Long-term incidence of HPV-related cancers, and cases preventable by HPV vaccination: a registry-based study in Norway. BMJ Open. 2018;8(2):e019005.
Barbieri RL. Advances in protection against oncogenic human papillomaviruses: the 9-valent vaccine. OBG Manag. 2015;27(5):6–8.
Massad LS. Anticipating the impact of human papillomavirus vaccination on US cervical cancer prevention strategies. J Low Genit Tract Dis. 2018;22(2):123–125.
Castanon A, Landy R, Pesola F, Windridge P, Sasieni P. Prediction of cervical cancer incidence in England, UK, up to 2040, under four scenarios: a modeling study. Lancet Public Health. 2018;3(1):e34–e43.
Moyer VA; U.S. Preventive Services Task Force. Screening for cervical cancer: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med. 2012;156(12):880–891.
Moukarzel LA, Angarita AM, VandenBussche C, et al. Preinvasive and invasive cervical adenocarcinoma: preceding low-risk or negative Pap result increases time to diagnosis. J Low Genital Tract Dis. 2017;21(2):91–96.
Mayrand MH, Duarte-Franco E, Rodrigues I, et al; Canadian Cervical Cancer Screening Trial Study Group. Human papillomavirus DNA versus Papanicolaou screening tests for cervical cancer. N Engl J Med. 2007;357(16):1579–1588.
Hammond I, Canfell K, Saville M. A new era for cervical cancer screening in Australia: watch this space! Aust N Z J Obstet Gynaecol. 2017;57(5):499–501.
Canfell K, Saville M, Caruana M, et al. Protocol for Compass: a randomised controlled trial of primary HPV testing versus cytology screening for cervical cancer in HPV-unvaccinated and vaccinated women aged 25-69 years living in Australia. BMJ Open. 2018;8(1):e016700.
Wood B, Lofters A, Vahabi M. Strategies to reach marginalized women for cervical cancer screening: a qualitative study of stakeholder perspectives. Curr Oncol. 2018;25(1):e8–e16.
Patel H, Moss EL, Sherman SM. HPV primary cervical cancer screening in England: women’s awareness and attitudes. Psychooncology. 2018;27(6):1559–1564.
Obermair HM, Dodd RH, Bonner C, Jansen J, McCaffery K. “It has saved thousands of lives, so why change it?” Content analysis of objections to cervical cancer screening programme changes in Australia. BMJ Open. 2018;8(2):e019171.
Hall MT, Simms KT, Lew JB, Smith MA, Saville M, Canfell K. Projected future impact of HPV vaccination and primary HPV screening on cervical cancer rates from 2017-2035: Example from Australia. PLoS One. 2018;13(2):e0185332.
Rebolj M, Bonde J, Preisler S, Ejegod D, Rygaard C, Lynge E. Human papillomavirus assays and cytology in primary cervical screening of women aged 30 years and above. PLoS One. 2016;11(1):e0147326.
Khunamornpong S, Settakorn J, Sukpan K, Suprasert P, Srisomboon J, Intaraphet S, Siriaunkgul S. Genotyping for human papillomavirus (HPV) 16/18/52/58 has a higher performance than HPV16/18 genotyping in triaging women with positive high-risk HPV test in Northern Thailand. PLoS One. 2016;11(6):e0158184.
Wright TC, Stoler MH, Behrens CM, Sharma A, Zhang G, Wright TL. Primary cervical cancer screening with human papillomavirus: end of study results from the ATHENA study using HPV as the first-line screening test. Gynecol Oncol. 2015;136(2):189–197.
Huh WK, Ault KA, Chelmow D, et al. Use of primary high-risk human papillomavirus testing for cervical cancer screening: interim clinical guidance. Obstet Gynecol. 2015;125(2):330–337.
American College of Obstetricians and Gynecologists Committee on Practice Bulletins–Gynecology. Practice Bulletin No. 168: cervical cancer screening and prevention. Obstet Gynecol. 2016;128(4):e111–e130.
Gladwell M. The Tipping Point: How Little Things Can Make a Big Difference. New York, New York: Little Brown; 2000.
