Major clinical research advances in gynecologic cancer in 2013

Bevacizumab (BEV), a humanized anti-vascular endothelial growth factor (anti-VEGF) monoclonal antibody, has long been studied with respect to its clinical efficacy in patients with advanced ovarian cancer; however, the previously available results were not satisfactory. Surprisingly, an outstanding study demonstrated a substantial overall survival (OS) benefit of BEV in recurrent or metastatic cervical cancer, which was considered difficult to cure. This was the first study to demonstrate improved OS in gynecologic cancer patients following the addition of BEV. Moreover, the treatment efficacy of cediranib, another targeted agent that acts as a tyrosine kinase inhibitor and blocks VEGF receptors (VEGFRs), was proven against advanced epithelial ovarian cancer (EOC). Besides these two great achievements, this review will cover most of the influential studies published in 2013 in the field of gynecologic oncology.

In the plenary session of the 2013 American Society of Clinical Oncology (ASCO) Annual Meeting in Chicago, Dr. Tewari presented the interim analytical results of a phase III randomized trial conducted by the Gynecologic Oncology Group (GOG), GOG 240, which regarded the incorporation of BEV for the treatment of recurrent and metastatic cervical cancers [1]. A total of 452 patients with metastatic, recurrent, or persistent cervical cancers that were incurable with standard treatments were enrolled in this study and randomized to one of four treatment arms: (1) cisplatin (50 mg/m²) plus paclitaxel (135 to 175 mg/m²) alone; or (2) with BEV; or (3) topotecan (0.75 mg/m² on days 1 to 3) plus paclitaxel (175 mg/m² on day 1) alone; or (4) with BEV. The primary endpoint was OS, and a 30% risk of death with BEV was considered important (90% power; 1-sided α, 2.5%). The first interim analysis conducted following 174 deaths in 2012 showed that the topotecan-paclitaxel backbone was not superior to the cisplatin-paclitaxel backbone. A second interim analysis after 271 deaths revealed a significant difference in the median OS between the BEV and no-BEV groups (hazard ratio [HR], 0.71; 97% confidence interval [CI], 0.54 to 0.95; 1-sided p=0.0035). The relative risks (RRs) were 48% (BEV group) and 36% (no-BEV group; p=0.0078). However, patients who received BEV experienced more side effects than those who did not; these included grade 3 to 4 bleeding (5% vs. 1%), thromboembolism (9% vs. 2%), and gastrointestinal (GI) fistula (3% vs. 0%). Despite the potential toxicity, the therapeutic benefits of BEV seem to outweigh the potential toxicity because the former are likely to affect current clinical practice with respect to the treatment of recurrent cervical cancer, which previously had very limited treatment options. Furthermore, it is noteworthy that this was the first study to prove an improvement in the OS of gynecologic cancer patients following the addition of BEV. In consideration of this outstanding clinical impact of GOG 240, the National Comprehensive Cancer Network guidelines for cervical cancer recently adopted the triple regimen of cisplatin, paclitaxel, and BEV as category 2A for the treatment of metastatic/recurrent cervical cancer [2].

Extended-field radiotherapy (RT) of the pelvic and para-aortic areas with concomitant cisplatin chemotherapy remains the safest strategy for optimizing the survival of patients with locally advanced cervical cancer (LACC) and para-aortic lymph node (LN) metastasis. However, the inherent false negative rate of positron emission tomography (PET) is as high as 22% [17], although PET has been shown to have the highest sensitivity for detecting extracervical lesions before chemoradiation [18]. This finding has driven researchers to evaluate the therapeutic impact of laparoscopic surgical para-aortic staging surgery in patients with LACC with negative PET imaging results of the para-aortic area [19, 20]. Gouy et al. [21] reported the results from the previously largest prospective multicenter study of 237 patients with stage IB to IVA cervical cancer in the Journal of Clinical Oncology. All patients had negative PET imaging results of the para-aortic area and underwent laparoscopic para-aortic lymphadenectomy. Extended-field RT covered up to the level of the para-aortic area when the para-aortic LNs were involved. The primary endpoint was OS and secondary endpoint was event-free survival (EFS). Twenty-nine patients (12%) had para-aortic LN metastasis, indicating false negative PET results; 16 of these patients had nodal metastases >5 mm and 13 had nodal metastases ≤5 mm. The 3-year EFSs in patients without para-aortic involvement, with para-aortic involvement ≤5 mm, and para-aortic involvement >5 mm were 74%, 69%, and 17%, respectively (p<0.001). Two factors were significantly associated with OS: the presence and size of the metastatic para-aortic LNs and a delay of ≥45 days between PET-computed tomography (CT) and the beginning of RT.

