Findings from a phase 2 trial suggest that patients with vulvar cancer and sentinel micrometastases may be able to avoid the morbidity of a lymphadenectomy by receiving inguinofemoral radiotherapy. Full study results the trial, 1 GROINSS-V-II ((NTR608/NL552) were recently published in the 

Of a total of 1535 patients registered to the trial, 21.0% (n = 322) had sentinel node metastasis. The stopping rule was activated in June 2010 because the isolated groin recurrence rate in 91 patients with sentinel node positivity went above the predefined threshold for the trial.

In 10 patients who had isolated groin recurrence, 9 had sentinel node metastases that were bigger than 2 mm and/or they had extracapsular spread. The trial protocol was amended so that those with macrometastases in the sentinel node, which was defined as bigger than 2 mm, received standard-of-care inguinofemoral lymphadenectomy (IFL). Those with sentinel node micrometastases, defined as smaller than 2 mm, continued to receive inguinofemoral radiotherapy.

Of the 160 patients with sentinel node micrometastases, 126 were given inguinofemoral radiotherapy and experienced a 2-year ipsilateral isolated groin recurrence rate of 1.6%. In the 162 patients with macrometastases in the sentinel nodes, the 2-year ipsilateral isolated groin recurrence rate was 22% in those who received radiotherapy and 6.9% in those given standard of care (

“GROINSS-V-II demonstrated that inguinofemoral radiotherapy in patients with sentinel node micrometastases results in a very low isolated groin recurrence rate, with acceptable treatment-related morbidity,” Maaike H. M. Oonk, PhD, of the Department of Obstetrics and Gynecology at The University Medical Center Groningen, The Netherlands, and colleagues, wrote. “For patients with sentinel node macrometastases, inguinofemoral radiotherapy with a total dose of 50 Gy is not a safe alternative for IFL in view of the higher risk of isolated groin recurrence.”

Over the past decade, several advances have been made in the treatment of patients with early-stage vulvar cancer. In those with unifocal tumors that are smaller than 4 cm and nonsuspicious groin nodes, a sentinel node biopsy has become standard of care rather than elective IFL. However, for those with sentinel node metastases, further treatment with IFL remains standard.

The GROINSS-V-I trial demonstrated that inguinofemoral lymphadenectomy can be safely omitted in patients who have negative sentinel nodes, leading to a significant decrease in morbidity. Patients with metastases in the sentinel node still need to undergo IFL to prevent groin recurrences, which are often fatal.

Investigators launched GROINSS-V-II to identify an equally effective, but less morbid, approach for patients with a metastatic sentinel node. To do this, they set out to determine whether inguinofemoral radiotherapy may represent a safe alternative to IFL in this population. They also wanted to examine the short- and long-term treatment-related morbidity for this strategy.

The prospective, multicenter, single-arm trial enrolled patients with early-stage vulvar cancer who were planned to undergo surgery. To be eligible for enrollment, patients needed to have unifocal microinvasive squamous cell carcinoma of the vulva that was less than 4 cm, and preoperative imaging of their groins could not reveal any suspicious nodes.

The primary end point of the research was the 24-month isolated groin recurrence rate.

Investigators utilized a radioactive tracer with performance of a lymphoscintigram and blue dye to perform sentinel node biopsies on study participants. When metastases were identified, the size and presence of extracapsular spread were noted. If the sentinel node could not be identified, an IFL was recommended. If the sentinel node was negative following ultrastaging, no further treatment was given. If tumor cells were detected, patients were regarded to have metastatic disease.

If metastatic disease in the sentinel node was identified, inguinofemoral radiotherapy was indicated. The decision of whether the treatment would be administered to 1 or both sides in those with unilateral sentinel node involvement was dependent on the participating center. Radiotherapy had to be given within 6 weeks after surgery, and it was given at a total dose of 50 Gy in 25 to 28 fractions of 1.8 Gy to 2.0 Gy, 5 fractions per week. The target dose of 50 Gy was selected because it was an effective dose for subclinical disease.

A total of 1708 patients were registered to the trial between December 2005 and October 2016. Among 1535 patients determined to meet the eligibility criteria for the trial, 79.0% (n = 1213) had a negative sentinel node and 21.0% (n = 322) had a metastatic sentinel node. Of the 322 patients with a metastatic sentinel node, 160 had micrometastases and 162 had macrometastases.

Among those with micrometastases, 78.8% (n = 126) were given inguinofemoral radiotherapy. Fourteen of these patients received radiotherapy plus chemotherapy; 9 were given cisplatin, and 5 had cisplatin and fluorouracil. Ten percent of the 126 patients underwent IFL rather than radiotherapy and 11.3% did not receive any further treatment because of either patient refusal, severe comorbidity, or older age.

Among the 160 patients, 6 isolated groin recurrences had occurred at 2 years following primary surgery; the 2-year rate was 3.8% (95% CI, 0.8%-6.8%) in this population. In the 126 patients who were given the radiotherapy, only 2 isolated ipsilateral groin recurrences were observed, in addition to 1 in a contralateral sentinel node–negative groin. Another 2 of 6 groin recurrences were reported in those who did not receive further treatment with IFL or radiotherapy. Additionally, 1 groin recurrence was observed in the contralateral sentinel node–negative groin following unilateral IFL for a metastatic node.

Among the 18 patients who were not given any additional treatment, the ipsilateral isolated groin recurrence rate proved to be higher than what was reported in those who received radiotherapy; the 2-year rates were 11.8% (95% CI, 0.0%-27.2%) and 1.6% (95% CI, 0.0%-3.9%), respectively (

Among the 162 patients who had macrometastases, 31.5% received only radiotherapy to the groins and 13.7% received radiotherapy plus chemotherapy in the form of cisplatin. Moreover, 64.8% of these patients (n = 105) had a unilateral or bilateral IFL; 56.2% of these patients also received adjuvant radiotherapy. Six patients did not receive further treatment following the removal of the sentinel nodes.

Among those with macrometastases, 19 groin recurrences were reported. The 2-year groin recurrence rates in those who received radiotherapy vs those who underwent IFL were 22.0% (95% CI, 10.5%-33.5%) and 6.9% (95% CI, 2.0%-11.8%), respectively. One recurrence was observed in a patient with 2 sentinel node macrometastases who did not receive any adjuvant treatment. No recurrences were reported in the contralateral nonirradiated groin.

