At the 2014 European Society for Medical Oncology (ESMO) Congress held in Madrid, Spain, 2 oral abstracts were presented on the use of antiangiogenic-targeted agents in cervical cancer under the theme of "Precision Medicine in Cancer Care." The first abstract summarized the final overall survival (OS) results from the Gynecologic Oncology Group (GOG) 240, a phase III randomized trial of bevacizumab for the treatment of recurrent and metastatic cervical cancer, as reported by Tewari et al. [1]. Briefly, a total of 452 women with metastatic, recurrent, or persistent cervical cancers that were incurable with standard treatment options were randomized to 1 of 4 treatment arms: (1) cisplatin (50 mg/m²) plus paclitaxel alone (135-175 mg/m²), or (2) with bevacizumab 15 mg/kg, or (3) topotecan (0.75 mg/m² on days 1-3) plus paclitaxel alone (175 mg/m² on day 1), or (4) with bevacizumab. The second interim analysis after 271 deaths revealed a significant difference in median OS between bevacizumab and non-bevacizumab groups (hazard ratio [HR], 0.71; 95% confidence interval [CI], 0.54 to 0.95; 1-sided p=0.0035); the OS difference remained significant at the time of March 7, 2014, when 348 deaths occurred (16.8 months vs. 13.3 months; HR, 0.765; 95% CI, 0.62 to 0.95; p=0.0068). Similar results were obtained for both chemotherapy regimens. This report confirmed a >50-month sustained clinical benefit with the incorporation of bevacizumab into chemotherapy for advanced cervical cancer. However, more severe toxicity profiles were observed with the addition of bevacizumab, including 3.2% gastrointestinal (GI) perforation rate, a higher incidence of GI-vaginal fistulae (8.2% vs. 0.9%), and higher incidence of ≥ grade 3 thromboembolic events (10.6% vs. 5.4%).

The second abstract on an antiangiogenic targeted agent in cervical cancer presented in the 2014 ESMO Congress was the CIRCCa trial [2]. In the CIRCCa trial, 69 women with primary metastatic or relapsed cervical cancer were randomized (1:1) to receive carboplatin (area under the curve [AUC], 5) plus paclitaxel (175 mg/m² tri-weekly) for a maximum of 6 cycles plus cediranib (20 mg/day; n=34); a potent tyrosine kinase inhibitor of vascular endothelial growth factor receptor (VEGFR) 1, 2, and 3; or placebo (n=35) concurrently with chemotherapy, and later as maintenance therapy until progression. A total of 79% of the patients completed 6 cycles of chemotherapy, 22% stopped placebo and 17% stopped cediranib during the study period. Median progression-free survival (PFS) of cediranib group was superior to that of placebo group (35 months vs. 30 months; HR, 0.61; 80% CI, 0.41 to 0.89; p=0.046). However, as CIRCCa closed prematurely owing to the cessation of commercial production of cediranib, the statistical analysis of the difference in median OS between the two groups was underpowered for comparison (59 weeks vs. 63 weeks; HR, 0.93; 80% CI, 0.64 to 1.36; p=0.401). Typical toxicities of antiangiogenic and tyrosine kinase inhibitor were more frequently observed in the cediranib group than in the placebo group: grade 2 to 4 diarrhea (50% vs. 18% during chemotherapy and 19% vs. 9% during the maintenance period), and grade 2 to 4 hypertension (34% vs. 12%). Although the results were inconclusive, the CIRCCa trial demonstrated the effectiveness of cediranib in advanced cervical cancer, which deserves a phase III study.