This study could not reach a definite conclusion regarding the therapeutic impact of laparoscopic para-aortic staging prior to chemoradiation for LACC because it was unclear whether the similar prognosis of patients with small para-aortic metastases (≤5 mm) and no para-aortic metastases was due to the whole treatment combination or merely the surgical resection [21]. Nevertheless, given the considerable PET-CT false negative rate for detecting para-aortic lesions and the poor prognosis of patients with para-aortic metastases >5 mm despite treatment with extended-field RT and concomitant chemotherapy, laparoscopic para-aortic staging prior to chemoradiation for LACC could be highly efficient for patients with negative PET-CT imaging. Additional information is anticipated from related ongoing randomized trials (ClinicalTrials.gov identifiers: NCT01049100 and NCT01365156).

After the preliminary report of a significant improvement in PFS with a chemotherapy and BEV combination versus chemotherapy alone in patients with platinum-resistant recurrent ovarian cancer (median 6.7 months vs. 3.4 months; HR, 0.48; 95% CI, 0.38 to 0.60; p<0.001) was given at the 2012 ASCO Annual Meeting, the final OS outcomes of the AURELIA study were presented at the 2013 European Cancer Conference in Amsterdam. After investigators' completed the chemotherapy selection (pegylated liposomal doxorubicin, topotecan, or wPAC), the patients were randomized to receive either chemotherapy alone or with added BEV (10 mg/kg every 2 weeks or 15 mg/kg every 3 weeks) until progression, unacceptable toxicity, or consent withdrawal. At the median follow-up of 27.4 months in both arms, the unstratified OS durations were similar in the two arms (median, 16.6 months vs. 13.3 months for chemotherapy alone vs. BEV added, respectively; HR, 0.85; 95% CI, 0.66 to 1.08; p=0.174). The insignificant 3-month OS benefit in the BEV added group appeared to be driven by the wPAC cohort, a finding that requires prospective validation. Notwithstanding, the AURELIA trial supports the addition of BEV to palliative chemotherapy for selective patients with platinum-resistant ovarian cancer based on the significant improvement in PFS. Another promising finding from the AURELIA trial was the result of an analysis of patient-reported outcomes that was reported by Stockler et al. [41]. This analysis demonstrated a significant improvement in abdominal/GI symptoms in women with recurrent platinum-resistant ovarian cancer who were treated with BEV plus chemotherapy as well as significant improvements in other symptoms and global health/QOL measures.

Metformin, which is among the most commonly used antidiabetic medications, is known to exhibit antitumor effects via 5' adenosine monophosphate-activated protein kinase activation and mammalian target of rapamycin pathway inhibition. Based on the close association of endometrial cancer with obesity and diabetes, metformin has been thought to exhibit excellent treatment efficacy against endometrial cancer. A preoperative window clinical trial of metformin in obese patients with endometrial cancer was conducted to evaluate the short-term molecular changes, and the results were presented at the 2013 ASCO Annual Meeting [42]. Twenty women with endometrial cancer and body mass indices >30 were enrolled. After pretreatment endometrial biopsy, metformin (850 mg per day) was administered for 1 to 4 weeks prior to hysterectomy. Formalin-fixed, paraffin-embedded blocks of the endometrial biopsy and hysterectomy specimens were paired. The differences in Ki-67 expression in the samples collected before and after metformin treatment were immunohistochemically evaluated. Among the 16 patients who completed the protocol, the percent Ki-67 expression decreased significantly with a mean 14.5-month metformin treatment duration (mean, 19.5% decrease; p=0.026). The pretreatment Ki-67 levels were higher in the metformin responders than in the nonresponders (52% vs. 27.5%, p=0.007). These results indicated that metformin could reduce cancer cell proliferation in obese patients with endometrial cancer during a preoperative window.