Among those who received IFL, the groin recurrence rate in those who received adjuvant radiotherapy was not found to differ from those who did not receive adjuvant radiotherapy (

 = .43). In the 7 patients who received radiation plus chemotherapy, no recurrences were reported. A trend toward better disease control was observed in those who received this combination (

Of the 1213 patients who had sentinel node negativity, 31 had isolated groin recurrences. For 2 patients, metastases were noted to have been present in retrospect. In 4 patients, not all nodes visualized on the lymphoscintigram were removed. No concrete explanations were found for the other cases.

In patients with negative sentinel nodes, the estimated risk of disease-specific death at 2 years was 2.1% (95% CI, 1.3%-2.9%). In those with micrometastases, this rate was 6.5% (95% CI, 2.6%-10.4%); this rate was highest in those with macrometastases, at 25.5% (95% CI, 18.6%-32.5%; 

 < .0001). At 2 years following primary treatment, OS rates in those with negative sentinel nodes, micrometastases, and macrometastases were 95.2% (95% CI, 94.0%-96.5%), 88.3% (95% CI, 83.2%-93.4%), and 69.3% (95% CI, 62.0%-76.6%), respectively (

Of the 56 patients who experienced recurrence, 31 died from their disease during study follow-up. The estimated risk of disease-specific death at 2 years in those with macrometastases proved to be comparable in those who received IFL with or without radiotherapy and those who only received radiotherapy, at 24.2% (95% CI, 15.7%-32.6%) and 24.4% (95% CI, 12.4%-36.4%), respectively (

 = .88). Moreover, 25.5% of patients who received radiotherapy only died of vulvar cancer vs 22.9% of those who underwent IFL.

Notably, a sentinel node biopsy and subsequent radiotherapy to the groins was linked with low-grade toxicity. Cases of nausea, vomiting, mucositis, or anal and urinary incontinence were only grade 1 or 2 in severity. Diarrhea most frequently occurred at 4 to 6 weeks (grade 1, 12.3%; grade 2, 2.3%; grade 3, 0.6%) or 6 months following radiotherapy (7.9%, 0.0%, and 0.7%, respectively).

Moreover, 21.3% of patients reported grade 1 toxicity associated with the skin in the irradiated groin; in 14.8% and 1.3% of patients, respectively, this effect was grade 2 or 3 in severity. However, at 6 months, the incidence of this toxicity was found to significantly decrease. Notably, no grade 4 or 5 effects were observed.

Among patients who experienced lymphedema more than once at 6 months or 12 months following treatment, this effect was less frequent following biopsy alone, at 5.1% and 4.1%, respectively, vs when biopsy was done and followed by radiotherapy, at 16.4% and 10.7%, respectively (

 < .0001). The highest incidence of this toxicity was observed in those who underwent IFL, at 32.0% in those who also received radiotherapy and 22.9% in those who did not (

“Inguinofemoral radiotherapy for vulvar cancer patients with sentinel node micrometastases appears to be a safe alternative for IFL. The toxicity of radiotherapy is acceptable, and treatment-related morbidity is less frequent compared with IFL,” study authors concluded. “For patients with sentinel node macrometastases, radiotherapy with a total dose of 50 Gy showed more isolated groin recurrences than IFL.”

The GROINSS-V-III trial (NTR7677/NL7435) will examine radiotherapy dose escalation in combination with chemotherapy in patients with sentinel node macrometastases.

Oonk MHM, Slomovitz B, Baldwin PJW, et al. Radiotherapy versus inguinofemoral lymphadenectomy as treatment for vulvar cancer patients with micrometastases in the sentinel node: results of GROINSS-V II. 

. Published online August 25, 2021. doi:10.1200/JCO.21.00006

This article was originally published on OncLive as “Inguinofemoral Radiotherapy Represents Safe Alternative to Lymphadenectomy in Vulvar Cancer With Micrometastases”

Articles

Inguinofemoral radiotherapy may be a safe alternative for patients with vulvar cancer and sentinel node micrometastases who might otherwise face the morbidity of a lymphadenectomy.

Inguinofemoral Radiotherapy May Be Potential Alternative To Lymphadenectomy In Select Vulvar Cancer

The FDA approved pembrolizumab (Keytruda) in combination with chemotherapy, with or without bevacizumab (Avastin), to treat patients with persistent, recurrent, or metastatic cervical cancer whose tumors harbor PD-L1, as demonstrated by an FDA-approved test, according to a press release issued by the agency.

Notably, the FDA has also granted regular approval to pembrolizumab as a monotherapy for the same patient population on or after chemotherapy. The agency granted this indication an accelerated approval, with its companion diagnostic, PD-L1 IHC 22C3 pharmDx, in June 2018.

This approval was based on findings from the multicenter, randomized, double-blind, placebo-controlled, phase 3 KEYNOTE-826 trial (NCT03635567). Findings from the trial’s interim analysis were recently presented at the 

The trial assessed 617 patients with persistent, recurrent, or first-line metastatic cervical cancer who had not been treated with chemotherapy, irrespective of PD-L1 expression status. Participants were randomized into 2 treatment cohorts: The experimental cohort received pembrolizumab 200 mg plus chemotherapy with or without bevacizumab, while the control cohort received placebo plus chemotherapy with or without bevacizumab. Pembrolizumab was administered until disease progression, unacceptable toxicity, or 24 months of treatment.

The trial’s primary end points were overall survival (OS) and progression-free survival (PFS) as determined by RECIST v1. With a maximum of 10 target lesions and a maximum of 5 target lesions per organ. Median OS was not reached in the pembrolizumab arm (95% CI, 19.8-not reached [NR]) and was 16.3 months (95% CI, 14.5-19.4) in the placebo arm (HR, 0.64; 95% CI, 0.50-0.81; 

 = 0.0001). Median PFS was 10.4 months in the experimental arm (95% CI, 9.7-12.3) and 8.2 months in the control arm (95% CI, 6.3-8.5), respectively (HR, 0.62; 95% CI, 0.50-0.77; 

Objective response rates were 68% in the experimental group and 50% in the control. In addition, patients taking pembrolizumab experienced a median DOR of 18.0 months, compared with 10.4 months in the pembrolizumab arm.