Immunotherapy is still in the early developmental stages for use in cervical cancer therapy. In 2014, there were some promising study results for immunotherapy in the treatment of cervical cancer: human papillomavirus (HPV)-targeted tumor-infiltrating lymphocytes (TIL) in metastatic disease; Z-100 in locally advanced cervical cancer (LACC). The first study was a small, proof-of-concept study presented by Christian S. Hinrichs at the annual meeting of the American Society of Clinical Oncology (ASCO) in Chicago in July 2014 [3]. In the clinical trial (NCT01585428), nine patients with metastatic cervical cancer were treated with an infusion of HPV-TIL selected for HPV E6- and E7-reactivity after non-myeloablative conditioning with cyclophosphamide (60 mg/kg × 2 days) plus fludarabine (25 mg/m² × 5 days) and followed by a high-dose aldesleukin bolus. Except for two patients who showed no HPV reactivity, which was assessed by ELISPOT, interferon-γ production, and CD137 expression assays, the infused cells showed reactivity against high-risk HPV E6 and/or E7 in six patients. However, objective clinical response that was greater than partial response was observed only for three patients: two patients achieved complete response (CR; >22 and >15 months) and one patient showed partial response (3 months). Of the two CRs, one patient had chemotherapy-refractory HPV-16+squamous cell carcinoma and the other had chemoradiation-refractory HPV-18+ adenocarcinoma. Both patients demonstrated prolonged repopulation with HPV-reactive T cells following treatment. All participants experienced ≥ grade 3 cytopenia, and 6 experienced infection, as demonstrated by positive blood culture.

The subject of immunotherapy in cervical cancer was covered by another Japanese GOG study, a randomized phase III trial for LACC using immunomodulator Z-100, which is a hot-water extract from human tuberculosis bacilli that contains polysaccharides such as arabinomannan and mannan [4]. The authors of the Z-100 study had previously conducted a phase II study (2 µg vs. 20 µg vs. 40 µg) with radiotherapy, and a double-blind randomized phase III trial (40, lead of the phase II study vs. 0.2 µg, substitute with placebo) with radiotherapy for stage III cervical cancer [5,6]. The unexpected lead agent of the phase III trial, 0.2 µg of Z-100, was selected for the subsequent phase III placebo-controlled double-blind randomized trial of radiotherapy for LACC with or without Z-100. In this study, a total of 249 patients with stage IIB-IVA squamous cell carcinoma of the cervix were randomly assigned to receive 0.2 µg of Z-100, or placebo subcutaneously twice a week during radiotherapy, followed by maintenance therapy of once every 2 weeks until progression. Z-100 showed a trend of OS improvement compared with placebo (5-year OS rate, 75.7% vs. 6.58%; HR, 0.65; 95% CI, 0.40 to 1.04; p=0.07) regardless of whether the cohort received chemoradiation or radiotherapy alone. There were no significant differences in adverse events between the two groups. Based on the promising results of OS improvement potential and tolerable side effects in the Z-100 group, they concluded that additional validation should be made in the near future regarding the survival benefit of Z-100 in cervical cancer.

Of the several HPV tests for high-risk HPV approved by the US Food and Drug Administration (FDA), the Cobas HPV test (Roche Molecular Systems, Pleasanton, CA, USA) received FDA approval for the first time for use as a primary screening tool of cervical cancer for women 25 and older in April, 2014, based on the results of the ATHENA trial [7]. The Cobas HPV test is a fully automated qualitative in vitro test for the detection of HPV in 3 separate variants: HPV16, HPV18, and a pool of 12 other HPV genotypes (31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, and 68) using amplification of target DNA by the polymerase chain reaction (PCR) and nucleic acid hybridization. Until now, the HPV test had been used primarily as a follow-up test to resolve ambiguous Pap results, or used jointly with Pap testing. Current United State guidelines recommend that women 30 to 65 years undergo either co-testing with both HPV and Pap every 5 years or Pap testing alone every 3 years [8]. Women 21 to 30 years are expected to undergo Pap testing every 3 years. The ATHENA study for HPV DNA tests versus liquid-based cytology for cervical cancer screening demonstrated that the Cobas HPV test outperformed Pap testing alone in detecting precancerous lesions and its performance was comparable to the hybrid test [9,10]. In women who had colposcopy, the Cobas HPV test was more sensitive than liquid-based cytology for detection of cervical intraepithelial neoplasia (CIN) ≥3 (92.0%, 95% CI, 88.1 to 94.6 vs. 53.3%, 95% CI, 47.4 to 59.1; difference 38.7%, 95% CI, 31.9 to 45.5; p<0.0001). Addition of liquid-based cytology to HPV testing increased sensitivity for CIN ≥3 to 96.7% (95% CI, 93.9 to 98.3), but increased the number of screened positives by 35.2% compared with HPV testing alone. They concluded that Cobas HPV testing with distinct HPV16 and HPV18 detection could provide an alternative, more sensitive, and efficient strategy for cervical cancer screening than methods based solely on cytology.