Following a report from The Cancer Genome Atlas (TCGA) Research Network regarding integrated genomic analyses of high-grade serous ovarian cancers [43], TCGA published the integrated genomic analyses of endometrial carcinoma in 2013 [44]. Whereas early-stage endometrioid cancers are often treated with adjuvant RT, serous tumors are treated with chemotherapy. However, clinicians sometimes encounter tumors that are likely to recur within 1 year even after staging surgery and adjuvant RT. To improve the poor prognosis associated with aggressive histologic subtypes, including high-grade endometrioid and serous tumors, researchers attempted to provide key molecular insights into tumor classification that might affect postoperative adjuvant treatment. Commonly mutated genes in type I tumors reportedly include PTEN, FGFR2, ARID1A, CTNNB1, PIK3CA, PIK3R1, and KRAS, whereas TP53, PIK3CA, and PPP2R1A mutations are frequently found in type II tumors [45, 46]. A hierarchical clustering analysis based on somatic copy number alterations (SCNAs) revealed that cluster 4, which was characterized by a very high level of SCNAs, included focal amplifications of oncogenes such as MYC, ERBB2, and CCNE1 and SCNAs such as FGFR3 and SOX17. Cluster 4 also had frequent TP53 mutations (90%), a low level of microsatellite instability (MSI; 6%), and fewer PTEN mutations (11%) relative to other endometrioid tumors (clusters 1 to 3; 84%). Cluster 4, which included most of the serous (94%) tumors and 12% of the endometrioid tumors, had a significantly worse PFS than the other endometrioid clusters (p=0.003). On the other hand, among the four groups based on somatic nucleotide substitutions, MSI, and SCNAs the ultramutated group comprised 17 tumors exemplified by an increased transversion frequency in the exonuclease domain of POLE, a catalytic DNA polymerase epsilon subunit involved in nuclear DNA replication and repair [44]. A final integrated clustering of the four groups found that ultramutated POLE (7.3%), MSI (28.0%), low copy number (38.8%), and high copy number (25.9%) were significantly correlated with mRNA expression (mitotic, hormonal, and immunoreactive; p<0.001). The signature POLE cluster genes are primarily involved in cellular metabolism and POLE-mutant tumors had a better PFS, whereas the poorest PFS was noted in the high copy number cluster, which included most of the serous and serous-like endometrioid tumors. The majority of cases (85%) in the high copy number cluster were associated with the mitotic mRNA subtype. Therefore, up to 25% of high-grade endometrioid-type tumors have a molecular phenotype similar to that of serous carcinomas, which are characterized by frequent TP53 mutations and extensive SCNA. These findings suggested that clinicians should consider treating high copy number-altered endometrioid tumors with chemotherapy rather than adjuvant RT.

In 2013, three outstanding reports regarding breast cancer treatment were published.

Firstly, the long-term effects of continuing adjuvant tamoxifen for up to 10 years vs. ceasing at 5 years on breast cancer patients were reported by two different study groups: the Adjuvant Tamoxifen: Longer Against Shorter (ATLAS) collaborative group in Lancet [47], and the Adjuvant Tamoxifen: To Offer More? (aTTom) collaborative group at the 2013 ASCO Annual Meeting in Chicago [48]. In the ATLAS trial, 12,894 women with early-stage breast cancer who had completed a 5-year tamoxifen treatment regimen were randomized to continue tamoxifen treatment for up to 10 years (experimental arm) or cease treatment at 5 years (open control arm) [47]. Whereas the treatment assignment had no significant effect on the treatment outcomes of 1,248 (9.7%) women with human epidermal growth factor receptor 2 (HER2)-negative disease, there were significant reductions in the risks of recurrence (18.0% vs. 20.8%, p=0.002), disease-specific mortality (331 deaths vs. 397 deaths, p=0.01), and overall mortality (639 deaths vs. 722 deaths, p=0.01) in the experimental arm relative to the open control arm among the HER2-positive breast cancer patients. Interestingly, these reducing effects with respect to the adverse breast cancer outcomes seemed to be limited in years 5 to 9 of tamoxifen treatment, and most of the benefit was observed after year 10 of treatment (recurrence rate ratio [RRR], 0.90; 95% CI, 0.79 to 1.02 vs. RRR, 0.75; 95% CI, 0.62 to 0.90; and MRR, 0.97; 95% CI, 0.79 to 1.18 vs. MRR, 0.71; 95% CI, 0.58 to 0.88).