“Adding pembrolizumab to chemotherapy with or without bevacizumab provides statistically significant, clinically meaningful improvements in PFS and OS in patients with persistent, recurrent, or metastatic cervical cancer. The significant benefit was observed in all primary analysis populations and was generally consistent across protocol-specified subgroups,” lead study author Nicoletta Colombo, MD, PhD, director of the Gynecologic Oncology Division at the European Institute of Oncology and associate professor of Obstetrics and Gynecology at the University of Milan-Bicocca in Milan, Italy, said in a recent presentation of the findings. “Overall, data from KEYNOTE-826 suggest that pembrolizumab plus platinum-based chemotherapy with or without bevacizumab may be a new first-line standard of care for the treatment [of these patients].”

The most common adverse events (AEs) observed in the experimental arm included peripheral neuropathy, alopecia, anemia, fatigue/asthenia, nausea, neutropenia, diarrhea, hypertension, thrombocytopenia, constipation, arthralgia, vomiting, urinary tract infection, rash, leukopenia, hypothyroidism, and decreased appetite.

Pembrolizumab should be administered at 200 mg every 3 weeks or 400 mg every 6 weeks until disease progression, unacceptable toxicity, or up to 24 months.

FDA approves pembrolizumab combination for the first-line treatment of cervical cancer. News release. FDA. October 13, 2021. Accessed October 13, 2021. https://bit.ly/3lE3vNS

Colombo N, Dubot C, Lorusso D, et al. Pembrolizumab plus chemotherapy versus placebo plus chemotherapy for persistent, recurrent, or metastatic cervical cancer: randomized, double-blind, phase 3 KEYNOTE-826 study. Presented at: 2021 ESMO Congress; September 16-21, 2021; virtual. Abstract LBA2_PR

Pembrolizumab is approved both in combination with chemotherapy, with or without bevacizumab, and as a single agent for the treatment of patients with recurrent or metastatic cervical cancer. 

FDA Approves Pembrolizumab Combination to Treat First-Line Cervical Cancer

Although single-agent checkpoint inhibitors have not induced superior outcomes in patients with ovarian cancer, combining those agents with other therapies, like different checkpoint inhibitors, PARP inhibitors, and bevacizumab (Avastin), could improve the efficacy of treatment for these patients, explained Ritu Salani, MD, MBA.

“It is a very exciting time in ovarian cancer,” Salani said. “I am thrilled that there is so much investment and development of novel agents and continue [enhancement of] the strategies we have currently, such as PARP inhibitors, checkpoint inhibitors, and bevacizumab.”

Salani noted that the current limitations to these treatment strategies include potential financial and treatment-related toxicities.

 during an Institutional Perspectives in Cancer webinar on gynecologic cancer, Salani, division director for Gynecologic Oncology and professor of obstetrics and gynecology at the University of California, Los Angeles, discussed the clinical rationale to evaluate combination strategies with immunotherapy in ovarian cancer, as well as novel agents in clinical development that could further influence the treatment paradigm.

: How may immunotherapy combinations improve upon the lackluster responses observed with single-agent checkpoint inhibitors thus far in recurrent ovarian cancer?

: Novel immunotherapy, predominantly with checkpoint inhibitor strategies, have been really disappointing in the treatment of [patients with] recurrent ovarian cancer. With single agents, we are seeing response rates that are modest at best.

There are some opportunities for combination therapy. One exciting avenue is whether there is a role for immunotherapy combinations with checkpoint inhibitors and bevacizumab, [with or without PARP inhibitors]. We are seeing some provocative response rates in limited subsets. This is a potential opportunity to enhance the care of our patients. It will be challenging in patients who may have received PARP inhibitors [in earlier lines of therapy], so that may put a bit of a wrinkle in the therapy approaches. It may be an opportunity for patients who have not received [PARP inhibitors].

We do have to mindful of toxicities with these 3 treatments in the recurrent setting, especially for patients who have been heavily pretreated. [We also must be aware] of the potential financial toxicities from these approaches. Once we continue to explore these avenues, we need to find a balance between the physical, emotional, and financial toxicities and response rates.

What is the scientific rationale to combine PARP inhibitors with checkpoint inhibitors?

Something exciting about combinations with PARP inhibitors and immunotherapy is that it is kind of based off capitalizing on DNA damage repair and priming the immune system so that immunotherapy can be more active in these tumors that are not essentially “hot.” We are capitalizing on exploiting one deficiency to make it opportunistic for immunotherapy.

In the preliminary, limited data that we have seen from small, phase 2 trials, this combination of checkpoint inhibitors and PARP inhibitors has shown some provocative response rates. What is more exciting is the combination of VEGF inhibitors, such as bevacizumab, [plus checkpoint inhibitors]. We are seeing that combining these agents might have a synergistic effect in patients with ovarian cancer.

 status or homologous recombination deficient [HRD] status or the biomarkers that we use for immunotherapy, such as PD-L1 expression.

The phase 3 PRIMA study (NCT02655016) evaluated niraparib (Zejula) vs placebo in patients with stage III or IV ovarian cancer. Could you discuss the efficacy and safety profile observed with the PARP inhibitor in this trial and what the next steps might be with niraparib?

The PRIMA trial was exciting because it was the first study to look at all-comers for PARP inhibitor maintenance strategies after frontline chemotherapy in advanced ovarian cancer. [The trial] looked at a very complicated cohort of patients.

The next steps for niraparib in ovarian cancer are to continue to capitalize on these tumors. We know that patients with 

 mutations and, for the most part, patients with HRD tumors should be offered a PARP inhibitor in frontline strategies.

Determining what the best treatment is for those homologous recombination proficient patients, as well as for patients in the recurrent setting who may not have received PARP inhibitors, [will be important]. Perhaps [utilizing] single-agent niraparib is not the right choice, but maybe [niraparib] in combination with bevacizumab or a checkpoint inhibitor would be the next best steps.

What investigational agents are you keeping your eyes on in the ovarian cancer pipeline?

The future of ovarian cancer is exciting. As we further refine the role of PARP inhibitors and understand that role, we are going to be looking at novel strategies outside of the world of immunotherapy and PARP inhibitors. Some exciting opportunities include mirvetuximab soravtansine, which is targeting folate receptor alpha; that is highly expressed in ovarian cancer. [Mirvetuximab soravtansine can be used] as a single agent or in combination with chemotherapy or bevacizumab. Those studies are ongoing.

Some interesting trials are [evaluating novel agents] in combination with weekly paclitaxel in patients with platinum-resistant ovarian cancer. This includes using VB-111, which is gene therapy targeting tumor vascular and the immune response, tumor treatment fields, and AVB-500, which targets 

. These are exciting preliminary studies, so I look forward to what future trials show. These may help to change the treatment landscape of women with platinum-resistant ovarian cancers.