A recently published follow-up study of 4 European randomized controlled trials of HPV-based screening for cervical cancer versus cytology-based screening underscores the importance of HPV-based screening [11]. Ronco et al. [11] followed up a total of 176,464 women aged 20-64 years from the 4 previous studies: Swedescreen [12], POBASCAM [13,14], ARTISTIC [15], and NTCC [16], for a median 6.5 years and calculated the cumulative and study-adjusted rate ratio of incidence of invasive cervical cancer. The overall rate ratio for invasive cervical carcinoma was 0.60 (95% CI, 0.40 to 0.89), however, the rate ratio in women with a negative screening test at entry was 0.30 (95% CI, 0.15 to 0.60). The cumulative incidence of invasive cervical carcinoma in women with negative entry tests was 4.6/10⁵ (95% CI, 1.1 to 12.1) and 8.7/10⁵ (95% CI, 3.3 to 18.6) at 3.5 and 5.5 years, respectively, in the HPV-based group, and 15.4/10⁵ (95% CI, 7.9 to 27.0) and 36.0/10⁵ (95% CI, 23.2 to 53.5), respectively, in the cytology-based group. They concluded that HPV-based screening was 60% to 70% more effective in reducing the incidence of invasive cervical carcinomas than cytology-based screening.

Finally, the clinical accuracy of HPV testing on self-collected versus clinician-collected vaginal samples was systematically reviewed in the recent meta-analysis by Arbyn et al. [17]. They showed that the pooled sensitivity (ratio 0.88 [95% CI, 0.85 to 0.91] for CIN ≥2 and 0.89 [95% CI, 0.83 to 0.96] for CIN ≥3) and specificity (ratio 0.96 [95% CI, 0.95 to 0.97] for CIN ≥2 and 0.96 [95% CI, 0.93 to 0.99] for CIN ≥3) of HPV testing on self-samples was lower than those on clinician-collected samples. Compared with the lower sensitivity and specificity of HPV testing with signal-based assays on self-versus clinician-collected samples, some PCR-based HPV tests showed similar sensitivity on self- and clinician-collected samples. Accordingly, the vaginal samples for signal-based HPV screening tests should be collected by a clinician. However, PCR-based HPV test on self-collected samples could be considered as an additional strategy for increasing screening coverage.

The GOG 249 conducted a randomized phase III trial of pelvic radiation therapy (RT) versus vaginal cuff brachytherapy (VCB) followed by paclitaxel/carboplatin chemotherapy (VCB/C) in patients with high risk, early stage endometrial cancer, based on the promising results of a phase II trial of VCB followed by chemotherapy in early endometrial cancer patients with high-intermediate risk factors [18]. The results were first presented as a late-breaking abstract in the Annual Meeting of the Society of Gynecologic Oncology (SGO) in Tampa, FL, USA [19]. According to the high intermediate risk factors in GOG 99, the eligibility criteria of GOG 249 were based on age, tumor grade, depth of invasion, and presence of lymphovascular space invasion (LVSI), stage II, or stage I-II serous or clear cell tumors. A total of 601 patients were randomized to pelvic RT group (n=301) or VCB/C group (n=300, vaginal brachytherapy followed by paclitaxel (175 mg/m² , 3 hours) plus carboplatin (AUC=6; q 21 days for 3 cycles). Additional VCB was optional for patients with serous or clear cell tumors or stage II disease. Recurrence-free survival (RFS) was the primary endpoint. Although acute toxicity was observed more frequently in the VCB/C group, a majority of the patients in both groups completed the therapy (91% pelvic RT and 87% VCB/C). With a median follow-up of 24 months, RFS of pelvic RT group was similar to that of VCB/C group (82% vs. 84%; HR, 0.97; 95% CI, 0.64 to 1.43). Thus, they failed to demonstrate the RFS superiority of VCB/C to pelvic RT. Based on the similar RFS and tolerability for both groups, the authors concluded that pelvic RT and VCB/C appeared to be a well-tolerated adjuvant treatment option in women with high-risk endometrial cancer.