References
Hinsey JC. George Nicholas Papanicolaou, May 13, 1883–February 19, 1962. Acta Cytol. 1962;6:483–486.
zur Hausen H. Papillomaviruses in human cancers. Proc Assoc Am Physicians. 1999;111(6):581–587.
International Agency for Research on Cancer. IARC Handbooks of Cancer Prevention, Vol 10: Cervix Cancer Screening. Lyon, France: IARC Press; 2005.
Adegoke O, Kulasingam S, Virnig B. Cervical cancer trends in the United States: a 35-year population-based analysis. J Women’s Health (Larchmt). 2012;21(10):1031–1037.
Michels KB, zur Hausen H. HPV vaccine for all. Lancet. 2009;374(9686):268–270.
Hansen BT, Campbell S, Nygaard M. Long-term incidence of HPV-related cancers, and cases preventable by HPV vaccination: a registry-based study in Norway. BMJ Open. 2018;8(2):e019005.
Barbieri RL. Advances in protection against oncogenic human papillomaviruses: the 9-valent vaccine. OBG Manag. 2015;27(5):6–8.
Massad LS. Anticipating the impact of human papillomavirus vaccination on US cervical cancer prevention strategies. J Low Genit Tract Dis. 2018;22(2):123–125.
Castanon A, Landy R, Pesola F, Windridge P, Sasieni P. Prediction of cervical cancer incidence in England, UK, up to 2040, under four scenarios: a modeling study. Lancet Public Health. 2018;3(1):e34–e43.
Moyer VA; U.S. Preventive Services Task Force. Screening for cervical cancer: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med. 2012;156(12):880–891.
Moukarzel LA, Angarita AM, VandenBussche C, et al. Preinvasive and invasive cervical adenocarcinoma: preceding low-risk or negative Pap result increases time to diagnosis. J Low Genital Tract Dis. 2017;21(2):91–96.
Mayrand MH, Duarte-Franco E, Rodrigues I, et al; Canadian Cervical Cancer Screening Trial Study Group. Human papillomavirus DNA versus Papanicolaou screening tests for cervical cancer. N Engl J Med. 2007;357(16):1579–1588.
Hammond I, Canfell K, Saville M. A new era for cervical cancer screening in Australia: watch this space! Aust N Z J Obstet Gynaecol. 2017;57(5):499–501.
Canfell K, Saville M, Caruana M, et al. Protocol for Compass: a randomised controlled trial of primary HPV testing versus cytology screening for cervical cancer in HPV-unvaccinated and vaccinated women aged 25-69 years living in Australia. BMJ Open. 2018;8(1):e016700.
Wood B, Lofters A, Vahabi M. Strategies to reach marginalized women for cervical cancer screening: a qualitative study of stakeholder perspectives. Curr Oncol. 2018;25(1):e8–e16.
Patel H, Moss EL, Sherman SM. HPV primary cervical cancer screening in England: women’s awareness and attitudes. Psychooncology. 2018;27(6):1559–1564.
Obermair HM, Dodd RH, Bonner C, Jansen J, McCaffery K. “It has saved thousands of lives, so why change it?” Content analysis of objections to cervical cancer screening programme changes in Australia. BMJ Open. 2018;8(2):e019171.
Hall MT, Simms KT, Lew JB, Smith MA, Saville M, Canfell K. Projected future impact of HPV vaccination and primary HPV screening on cervical cancer rates from 2017-2035: Example from Australia. PLoS One. 2018;13(2):e0185332.
Rebolj M, Bonde J, Preisler S, Ejegod D, Rygaard C, Lynge E. Human papillomavirus assays and cytology in primary cervical screening of women aged 30 years and above. PLoS One. 2016;11(1):e0147326.
Khunamornpong S, Settakorn J, Sukpan K, Suprasert P, Srisomboon J, Intaraphet S, Siriaunkgul S. Genotyping for human papillomavirus (HPV) 16/18/52/58 has a higher performance than HPV16/18 genotyping in triaging women with positive high-risk HPV test in Northern Thailand. PLoS One. 2016;11(6):e0158184.