In the recurrent ovarian cancer landscape, we need to enroll [patients on] clinical trials so that we understand the [implications] of these treatments regarding toxicity on our patients. Then, we can provide these patients with the best outcomes and minimal toxicity risk from our therapies.

This article was originally published on OncLive as “Immunotherapy Combos, Novel Agents Hold Promise in Recurrent Ovarian Cancer”

Combining immunotherapy with other targeted therapies may result in more promising outcomes than immunotherapy alone in the treatment of recurrent ovarian cancer, according to an expert at University of California, Los Angeles.  

Strategies That Combine Immunotherapies With Bevacizumab, Other Agents May Expand Utility of Immunotherapy in Recurrent Ovarian Cancer

Although generally curable if found and treated early, germ cell tumors are aggressive.

Germ cell tumors constitute 20% to 25% of all ovarian neoplasms. These tumors of the ovary are derived from the from the primitive germ cells of the embryonic gonad and typically present in young women and adolescent girls.

The vast majority of these tumors are benign mature cystic teratomas; only 5% of germ cell tumors are malignant. Ovarian malignant germ cell tumors (OMGCTs) include, in order of frequency, dysgerminomas, immature teratomas, yolk sac tumors, and mixed germ cell tumors.

OMGCTs constitute about 2.6% of malignant ovarian neoplasms compared with approximately ovarian epithelial neoplasms, which constitute about 95%.

Prior to the establishment of systemic chemotherapy in the 1970s, prognosis was poor for these patients—the World Health Organization (WHO) says the chance of survival without chemotherapy is 0%.

 Today, the outlook for these patients is significantly better due to the standard-of-care regimen of bleomycin plus etoposide and cisplatin (BEP), which is often combined with surgery and/or radiation. A 1993 report demonstrated that treatment with BEP induced overall disease-free survival rates greater than 95%.

The WHO says the 5-year survival rate of 95% to 100% among patients with stage I disease who receive the adjuvant BEP regimen following surgery and up to 85% among those with metastatic disease.

OMGCTs fall into 3 understudied categories of disease: it is a rare cancer, a gynecologic cancer, and often a pediatric cancer. Much of the available data are derived literature developed for male germ cell tumors.

“There are a lot of similarities between the germ cell tumors in men and women. They have some similar origins, although one is the male version and the female version, of course, but also the treatments are effective for both,” said Floor J. Backes, MD, a professor in the Division of Gynecologic Oncology at The Ohio State University Comprehensive Cancer Center—James. “There are more of these tumors in men and [they are] more studied that we do have to extrapolate some of the data that we see in men to women.”

The lack of data present challenges for both treatment and staging. The Children’s Oncology Group and International Federation of Gynecology and Obstetrics (FIGO) use different staging criteria. The different staging means different recommendations for removing lymph nodes during oophorectomy.

Backes said that, at present, investigators are focused on decreasing side effects, improving quality of life, preserving fertility, and reducing the chances for secondary cancers later in life.

That includes using less toxic therapies and, in some cases, close surveillance rather than adjuvant chemotherapy.

“There are actually some data out there that, at least in earlier-stage patients, not all of them need to receive treatment and…if the patient develops a recurrence to their cancer, you can still successfully treat them at that time,” she said. “That is an option not for all cancers, but germ cell tumors are so sensitive overall to chemotherapy, and that still carries over that even if the cancer comes back, there’s still a high chance of curing these patients.”

Despite the general lack of research into OMGCTs, there is evidence that fertility-sparing surgery can be safe and effective. Investigators at Vali-e-asr Hospital in Tehran, Iran conducted a retrospective study on 79 women treated at the hospital’s gynecologic oncology department for OMGCTs from 2001 to 2006.5

Physicians collected each patient’s medical history and conducted a physical exam before the patient underwent FSS. Complete and optimal FSS is defined as preserving the uterus with no residual tumor and preserving at least part of the contralateral ovary with no more than 1 cm of residual tumor. Debulking and staging surgery were done by omentectomy and lymphadenectomy and peritoneal biopsy and cytology of peritoneal washing.

Investigators collected patient data including age, chief complaint, time of surgery, pathology, grade, and stage based on FIGO classification, through inpatient case files. They also recorded information about adjuvant chemotherapy that the patients received after surgery.

Participants completed questionnaires on reproductive outcomes and menstruation status several months after treatment. Investigators followed the patients by calling them or visiting in the clinic again and collected fertility information including number of pregnancies and childbirth, childbearing desire, menstrual status, methods of pregnancy, gestational weeks at delivery, and obstetrical complication.

The mean patient age was 23 years (range, 19-34). Three patients were excluded because of death, 3 due to XY genotyping, and 1 due to bilateral ovarian involvement. Sixty (83%) of the remaining 72 patients in the cohort received adjuvant chemotherapy.

Eleven patients had FIGO stage I disease, 23 had stage II, and 38 had stage III. Physicians advised most patients to undergo adjuvant chemotherapy following surgery except for patients with stage IA, grade 1 immature teratoma and stage IA dysgerminoma because those patients tend to have excellent outcomes from surgery alone.

The median follow-up was 56 months (range, 8-194 months). Disease-free survival (DFS) was 87% at 5 years and 94.4% at 10 years. Overall survival (OS) was 94.4% at both 5 and 10 years. The 5- to 10-year DFS and OS rates were 100% in patients with stage I disease compared with 83% for stage 2 and 90% for stage III.

Sixty (83%) patients recovered regular menstruation following treatment. All patients without adjuvant chemotherapy experienced regular menstruation, while 78% in the adjuvant chemotherapy group had normal menstruation at the end of treatment. Retrieval of regular menstruation was not dependent on the age or number of chemotherapy cycles.

Twenty-six women in the study attempted to become pregnant, 19 (73%) of whom had successful pregnancies that led to delivery. No patient required fertility treatments and the pregnancy rate was independent of age, stage, or type of pathology.

Backes said that investigators have made great progress in developing fertility-sparing treatments for this patient population. When only one ovary is affected, it is possible to remove that organ, leaving the other ovary and uterus in place, maintaining the patient’s childbearing capacity.

“Not just surgically, but also incorporating what we call onco-fertility. There are fertility doctors and oncologists specialized in fertility preservation and all the options that we have for that,” she added. “For example, we can harvest either oocytes before surgery or ovarian cortex, part of the ovary that we can freeze and preserve and reimplant later, so that patients still can have their ovarian function come back after the cancer is gone.”