The SGO recently stated that the American Society for Radiation Oncology (ASTRO) had issued guideline recommendations along with 5 key questions Regarding postoperative adjuvant RT in patients with endometrial cancer [7]. During the process of drafting these recommendations, they considered that data from the literature did not support an OS benefit for adjuvant RT in all patients; however, there was some evidence of increased risk of second malignancy in women <60 years of age at diagnosis, who received pelvic RT with VCB compared with those received VCB only [20]. The first key question sought to identify the patients with endometrioid endometrial cancer who did not require adjuvant therapy after hysterectomy. Foregoing adjuvant RT is a reasonable option for patients with no residual disease in the hysterectomy specimen despite positive biopsy, or grade 1 or 2 cancers with either no invasion or <50% myometrial invasion, especially when no other high-risk features were present. Patients with grade 3 cancers without myometrial invasion or grade 1 or 2 cancers with <50% myometrial invasion and higher risk factors such as age >60 years and/or LVSI could reasonably be treated with or without VCB. The second key question sought to identify the patients with endometrioid endometrial cancer who should receive VCB. The recently released GOG 249 results of the aforementioned questions provide substantial evidence supporting the effectiveness of VCB as pelvic RT for preventing vaginal recurrence in patients with high-intermediate risk factors. They stated that VCB was superior to pelvic RT in patients with these risk factors, particularly in patients who have underwent pelvic and paraaortic lymph node dissection. The third key question sought to identify the women who should receive adjuvant pelvic RT; patients with stage I, grade 1 or 2 with >50% myometrial invasion, and other risk factors such as age >60 years or LVSI, or grade 3 with >50% myometrial invasion may benefit from the reduced risk of pelvic recurrence. Patients with stage II with cervical stroma invasion could also benefit from pelvic RT. For stage III disease with lymph node metastasis or involved uterine serosa, ovaries/fallopian tubes, vagina, bladder, or rectum, pelvic RT should be included in postoperative adjuvant treatment together with adjuvant chemotherapy. The fourth key question addressed when VCB should be used in addition to external pelvic RT. Given the lack of substantive evidence favoring the use of VCB after pelvic RT, VCB may not generally be warranted in patients who are also undergoing external pelvic RT, unless the risk factors for vaginal recurrence are present. The fifth key question concerned how RT and chemotherapy should be integrated in the management of endometrial cancer. The best available evidence that the panel concurred on was for concurrent chemoradiation followed by adjuvant chemotherapy in the advanced-stage endometrial cancer patients with positive nodes or involved uterine serosa, ovaries/fallopian tubes, vagina, bladder, or rectum. Alternative sequencing strategies with external pelvic RT and chemotherapy could provide another option.

In 2014, there were publications of 3 randomized phase II studies of olaparib in patients with recurrent platinum-sensitive ovarian cancer. The first report was published after the 2013 ASCO presentation of the results of BRCA mutation status subgroup analysis from a randomized, phase II study that assessed maintenance therapy with olaparib (400 mg twice a day) versus placebo in patients with platinum-sensitive recurrent serous ovarian cancer who had received ≥2 platinum-based regimens and who had a partial or CR to their most recent platinum-based regimen; PFS and data from the second interim analysis of OS were reported [33]. A total of 265 patients were randomized to olaparib (n=136) and placebo (n=129). A significant improvement of PFS was observed in the olaparib group, which was most marked in patients with a germline BRCA mutation (11.2 months [95% CI, 8.3 to not calculable] vs. 4.3 months [95% CI, 3.0 to 5.4]; HR, 0.18 [95% CI, 0.10 to 0.31]; p<0.0001), but also in patients with wild-type BRCA (7.4 months [95% CI, 5.5 to 10.3] vs. 5.5 months [95% CI, 3.7 to 5.6]; HR, 0.54 [95% CI, 0.34 to 0.85]; p=0.0075). There was no significant difference in OS between the groups at the second interim analysis with 58% maturity (HR, 0.88; 95% CI, 0.64 to 1.21; p=0.44); (HR, 0.73; 95% CI, 0.45 to 1.17; p=0.19) for patients with BRCA mutation, and (HR, 0.99; 95% CI, 0.63 to 1.55; p=0.96) for patients with wild-type BRCA. The quality of life sub-study data from this study were presented in the 2014 ESMO Congress in Madrid, Spain [34]. There was no detrimental effect of olaparib on quality of life during the course of maintenance therapy and it there were no differences depending on BRCA mutation status.