Wright TC, Stoler MH, Behrens CM, Sharma A, Zhang G, Wright TL. Primary cervical cancer screening with human papillomavirus: end of study results from the ATHENA study using HPV as the first-line screening test. Gynecol Oncol. 2015;136(2):189–197.
Huh WK, Ault KA, Chelmow D, et al. Use of primary high-risk human papillomavirus testing for cervical cancer screening: interim clinical guidance. Obstet Gynecol. 2015;125(2):330–337.
American College of Obstetricians and Gynecologists Committee on Practice Bulletins–Gynecology. Practice Bulletin No. 168: cervical cancer screening and prevention. Obstet Gynecol. 2016;128(4):e111–e130.
Gladwell M. The Tipping Point: How Little Things Can Make a Big Difference. New York, New York: Little Brown; 2000.
Researchers conducting a cost-utility analysis of sentinel lymph node (SLN) mapping and lymph node dissection (LND), both selective and routine, for low-risk endometrial carcinoma (clinical stage 1 disease with grade 1-2 endometrioid histology on preoperative endometrial biopsy), found that the SLN mapping had the lowest costs and the highest quality-adjusted survival of the three strategies.
Between the two strategies of LND, selective LND based on intraoperative frozen section was more cost-effective than routine LND.
The researchers created a model using data from past studies and clinical estimates. “Our biggest assumption was that sentinel lymph node mapping is associated with a decreased risk of lymphedema compared with lymph node dissection ... [from] several studies showing that having less than five lymph nodes excised was associated with a much smaller risk of developing lymphedema,” wrote Rudy S. Suidan, MD, of the MD Anderson Cancer Center, Houston, and his coauthors. Lymphedema was the main factor affecting quality of life in the analysis.
The analysis included estimates of rates of lymphadenectomy, bilateral mapping, and unilateral mapping, 3-year disease-specific survival, and overall survival, all of which were compared with third-party reimbursement costs at 2016 Medicare rates.
SLN mapping cost $16,401 per patient, while selective LND cost $17,036 per patient and routine LND cost $18,041 per patient. These strategies had quality-adjusted life years of 2.87, 2.81, and 2.79, respectively.
The superior cost-effectiveness of SLN mapping held, even when the researchers altered several of the variables in the model, including assuming open surgery instead of minimally invasive, and altering the assumed risk of lymphedema.
In addition to the possible limitation of making assumptions about SLN mapping and lymphedema, the researchers also pointed to the 3-year survival rates as shorter-term than preferable, driven by the available literature. The quality-adjusted life years did not differ much between the strategies because “most patients with low-risk cancer tend to have good clinical outcomes,” they wrote.
“This adds to the body of literature evaluating the clinical benefits of this strategy and may help health care providers in the decision-making process as they consider which approach to use,” the researchers wrote.
Dr. Suidan is supported by an NIH grant. Three coauthors reported other grants and fellowships. Five coauthors reported research support from AstraZeneca, Bayer, Clovis Oncology, and several other companies.
Researchers conducting a cost-utility analysis of sentinel lymph node (SLN) mapping and lymph node dissection (LND), both selective and routine, for low-risk endometrial carcinoma (clinical stage 1 disease with grade 1-2 endometrioid histology on preoperative endometrial biopsy), found that the SLN mapping had the lowest costs and the highest quality-adjusted survival of the three strategies.
Between the two strategies of LND, selective LND based on intraoperative frozen section was more cost-effective than routine LND.
The researchers created a model using data from past studies and clinical estimates. “Our biggest assumption was that sentinel lymph node mapping is associated with a decreased risk of lymphedema compared with lymph node dissection ... [from] several studies showing that having less than five lymph nodes excised was associated with a much smaller risk of developing lymphedema,” wrote Rudy S. Suidan, MD, of the MD Anderson Cancer Center, Houston, and his coauthors. Lymphedema was the main factor affecting quality of life in the analysis.
The analysis included estimates of rates of lymphadenectomy, bilateral mapping, and unilateral mapping, 3-year disease-specific survival, and overall survival, all of which were compared with third-party reimbursement costs at 2016 Medicare rates.