Talerman A. Germ cell tumors of the ovary. 

Quirk JT, Natarajan N. Ovarian cancer incidence in the United States, 1992-1999. 

. 2005;97(2):519-23. doi:10.1016/j.ygyno.2005.02.007

Gershenson DM. Update on malignant ovarian germ cell tumors. 

. 1993;71(4 suppl):1581-90. doi:10.1002/cncr.2820710425

Union for International Cancer Control. 2014 Review of cancer medicines on the WHO list of essential medicines—ovarian germ cell tumors. Accessed September 23, 2021. https://bit.ly/3uggfNh

Zamani N, Rezaei SMP, Dizajmehr SG, et al. Fertility sparing surgery in malignant ovarian Germ cell tumor (MOGCT): 15 years experiences. 

. 2021;21(1):282. doi:10.1186/s12905-021-01437-8

This article was originally published on OncLive as “Investigators Seek to Preserve Fertility in Ovarian Malignant Germ Cell Tumors”

New research suggests that fertility-sparing surgery is feasible and safe in treating ovarian malignant germ cell tumors. 

New Research Seeks to Target Ovarian Malignant Germ Cell Tumors Without Compromising Fertility 

A recent analysis showed that the human papillomavirus (HPV) vaccine was not associated with primary ovarian insufficiency, according to a new retrospective cohort from the Danish vaccination register.

Girls and women who received 4 doses (4HPV) of the vaccine showed no significant different in primary ovarian insufficiency compared with women who were unvaccinated.

The retrospective analysis followed 996,300 Danish girls and women from 2007 to 2016 between the ages 11 to 34 years. Half of the women (n = 505,829 [50.8%]) had received 4 HPV vaccine doses while the other half (n = 490,471 [49.2%]) were unvaccinated. Overall, 144 women were diagnosed with primary ovarian insufficiency, 54 of which had received 4 doses of the HPV vaccination. Moreover, the researchers determined that 26.94 years was the median age of diagnosis.

The adjusted hazard ratio comparing both vaccinated individuals and unvaccinated individuals who were diagnosed with primary ovarian insufficiency was 0.96 (95% CI, 0.55-1.68).

“The HPV vaccines are cancer-preventing vaccines, and, thus, the lackluster uptake in many countries is disheartening,” wrote Anders Hviid, DrMedSci, Statens Serum Institut and Emilia Theissen, MSc, University of Copenhagen, in a corresponding paper. “Our study provides much-needed support for the ovarian safety of the 4HPV vaccine, which is of key importance for clinical and public health personnel when addressing parental concerns about fertility issues associated with vaccination. There is currently little evidence for an association between 4HPV vaccination and primary ovarian insufficiency. On the contrary, the vaccine protects against infections that may decrease fertility.”

Estimate hazard ratios were measured through the cox proportional hazards regression and adjustments for age, calendar periods, and propensity scores summarized health care use. The investigation began in October 2020 and concluded in January 2021.

A 4HPV vaccine (Gardasil) was introduced to Danish childhood immunization schedules in January 2009. Previously, girls older than 12 years had been offered a 3-dose vaccine schedule. Starting in October 2008, girls between the ages of 13 to 15 were offered a “catch-up” vaccine. By August 2012, the “catchup” vaccine was also available to women between 20 and 27 years of age. In February of 2016, the 4-dose vaccine was replaced with a bivalent vaccine (Cervarix, GlaxoSmithKline).

The Danish vaccination register included information for both women who received their HPV vaccinations through the free national childhood immunization program, as well as for older individuals who were not eligible for the program and consequently purchased their vaccinations privately. Individuals who were vaccinated prior to the study’s start date were not included in the assessment.

The Danish National Patient Registry provided the data for primary ovarian insufficiency. Researchers used the diagnoses codes E28.3 and E28.31 to locate data for both primary ovarian hypofunction and premature menopause, respectively.

Primary outcomes were contacting hospitals for primary ovarian insufficiency and were measured through hazard ratios comparing vaccinated and unvaccinated individuals.

Receiving an HPV vaccination that was not a 4-dose vaccine was marked as a censoring event, as were diagnoses of cancer or carcinoma in situ, hypogonadism after ovarian treatment, or major surgical procedures on the genitalia.

As noted previously, the adjusted hazard ratio between vaccine and unvaccinated women was 0.96 (95% CI, 0.55-1.68). The HR did not change significantly in periods following the final vaccination, nor by age, or calendar period at first vaccination. Regarding propensity score, the adjusted HR was 0.58 (95% CI, 0.19-1.73) for the first, second, and third decile, 0.79 (95% CI, 0.35-1.80), for the fourth through the seventh decile, and 1.98, (95% CI, 0.71-5.56) for the eighth through tenth decile.

Forty-five individuals received a diagnosis of primary ovarian insufficiency which proceeded to be an amenorrhea or oligomenorrhea diagnosis. Researchers re-estimated the HR of these individuals and determined an adjusted HR of 1.32 (95% CI, 0.73-2.38). A further sensitivity analysis accounting for a lack of menarche data revealed an adjusted HR of 1.03 (95% CI, 0.58-1.83).

“The main strength of our study is the use of a nationwide cohort of girls and women with independent ascertainment of exposure and outcome status,” concluded the study authors. “Our study is the largest to date of 4HPV vaccination and primary ovarian insufficiency diagnosis, with 144 individuals, including 54 vaccinated individuals. It is the first, to our knowledge, to evaluate a composite outcome of oligomenorrhea and amenorrhea in a cohort study.”

The authors acknowledged certain limitations that merit consideration in future studies. First, researchers did not have access to the symptom onset date, and they speculated that there was likely delay between symptom onset and diagnosis. They also noted that individuals would likely be diagnosed with primary ovarian insufficiency beyond the years of the analysis.

Because the study did not include information on menarche, some of the younger individuals included in the analysis may not have been at risk during the allotted follow-up period. Finally, the study did not include information about oral contraceptive use, which may prolong time to or even decrease risk of primary ovarian insufficiency diagnosis. The authors acknowledged that this could potentially mask an increased rate.

Hviid A, Myrup Thiesson E. Association Between Human Papillomavirus Vaccination and Primary Ovarian Insufficiency in a Nationwide Cohort. 