The aTTom study corroborated the findings of the international ATLAS study. A total of 6,953 women with early breast cancer were enrolled in this study after a 5-year tamoxifen treatment regimen and were randomized to the same allocation groups as in the ATLAS study. Those allocated to the continued tamoxifen group exhibited reduced breast cancer recurrence rate (16.7% vs. 19.3%, p=0.003). The time-dependent reduction in the recurrence and breast cancer mortality incidence was confirmed in the ATLAS study. Specifically, the RRRs were 0.99 (95% CI, 0.86 to 1.15) for years 5 to 6, 0.84 (95% CI, 0.73 to 0.95) for years 7 to 9, and 0.75 (95% CI, 0.66 to 0.86) for years 10 and beyond. The MRRs were 1.03 (95% CI, 0.84 to 1.27) for years 5 to 9 and 0.77 (95% CI, 0.64 to 0.92) for years 10 and beyond. Together, the combined data from the aTTom and ATLAS trials demonstrated an additional 25% reduction in the breast cancer mortality incidence with ≥10 years of treatment versus 5 years of treatment (p<0.001). These results indicated that compared with no tamoxifen treatment, a 10-year adjuvant tamoxifen regimen reduced breast cancer mortality by almost 33% in the first 10 years following diagnosis and by 50% subsequently for premenopausal women with HER2-positive breast cancer. One reasonable concern regarding long-term tamoxifen treatment might be the increased risk of endometrial cancer. The aTTom study demonstrated a significant increase in the risk of endometrial cancer after 10-year tamoxifen treatment relative to that after 5-year treatment (102 vs. 45; RR, 2.20; 95% CI, 1.31 to 2.34; p<0.001). There were 37 deaths (1.1%) and 20 deaths (0.6%) from endometrial cancer in the 10-year and 5-year treatment arms, respectively (absolute hazard, 0.5%; p=0.02). However, the authors clearly stated that the benefits greatly outweigh the risks because 10 years of tamoxifen treatment prevents 30 times as many breast cancer deaths, and recommended a longer regimen for patients at high risk of recurrence.

Secondly, in contrast to the beneficial effect of long-term use of tamoxifen for HER2-positive breast cancer, the negative results from a comparison of 2-year extended use versus 1-year use of adjuvant trastuzumab for HER2-positive breast cancer were published in the Lancet by the Herceptin Adjuvant (HERA) Trial Study Team [49]. Currently, the standard treatment for breast cancer with HER2 overexpression is a 1-year adjuvant trastuzumab regimen [50]. With this trial, Goldhirsch [50] attempted to provide supporting evidence for extending the use of adjuvant trastuzumab. Briefly, 5,102 patients with HER2-positive early breast cancer were randomly allocated after surgery and chemotherapy completion to the observation, adjuvant 1-year trastuzumab, or adjuvant 2-year trastuzumab arms. The median follow-up duration was 8 years (range, 0 to 10 years). During the first few years of follow-up, the 2-year treatment group exhibited slightly better disease-free survival (DFS) than the 1-year group (89.1% vs. 86.7% at 3 years after randomization), which was consistent with the results of the Protocol for Herceptin as Adjuvant therapy with Reduced Exposure study, which compared 6 months versus 12 months of adjuvant trastuzumab treatment after a median follow-up duration of 3.5 years [51]. However, this difference waned as the follow-up duration increased and, at the time of the study analysis, the same DFS events occurred in the two allocation groups (HR, 0.99; 95% CI, 0.85 to 1.14; p=0.86). The mortality rate was also the same in the two groups (196 in the 2-year group vs. 186 in the 1-year group). The 2-year treatment group was associated with more frequent decreases in left ventricular ejection fraction relative to the 1-year group (8.2%, 4.9%, and 1.0% for the 2-year, 1-year, and observation groups, respectively). The HERA study also confirmed that a 1-year trastuzumab regimen yielded superior DFS and OS relative to the observation group. Because a 2-year extension of adjuvant trastuzumab use failed to show superior efficacy to 1-year use while inducing increased toxicity, the 1-year adjuvant trastuzumab regimen remains the standard of care for patients with HER2-positive early breast cancer.

Lastly, in 2013, there was an important regulatory issue in the field of breast cancer management. The US Food and Drug Administration initially approved pertuzumab for a neoadjuvant indication in breast cancer, given the appropriateness of a pathological complete response (pCR) as a surrogate endpoint in the neoadjuvant setting. This accelerated approval of pertuzumab was mainly supported by three randomized trials: the NeoSphere [52], TRYPHAENA [53], and CLEOPATRA studies [54]. NeoSphere, the primary study to support the efficacy of pertuzumab in a neoadjuvant setting, showed statistically significant improvements in the achievement of pCR in patients receiving pertuzumab plus trastuzumab and docetaxel versus patients receiving only trastuzumab plus docetaxel. CLEOPATRA, a randomized double-blind, placebo-controlled trial, included 808 patients with HER2-positive metastatic breast cancer who received either pertuzumab plus trastuzumab and docetaxel or placebo plus trastuzumab and docetaxel. Along with the significant improvements in PFS and OS observed in the pertuzumab treatment arm, the CLEOPATRA study suggested the use of pCR as a surrogate clinical benefit endpoint in terms of DFS, EFS, and OS. The subsequent CTNeoBC pooled analysis, which included 11,955 patients, found associations of pCR with EFS and OS. These associations were strongest in patients with aggressive tumors, including HER2-positive and triple-negative tumors. Although the CTNeoBC analysis could not confirm these significant associations at a clinical trial level but rather at an individual patient level, the potential benefit of the concept of pCR as a surrogate endpoint in cases such as the use of pertuzumab in neoadjuvant breast cancer appears to be the early assessment of long-term survival outcomes and the consequent earlier approval of a drug to address an unmet medical need.