SLN mapping cost $16,401 per patient, while selective LND cost $17,036 per patient and routine LND cost $18,041 per patient. These strategies had quality-adjusted life years of 2.87, 2.81, and 2.79, respectively.
The superior cost-effectiveness of SLN mapping held, even when the researchers altered several of the variables in the model, including assuming open surgery instead of minimally invasive, and altering the assumed risk of lymphedema.
In addition to the possible limitation of making assumptions about SLN mapping and lymphedema, the researchers also pointed to the 3-year survival rates as shorter-term than preferable, driven by the available literature. The quality-adjusted life years did not differ much between the strategies because “most patients with low-risk cancer tend to have good clinical outcomes,” they wrote.
“This adds to the body of literature evaluating the clinical benefits of this strategy and may help health care providers in the decision-making process as they consider which approach to use,” the researchers wrote.
Dr. Suidan is supported by an NIH grant. Three coauthors reported other grants and fellowships. Five coauthors reported research support from AstraZeneca, Bayer, Clovis Oncology, and several other companies.
Researchers conducting a cost-utility analysis of sentinel lymph node (SLN) mapping and lymph node dissection (LND), both selective and routine, for low-risk endometrial carcinoma (clinical stage 1 disease with grade 1-2 endometrioid histology on preoperative endometrial biopsy), found that the SLN mapping had the lowest costs and the highest quality-adjusted survival of the three strategies.
Between the two strategies of LND, selective LND based on intraoperative frozen section was more cost-effective than routine LND.
The researchers created a model using data from past studies and clinical estimates. “Our biggest assumption was that sentinel lymph node mapping is associated with a decreased risk of lymphedema compared with lymph node dissection ... [from] several studies showing that having less than five lymph nodes excised was associated with a much smaller risk of developing lymphedema,” wrote Rudy S. Suidan, MD, of the MD Anderson Cancer Center, Houston, and his coauthors. Lymphedema was the main factor affecting quality of life in the analysis.
The analysis included estimates of rates of lymphadenectomy, bilateral mapping, and unilateral mapping, 3-year disease-specific survival, and overall survival, all of which were compared with third-party reimbursement costs at 2016 Medicare rates.
SLN mapping cost $16,401 per patient, while selective LND cost $17,036 per patient and routine LND cost $18,041 per patient. These strategies had quality-adjusted life years of 2.87, 2.81, and 2.79, respectively.
The superior cost-effectiveness of SLN mapping held, even when the researchers altered several of the variables in the model, including assuming open surgery instead of minimally invasive, and altering the assumed risk of lymphedema.
In addition to the possible limitation of making assumptions about SLN mapping and lymphedema, the researchers also pointed to the 3-year survival rates as shorter-term than preferable, driven by the available literature. The quality-adjusted life years did not differ much between the strategies because “most patients with low-risk cancer tend to have good clinical outcomes,” they wrote.
“This adds to the body of literature evaluating the clinical benefits of this strategy and may help health care providers in the decision-making process as they consider which approach to use,” the researchers wrote.
Dr. Suidan is supported by an NIH grant. Three coauthors reported other grants and fellowships. Five coauthors reported research support from AstraZeneca, Bayer, Clovis Oncology, and several other companies.
The Food and Drug Administration has approved bevacizumab (Avastin) for treating stage III or IV ovarian, fallopian tube, or primary peritoneal cancer following initial surgical resection, first in combination with chemotherapy (carboplatin and paclitaxel), then as monotherapy.
The approval was based on an improvement in progression-free survival (PFS) in the phase 3, three-arm GOG-0218 trial, evaluating the addition of bevacizumab to carboplatin and paclitaxel for patients with stage III or IV epithelial ovarian, fallopian tube, or primary peritoneal cancer following initial surgical resection, the FDA said in a press statement.
The study included 1,873 women with previously untreated disease randomized to receive either chemotherapy alone, chemotherapy plus bevacizumab followed by just placebo, or chemotherapy plus bevacizumab followed by bevacizumab alone. PFS was 18.2 months in the group that received bevacizumab plus chemotherapy then bevacizumab alone versus 12.0 months in the group that received only chemotherapy (hazard ratio, 0.62; 95% confidence interval, 0.52-0.75; P less than .0001).