 2021;4(8):e2120391. doi:10.1001/jamanetworkopen.2021.20391

A new retrospective cohort found that women who had received the human papillomavirus vaccine had similar rates of primary ovarian insufficiency as unvaccinated women.

Analysis Shows HPV Vaccine Not Associated with Infertility in Women 

Loop Electrical Excision Procedure (LEEP) was 40% more likely than cryotherapy to clear high-risk human papillomavirus (hrHPV) infections in women with cervical intraepithelial neoplasia (CIN2+), according to a secondary analysis of a randomized clinical trial in Kenya (

In addition, recurrent CIN was 5 times more likely than HPV to be associated with hrHPV detection.

Over a 24-month period, participants who underwent LEEP reported significantly higher hrHPV compared with cryotherapy recipients (HR, 1.40; 95% CI, 1.03-1.90; 

=.03). At the 12-month follow-up, a multivariable analysis revealed hrHPV type-specific persistence to be significantly associated with CIN2+ recurrence (adjusted hazard ratio, 4.70; 95% CI, 2.47 -8.95; 

 <.001). At 12 months, hrHPV testing for recurrent CIN2+ was 93% sensitivity, 46% specificity, 38% positive predictive value, and 95% negative predictive value.

“Cryotherapy is not as effective at clearing hrHPV because it may not achieve therapeutic depth compared with LEEP,” wrote Michael H. Chung, MD, MPH, Emory University, and study authors. “Unlike LEEP, cryotherapy does not excise tissue but causes necrosis through freezing up to a depth of 5 to 7 mm. Cervical dysplasia may be present in deeper tissue than cryotherapy can reach and may be infected with subclinical or latent hrHPV.”

The primary outcomes from this analysis were hrHPV positivity, which was defined as having 1 of 12 possible hrHPV types, (16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59) as well as disease recurrence, which meant a CIN grade 2 or higher with cervical biopsy.

Between June 2011 and September 2016, researchers screened 5,330 HIV- positive women through papanicolaou (PAP) testing. High-grade squamous intraepithelial lesions were found in 738 (13.8%) of the participants, and CIN 2+ subsequent colposcopy-directed biopsy was detected in 512 (9.6%) of participants.

The study included a total of 354 HIV-positive women with CIN2+. Among these participants, in the cryotherapy arm, median age was 37 years and baseline hrHPV prevalence was 90% (160 out of 177). In the LEEP arm, median age was 38 years and hrHPV prevalence was 94%. The randomized women received follow-ups every 6 months for 2 years, through hrHPV cervical swab and Pap test with cervical biopsy.

Between the 354 women with confirmed CIN2+ on colposcopy-directed biopsy as well as an hrHPV result at baseline testing, 177 women (50%) were treated with cryotherapy and 177 women (50%) were treated through LEEP. Sociodemographic and HIV characteristics were consistent between the two treatment groups; the average monthly household income was less than $150/month in both cohorts (62% vs 64%; P=.79) and immunocompromising was similar (CD4 count < 250 cells/mm3; 29% vs 27%; 

 = .75). In addition, the number of participants pretreated with ART for at least 2 years was comparable between the arms, (51% vs 57%; 

Researchers concluded that the results of the secondary analysis were consistent with those of the original clinical trial. LEEP has demonstrated clinical benefit over cryotherapy if and when this method is available and accessible in low-and middle-income countries. Testing for hrHPV following cervical treatment is potentially valuable in ruling out recurrent cervical disease among women living with HIV.

“These results correlate with the primary outcome analysis of the RCT, which demonstrated that LEEP was also better than cryotherapy in preventing recurrent CIN2+,” authors wrote. “Taken together, they demonstrate the superior treatment efficacy of LEEP over cryotherapy among women living with HIV.”

The study authors acknowledged a number of limitations. The first was that the secondary analysis assessed the findings of a trial conducted at a singular site in Kenya with 1 study clinician overseeing both the cryotherapy and LEEP procedures. Consequently, further research is needed to determine whether these study results extend to the rest of Kenya, or even other countries and regions.

Additionally, the study follow-up period was 2 years, which, according to the researchers, is too short a period to ascertain if hrHPV detection and CIN result in cervical cancer or mortality. This limitation is exacerbated by the fact that many participants were pretreated with ART, which might impact these outcomes. Future research should seek to extend the follow-up period to gain insight to the long-term implications of hrHPV persistence after treatment on cervical cancer and mortality among women living with HIV.

Chung MH, De Vuyst H, Greene SA, et al. Human papillomavirus persistence and association with recurrent cervical intraepithelial neoplasia after cryotherapy vs loop electrosurgical excision procedure among HIV-positive women. 

 August 5, 2021. Accessed September 8, 2021. doi:10.1001/jamaoncol.2021.2683

Loop electrical excision procedure (LEEP) demonstrated superior capabilities in clearing high-risk HPV infections in women with cervical intraepithelial neoplasia (CIN2+).

Loop Electrical Excision Procedure Superior to Cryotherapy in Clearing High-Risk HPV Infections 

The FDA has granted priority review to cemiplimab-rwlc (Libtayo) in response to the supplemental biologics license application (sBLA) on the indication of recurrent or metastatic cervical cancer whose disease progressed on or after chemotherapy.

The priority review is based off findings from the open-label, multi-center phase 3 EMPOWER-Cervical 1 trial, which is the largest randomized clinical trial in advanced cervical cancer to-date. Updated findings presented at the 2021 ESMO Virtual Plenary revealed that cemiplimab demonstrated superior overall survival (OS), progression-free survival (PFS), and objective response rate (ORR), compared with chemotherapy, as an advanced cervical cancer therapy. 

The FDA set a target action date of January 30, 2022.

Overall, the 304 participants treated with cemiplimab–a fully human monoclonal antibody that functions by targeting the PD-L1 immune checkpoint receptor on T-cells–experienced a 31% reduced risk of mortality (HR, 0.69; 95% CI, 0.56-0.84; 

 = .00011), a 25% reduced risk of disease progression (HR, 0.75; 95% CI, 0.63 -0.89; 

 = .00048), and an ORR of 16% compared with 6% with chemotherapy (95% CI, 13%-21%; 

"In this phase 3 trial, Libtayo demonstrated a significant improvement in overall survival in women with advanced cervical cancer after progression on chemotherapy, reducing the risk of death by 31% compared to chemotherapy in the overall population," said trial investigator Krishnansu S. Tewari, MD, professor and director of the Division of Gynecologic Oncology at the University of California, Irvine. "Improvements in progression-free survival and objective response rate were also demonstrated in the overall population compared to chemotherapy. Taken together, this landmark trial–which enrolled patients regardless of PD-L1 expression status–helps support the use of Libtayo as a potential new second-line treatment for women with advanced cervical cancer who face a poor prognosis and limited treatment options."