In the second report, the efficacy and tolerability of olaparib in combination with chemotherapy, followed by olaparib maintenance monotherapy, were compared with those of chemotherapy alone [35]. In this randomized phase II study in patients with platinum-sensitive recurrent high-grade serous ovarian cancer (HGSOC), a total of 162 women were randomly assigned to the olaparib (200 mg twice a day on days 1 to 10 of each 21-day cycle for the combination period, and 400 mg twice a day continuously until progression for maintenance monotherapy period) plus chemotherapy group (n=81), and the group that received chemotherapy alone (n=81). Chemotherapy comprised paclitaxel (175 mg/m² intravenous on day 1) and carboplatin (AUC=4; intravenous on day 1) for olaparib plus chemotherapy group, and paclitaxel (175 mg/m² intravenous on day 1) and carboplatin (AUC=6; intravenous on day 1) for the group that received chemotherapy alone. PFS was significantly longer in the olaparib plus chemotherapy group (median, 12.2 months [95% CI, 9.7 to 15.0]) than in the chemotherapy alone group (median, 9.6 months [95% CI, 9.1 to 9.7]; HR, 0.51 [95% CI, 0.34 to 0.77]; p=0.0012), especially in patients with BRCA mutations (HR, 0.21; 95% CI, 0.08 to 0.55; p=0.0015). The most common grade ≥3 adverse events during the combination period were neutropenia (43% vs. 35%) and anemia (9% vs. 7%). Thus, olaparib plus paclitaxel and carboplatin followed by maintenance monotherapy significantly improved PFS compared with paclitaxel and carboplatin alone, with an acceptable toxicity profile. The greatest clinical benefit was observed in patients with a BRCA mutation.

The last report evaluated a combination of olaparib and cediranib compared with olaparib alone in a randomized phase II study [36]. Improvements PFS and OS had previously been demonstrated in a randomized phase III trial of cediranib in patients with relapsed platinum-sensitive ovarian cancer (ICON 6), and had been briefly reviewed in the major clinical research advances in gynecologic cancer in 2013 [37]. Cediranib plus olaparib showed activity against recurrent ovarian cancer in a previous phase I trial, with an objective response rate of 44% [38]. Based on these trial results, a phase II trial that evaluated a combination of cediranib and olaparib maintenance therapy versus olaparib alone was conducted. A total of 90 patients were randomly assigned to receive olaparib (400 mg twice a day alone; n=46), or to receive a combination of olaparib (200 mg twice a day) and cediranib (30 mg a day; n=44). An interim analysis after 50% of expected events showed significant improvement in PFS in the combination group (median 17.7 months [95% CI, 14.7 to not reached]), compared with olaparib alone group (median, 9.0 months [95% CI, 5.7 to 16.5]; HR, 0.42; 95% CI, 0.23 to 0.76; p=0.005). Grade ≥3 adverse events, including fatigue, diarrhea, and hypertension, were more common in the combination group than in the monotherapy group. These promising results warrant a phase III trial, evaluating the efficacy of the combination of olaparib and cediranib in recurrent platinum-sensitive ovarian cancer.