The most serious adverse events of bevacizumab included gastrointestinal perforation, wounds that don’t heal, and serious bleeding. Other possible adverse events included kidney problems, fistula, severe high blood pressure, severe stroke or heart problems, and problems of the nervous system and vision. Less serious events included headache, nosebleeds, rectal bleeding, and dry skin.
The recommended bevacizumab dose for stage III or IV epithelial ovarian, fallopian tube, or primary peritoneal cancer following initial surgical resection is 15 mg/kg every 3 weeks with carboplatin and paclitaxel for up to 6 cycles, followed by 15 mg/kg every 3 weeks as a single agent, for a total of up to 22 cycles, the FDA said.
The Food and Drug Administration has approved bevacizumab (Avastin) for treating stage III or IV ovarian, fallopian tube, or primary peritoneal cancer following initial surgical resection, first in combination with chemotherapy (carboplatin and paclitaxel), then as monotherapy.
The approval was based on an improvement in progression-free survival (PFS) in the phase 3, three-arm GOG-0218 trial, evaluating the addition of bevacizumab to carboplatin and paclitaxel for patients with stage III or IV epithelial ovarian, fallopian tube, or primary peritoneal cancer following initial surgical resection, the FDA said in a press statement.
The study included 1,873 women with previously untreated disease randomized to receive either chemotherapy alone, chemotherapy plus bevacizumab followed by just placebo, or chemotherapy plus bevacizumab followed by bevacizumab alone. PFS was 18.2 months in the group that received bevacizumab plus chemotherapy then bevacizumab alone versus 12.0 months in the group that received only chemotherapy (hazard ratio, 0.62; 95% confidence interval, 0.52-0.75; P less than .0001).
The most serious adverse events of bevacizumab included gastrointestinal perforation, wounds that don’t heal, and serious bleeding. Other possible adverse events included kidney problems, fistula, severe high blood pressure, severe stroke or heart problems, and problems of the nervous system and vision. Less serious events included headache, nosebleeds, rectal bleeding, and dry skin.
The recommended bevacizumab dose for stage III or IV epithelial ovarian, fallopian tube, or primary peritoneal cancer following initial surgical resection is 15 mg/kg every 3 weeks with carboplatin and paclitaxel for up to 6 cycles, followed by 15 mg/kg every 3 weeks as a single agent, for a total of up to 22 cycles, the FDA said.
The Food and Drug Administration has approved bevacizumab (Avastin) for treating stage III or IV ovarian, fallopian tube, or primary peritoneal cancer following initial surgical resection, first in combination with chemotherapy (carboplatin and paclitaxel), then as monotherapy.
The approval was based on an improvement in progression-free survival (PFS) in the phase 3, three-arm GOG-0218 trial, evaluating the addition of bevacizumab to carboplatin and paclitaxel for patients with stage III or IV epithelial ovarian, fallopian tube, or primary peritoneal cancer following initial surgical resection, the FDA said in a press statement.
The study included 1,873 women with previously untreated disease randomized to receive either chemotherapy alone, chemotherapy plus bevacizumab followed by just placebo, or chemotherapy plus bevacizumab followed by bevacizumab alone. PFS was 18.2 months in the group that received bevacizumab plus chemotherapy then bevacizumab alone versus 12.0 months in the group that received only chemotherapy (hazard ratio, 0.62; 95% confidence interval, 0.52-0.75; P less than .0001).
The most serious adverse events of bevacizumab included gastrointestinal perforation, wounds that don’t heal, and serious bleeding. Other possible adverse events included kidney problems, fistula, severe high blood pressure, severe stroke or heart problems, and problems of the nervous system and vision. Less serious events included headache, nosebleeds, rectal bleeding, and dry skin.
The recommended bevacizumab dose for stage III or IV epithelial ovarian, fallopian tube, or primary peritoneal cancer following initial surgical resection is 15 mg/kg every 3 weeks with carboplatin and paclitaxel for up to 6 cycles, followed by 15 mg/kg every 3 weeks as a single agent, for a total of up to 22 cycles, the FDA said.