The study assessed women with recurrent or metastatic cervical cancer whose disease had progressed beyond platinum-based chemotherapy. PD-L1 expression status was not a factor in participant eligibility. Women from 14 countries participated in the trial, including the U.S., Japan, Taiwan, South Korea, Canada, Russia, Poland, Spain, Brazil, Australia, the UK, Italy, Greece and Belgium. Seventy-eight percent of patients had squamous cell carcinoma (SCC) and 22% had adenosquamous carcinoma.

In addition, a smaller subset of patients in the trial whose disease was identified as SCC experienced positive results with cemiplimab compared with chemotherapy. These 238 patients experienced a 27% reduced risk of mortality (HR, 0.73; 95% CI, 0.58-0.91; 

 = .00306), a 29% reduced risk of disease progression (HR, 0.71; 95% CI, 0.58 -0.86; 

 = .00026), and an ORR of 18% compared with 7% with chemotherapy (95% CI, 13%-23%).

A post-hoc analysis also determined that the 65 patients with adenocarcinoma experienced a 44% reduced risk of mortality (HR, 0.56; 95% CI, 0.36-0.85; 

 < .005), a 9% reduced risk of disease progression (HR, 0.91; 95% CI, 0.62-1.34), and an ORR of 12% compared with 5% with chemotherapy (95% CI, 1%-13%).

Notably, findings also determined that patients treated with the novel regimen experienced a superior global health status/quality of life (GHS/QoL) than those treated with chemotherapy. The change in status became clinically meaningful starting at cycle 8, with the improvement with cemiplimab being 1.01 and the worsening for chemotherapy being -6.81 (95% CI).

Investigators reported no new safety signals. Adverse events (AEs) occurred in 88% of participants in the experimental arm and 91% of the control arm. Common AEs included anemia (25% vs 45%, respectively), nausea (18% vs 33%), fatigue (17% vs 16%), vomiting, (16% vs 23%), decreased appetite (18% vs 33%), and constipation (15% vs 20%).

AEs with a grade 3 or higher severity occurred in 45% of patients receiving cemiplimab and 53% of patients receiving chemotherapy. These AEs included asthenia (2% vs 1%, respectively), and pyrexia (less than 1% vs 0%). In addition, immune-related were observed in 16% of patients receiving cemiplimab and in less than 1% of patients on chemotherapy.

Discontinuations were necessary among 8% of patients in the experimental cohort and in 5% of the control cohort.

Providers should ask their patients about any immune-related problems, organ transplant history, allogeneic stem cell transplant history, or nervous system conditions, before prescribing cemiplimab, as those factors may influence the suitability of the drug.

FDA accepts libtayo (cemiplimab-rwlc) for priority review for advanced cervical cancer. Regeneron. Press release. September 28, 2021.

Positive phase 3 libtayo (cemiplimab) results in advanced cervical cancer presented at ESMO virtual plenary. Regeneron. News release. May 12, 2021. Accessed September 28, 2021. 

https://newsroom.regeneron.com/news-releases/news-release-details/positive-phase-3-libtayor-cemiplimab-results-advanced-cervical

The FDA has granted cemiplimab-rwlc a priority review based on findings from the largest to-date, randomized clinical trial in advanced cervical cancer. 

FDA Grants Priority Review to Cemiplimab for Advanced Cervical Cancer

Impressive response rates, duration of response (DOR) and overall survival were all observed in pretreated patients with recurrent/metastatic cervical cancer who were administered a combination of the anti-PD-1 antibody balstilimab and the anti-CTLA-4 antibody zalifrelimab (AGEN1884) in a single arm phase 2 trial (NCT03495882) recently presented at the 2021 ESMO Annual Congress.

Among the 125-patient efficacy evaluable population, the combination elicited an overall response rate (ORR) of 25.6%. Ten (8.8%) responders experienced a complete response (CR). Among the 67-patients with a positive PD-L1 status, the ORR was 32.8% compared with 9.1% in the PD-L1-negative subgroup (n = 33).

Notably, the median duration of response (DOR) was not reached (range, 9.3 months-not reached). The 6-month DOR rate was 86.4% and the 12-month rate was 66.7%.

“There remains a significant unmet medical need for patients with recurrent or metastatic cervical cancer who progress after platinum-containing chemotherapy,” explained David O'Malley, MD, the director of the Division of Gynecologic Oncology at The Ohio State University Comprehensive Cancer Center–Arthur G. James Cancer Hospital and Richard J. Solove Research Institute and a professor in the Department of Obstetrics and Gynecology at The Ohio State University College of Medicine in Columbus.

“We know that single agent PD-1 activity is modest while CTLA-4 inhibition demonstrates limited to no activity in patients with cervical cancer,” he added. “Combining anti-PD1 and anti-CTLA-4 [agents] is now an established treatment paradigm across a broad spectrum of solid tumors. In this phase 2 study design, we report the largest trial to date combining PD-1 and CTLA-4 in patients with cervical cancer.”

In order to be eligible for the trial, patients needed to have histologically confirmed squamous cell carcinoma, adenosquamous carcinoma, or adenocarcinoma of the cervix that relapsed after platinum-based treatment. Patients also had to have measurable disease and an ECOG performance status of 0 or 1.

The primary end point of the trial was ORR by RECIST v1.1 per an independent review committee. Secondary end points included OS, DOR, and progression-free survival. The trial enrolled a total of 155 patients in Europe, Australia, South America, and the United States.

The median age of the total population was 50 (range, 24-76). Most patients (70.3%) had squamous cell carcinoma, 27.1% had adenocarcinoma, and 2.6% had adenosquamous histology.ECOG performance status was well balanced, 57.4% registered a 0 and 42.6% were at 1. A majority of patients (56.8%) had positive PD-L1 tumor expression status, defined as a combined positive score of at least 1%. The most common prior therapy exposures, besides platinum-containing (99.4%), were taxane (78.7%) and bevacizumab (32.9%).

Balstilimab was administered at a dose of 3 mg/kg every 2 weeks. Zalifrelimab 1 mg/kg was given every 6 weeks. Treatment lasted for up to 24 months and follow-up imaging occurred every 6 weeks through 2 years.