In contrast to the promising phase II study results for olaparib, a phase II trial of veliparib failed to demonstrate PFS improvement in HGSOC [39]. In this trial, 75 patients with pretreated BRCA-mutant ovarian cancer, or patients with pretreated primary peritoneal, fallopian tube, or HGSOC were randomized to receive cyclophosphamide alone (n=38, 50 mg once a day) or with veliparib (n=37, 60 mg once a day) in 21-day cycles. There was no significant difference in median PFS between the 2 groups (2.3 months vs. 2.1 months). Stratification of patients by BRCA status did not reveal any significant improvement in PFS. Phase III studies of niraparib (NOVA, NCT01847274) and rucaparib (ARIEL3, NCT01968213) are currently accruing patients. Some of the current ongoing phase III studies of PARP inhibitors include patients with HGSOC, regardless of a germline BRCA mutation status. Notably, the possible responsiveness of non-HGSOC to PARP inhibitors would further broaden the population that might benefit from PARP inhibitors [40,41].

Tamoxifen has been regarded as a standard adjuvant treatment for premenopausal women with hormone-receptor-positive breast cancer, for at least the past 5 years. As compared with tamoxifen, adjuvant therapy with an aromatase inhibitor was shown to improve survival outcomes of postmenopausal women with breast cancer. However, the clinical value of suppression of ovarian function in premenopausal women with breast cancer, with the adjuvant-supplemented tamoxifen or aromatase inhibitor exemestane therapy, was not clear. In order to answer this question, the International Breast Cancer Study Group initiated 2 randomized, phase III trials, the tamoxifen and exemestane trial (TEXT) and the suppression of ovarian function trial (SOFT), involving premenopausal women with hormone-receptor-positive early breast cancer [55]. In 2014, the results of the primary analysis in SOFT comparing adjuvant tamoxifen plus ovarian suppression with tamoxifen alone [56], and the combined analysis of data from TEXT and SOFT comparing adjuvant exemestane plus ovarian suppression with adjuvant tamoxifen plus ovarian suppression were released [57].

First, in SOFT, 3066 premenopausal women, stratified according to whether they received prior chemotherapy or not, were randomly assigned in a 1:1:1 ratio to receive 5 years of exemestane plus ovarian suppression (triptorelin, bilateral oophorectomy, or ovarian irradiation), tamoxifen plus ovarian suppression, or tamoxifen alone. In the overall study population, after a median follow-up of 67 months, there was no significant difference in the estimated disease-free survival (DFS) rate at 5 years between the tamoxifen-ovarian suppression group and the tamoxifen group (86.6% vs. 84.7%; HR, 0.83; 95% CI, 0.66 to 1.04; p=0.10). However, in a cohort of 1084 women who had sufficient risk of recurrence to warrant adjuvant chemotherapy and maintained premenopausal status despite chemotherapy, the multivariable Cox model showed that tamoxifen plus ovarian suppression resulted in a 22% reduction in the relative risk of breast-cancer recurrence, secondary invasive cancer, or death (p=0.03) as compared with tamoxifen alone. Given the younger age of this cohort compared with the nochemotherapy cohort (median age, 40 years vs. 46 years; p<0.01), the results observed in this cohort in SOFT suggest that the addition of ovarian suppression to tamoxifen played an important role in younger premenopausal patients with hormone-receptor-positive early breast cancer.

Next, Pagani et al. [57] reported the results of a comparison of adjuvant exemestane plus ovarian suppression with adjuvant tamoxifen plus ovarian suppression in premenopausal women with hormone-receptor-positive early breast cancer using the combined data from 4,690 patients in TEXT and SOFT. In TEXT, a total of 2672 premenopausal women underwent randomization to receive exemestane plus ovarian suppression or tamoxifen plus ovarian suppression for a period of 5 years. Although there were no significant differences in OS between the 2 groups, DFS at 5 years of the exemestane plus ovarian suppression group was significantly better than that of tamoxifen plus ovarian suppression group after a median follow-up of 68 months (HR for disease recurrence, secondary invasive cancer, or death 0.72; 95% CI, 0.60 to 0.85; p<0.001). Similar incidence of grade 3 or 4 adverse events including hot flushes, musculoskeletal symptoms, and hypertension was observed for both groups: 30.6% in the exemestane plus ovarian suppression group and 29.4% in the tamoxifen plus ovarian suppression group. Accordingly, they concluded that adjuvant treatment with ovarian suppression plus exemestane, which was recommended only for postmenopausal women until now, could become a new treatment option for reducing the risk of recurrence in premenopausal women with hormone-receptor-positive early breast cancer.