Provision of the optimal target tissue dose with a minimal dose to normal tissues is the goal of RT. Intensity-modulated radiotherapy (IMRT) is among the recent technical advances in radiation delivery intended to satisfy this clinical goal. IMRT is a type of three-dimensional conformal radiotherapy (3D-CRT), in which the spatial distribution of the prescribed dose is conformed to the 3D target volume via a set of fixed radiation beams [55]. Compared with conventional 3D-CRT, IMRT uses optimized nonuniform radiation beam intensities that are incident on the patient [55]. The summation of the individual contributions from each beam results in complex 3D dose clouds and the delivery of minimal doses to the organs at risk. Based on this theoretical benefit of IMRT and the relevant clinical evidence, IMRT has become a standard RT method for prostate cancer as well as head and neck cancer treatment [56]. However, its potential benefit has not yet been fully demonstrated in gynecologic cancers. In 2012, a phase II feasibility trial conducted by the Radiation Therapy Oncology Group (RTOG) reported that IMRT led only to an insignificant 12% reduction in the incidence of grade 2 or higher bowel toxicities compared with historic controls (RTOG 0418) [57].

In 2013, two separate notable research reports attempted to demonstrate reduced toxicity and comparable survival outcomes with IMRT in cervical and endometrial cancer, respectively. For cervical cancer, the final report of a prospective randomized study of IMRT versus conventional pelvic RT in locally advanced disease in India was published in the International Journal of Radiation Oncology, Biology, Physics [58]. Although this study was small, it was the first prospective randomized trial to show a benefit of IMRT with regard to toxicity for intact cervical cancer patients. Briefly, 44 patients with FIGO stage IIB to IIIB squamous cell carcinoma of the cervix were randomly assigned to receive whole pelvic conventional RT or IMRT at a total dose of 50.4 Gy in 28 fractions plus concurrent weekly cisplatin (40 mg/m²). The median follow-up durations were 21.7 months (range, 10.7 to 37.4 months) and 21.6 months (range, 7.7 to 34.4 months) for the conventional RT and IMRT groups, respectively. At 27 months, no significant differences in DFS (79.4% vs. 60%, p=0.651) and OS (76% vs. 85.7%, p=0.645) were observed between the two groups. However, patients in the IMRT group were less likely to develop grade ≥2 acute GI toxicity (31.8% vs. 63.6%, p=0.034) and chronic GI toxicity (13.6% vs. 50%, p=0.011) relative to those in the conventional RT group. Because of a few study limitations, including the small sample size, short follow-up times, and lack of image guidance, the authors argued that an additional phase III randomized trial with a large sample size was needed.

Another notable IMRT study reported in 2013 was a population-based study that used the Surveillance, Epidemiology, and End Results (SEER)-Medicare database to analyze patients with endometrial cancer [57]. Among the 3,555 women with uterine cancer in the SEER-Medicare database, 328 patients (9.2%) who had undergone IMRT were identified. The incidence of late toxicities and costs were compared in the IMRT and 3D-CRT groups. The IMRT group had a higher incidence of bowel obstruction than did the 3D-CRT group (RR, 1.41; 95% CI, 1.03 to 1.93). However, there was little difference in the incidence of late toxicity, including other GI and genitourinary toxicities as well as hip fracture, between the IMRT and 3D-CRT groups. There was a possible explanation for these findings. Given the large tissue volume and a relatively low dose (45 to 55 Gy) of the adjuvant RT for endometrial cancer, the potential toxicity benefits of IMRT for uterine cancer might be less prominent than those of pelvic RT for cervical cancer, in which the total delivered RT dose is often much higher (>80 Gy) [57]. Given the increased cost of IMRT (US $12,000 greater than that of 3D-CRT), the authors concluded that the recent increased use of IMRT for women with uterine cancer should be further supported by randomized trials that examine the effectiveness as well as the safety of IMRT.

The therapeutic benefit of BEV for recurrent or metastatic cervical cancer was highly welcomed and readily incorporated into the practice guidelines. Dose-dense carboplatin and paclitaxel were also classified as category 1 in the guidelines as another standard front-line postoperative chemotherapy regimen for advanced EOC. Other targeted agents have begun to show some potential benefits for advanced EOC in different settings. Based on the integrated genomic characterization of endometrial carcinoma, a change in the therapeutic plan is expected for a subset of endometrioid tumors that are refractory to current treatment. We hope that many of these changes will transition to real clinical practice in the future.