At a median follow-up of 21 months, the median PFS was 2.7 months (95% CI, 1.5-3.7). The median OS was 12.8 months (95% CI, 8.8-17.6). In the PD-L1-positive subset, the median OS improved to 15.7 months (95% CI, 7.6-21.1).

“The response rates [for this combination] nearly double currently achieved with approved agents in the second-line setting, including single agent PD-1 antibodies,” noted O’Malley. “Beyond response rate, the distinguishing feature of combining CTLA-4 and PD-1 antibodies are improved depth and durability of responses as well as survival outcomes. Longer follow-up will hopefully confirm this exciting trend and establish long-term survival as an achievable goal in advanced/recurrent cervical cancer.”

In terms of safety, 71.0% of the 155-patient safety population experienced a treatment-related adverse event (TRAE) of any grade. Common TRAEs of any grade included hypothyroidism (16.8%), diarrhea (14.2%), and fatigue (11.6%). TRAEs of at least grade 3 occurred in 20.0% of patients and included increased alanine transaminase (2.6%) and diarrhea (1.9%). TRAEs that lead to dose interruption were reported in 12.3% of patients and TRAEs leading to dose discontinuation occurred in 7.7% of patients.

Immune-mediated AEs were less commonly observed (44.5%), and included hypothyroidism (14.2%), hyperthyroidism (7.1%), diarrhea (7.1%), and puritis (4.5%).

“[This was] the largest study to date evaluating dual PD-1/CTLA-4 checkpoint blockade in patients with recurrent/metastatic cervical cancer,” concluded O’Malley. “With a median follow-up of almost 2 years, the balstilimab and zalifrelimab combination showed high response rates, durable clinical activity, and promising overall survival results. Advocacy outcomes were particularly impressive in the PD-L1 positive patients, but also broadly seen in subgroups with poor risk features. A confirmatory randomized phase 2 study comparing balstilimab and zalifrelimab with balstilimab alone is actively enrolling.”

O’Malley DM, Neffa M, Monk BJ, et al. Balstilimab (anti-PD-1) in combination with zalifrelimab (anti-CTLA-4): Final results from a phase II study in patients (pts) with recurrent/metastatic (R/M) cervical cancer (CC). Presented at: 2021 European Society for Medical Oncology Congress. September 16-21, 2021; virtual. Abstr 724MO.

A phase 2 trial presented at the 2021 ESMO Annual Congress showed that Balstilimab plus Zalifrelimab induced superior response rates, duration of responses, and overall survival in patients with recurrent/metastatic cervical cancer. 

Balstilimab Zalifrelimab Combination Yields Promising Results in Recurrent/Metastatic Cervical Cancer

Adding pembrolizumab (Keytruda) to chemotherapy with or without bevacizumab (Avastin) proved to effectively improve survival rates and invoke responses in patients with recurrent, or metastatic cervical cancer in the phase 3 KEYNOTE-826 trial (NCT036355667). Data from the trial’s first interim analysis were presented as part of the Presidential Symposium during the 

In the subset of patients with a PD-L1 combined positive score (CPS) of 1 or higher, the median progression-free survival (PFS) in the investigative and control arms was 10.4 months (95% CI, 9.7-12.3) vs 8.2 months (95% CI, 6.3-8.5), respectively (HR, 0.62; 95% CI, 0.50-0.77; 

< .001). In this group, the median overall survival (OS) was not reached (NR) at the time of the data cutoff in the investigative arm (95% CI, 19.8–NR) vs 16.3 months (95% CI, 14.5-19.4) in the control arm (HR, 0.64; 95% CI, 0.50-0.81; 

In the all-comer population, the median PFS was 10.4 months (95% CI, 9.1-12.1) in the investigative arm vs 8.2 months (95% CI, 6.4-8.4) in the control arm (HR, 0.65; 95% CI, 0.53-0.79; 

< .001). The median OS in this population was 24.4 months (19.2–NR) with pembrolizumab vs 16.5 months (95% CI, 14.5-19.4) with placebo (HR, 0.67; 95% CI, 0.54-0.84; 

In the group of patients who had a PD-L1 CPS of 10 or higher, the median PFS with pembrolizumab plus chemotherapy with or without bevacizumab was 10.4 months (95% CI, 8.9-15.1) vs 8.1 months (95% CI, 6.2-8.8) with chemotherapy with or without bevacizumab (HR, 0.58; 95% CI, 0.44-0.77; 

< .001). The median OS was also NR (95% CI, 19.1-NR) in the investigative arm vs 16.4 months (95% CI, 14.0-25.0) in the control arm (HR, 0.61; 95% CI, 0.44-0.84; 

“Adding pembrolizumab to chemotherapy with or without bevacizumab provides statistically significant, clinically meaningful improvements in PFS and OS in patients with persistent, recurrent, or metastatic cervical cancer. The significant benefit was observed in all primary analysis populations and was generally consistent across protocol-specified subgroups,” lead study author Nicoletta Colombo, MD, PhD, director of the Gynecologic Oncology Division at the European Institute of Oncology and associate professor of Obstetrics and Gynecology at the University of Milan-Bicocca in Milan, Italy, said in a presentation of the findings. “Overall, data from KEYNOTE-826 suggest that pembrolizumab plus platinum-based chemotherapy with or without bevacizumab may be a new first-line standard of care for the treatment [of these patients].”

Platinum-based chemotherapy has served as standard treatment for patients with persistent, recurrent, or metastatic cervical cancer, with the preferred regimen being platinum, paclitaxel, and bevacizumab. Although PD-1 inhibitors, such as pembrolizumab and cemiplimab (Libtayo), have previously demonstrated efficacy in patients with previously treated cervical cancer, no data are available to indicate whether the addition of a PD-L1 inhibitor to chemotherapy with or without bevacizumab would improve outcomes.

To this end, investigators launched the double-blind KEYNOTE-826 trial, which enrolled patients with persistent, recurrent, or metastatic cervical cancer that was not amenable to curative treatment.

Eligible patients needed to have an ECOG performance status of 0 or 1 and could not have previously received systemic chemotherapy. However, prior radiotherapy and chemoradiotherapy was allowed.

Data presented at the 2021 ESMO Congress suggest that pembrolizumab in addition to chemo with or without bevacizumab may become new standard of care in the frontline setting of cervical cancer treatment.

Gynecologic Cancers