Somatic genomic landscape of East Asian epithelial ovarian carcinoma and its clinical implications from prospective clinical sequencing: A Korean Gynecologic Oncology Group study (KGOG 3047).

Through the wide adaptation of next-generation sequencing (NGS) technology within clinical practice, molecular profiling of the tumor has been the principal component of personalized treatment. In our study, we have generated a large collection of cancer genomes on East Asian epithelial ovarian carcinoma (EOC) patients and demonstrate the feasibility and utility of NGS platforms to explore the dynamic interrelations of major cancer driver alterations and their impacts on clinical prognosis and management. A total of 652 EOC patients have undergone clinical NGS panels to determine the prevalence of germline and somatic mutations. Notably, TP53 was the most frequently altered event (73%), followed by both BRCA1 and BRCA2 (22% each) and MYC (19%) through pan-EOC analysis. When analyzed based on individual histopathological levels, TP53 mutation was highly dominant in high-grade serous and mucinous histology, whereas mutations in PIK3CA and ARID1A were mostly observed in clear cell carcinoma, and KRAS, BRAF, and CDKN2A mutations were enriched in endometrioid, low-grade serous, and mucinous tumors, respectively. The network-based probabilistic model showed significant co-occurrences of TP53 with BRCA1 and ALK with BRCA2, NOTCH1, and ROS1, whereas mutual exclusivity of TP53 with KRAS and PIK3CA was evident. Furthermore, we utilized machine-learning algorithms to identify molecular correlates that conferred increased sensitivity to platinum and olaparib treatments including somatic mutations in BRCA1, ATM, and MYC. Conversely, patients with ALK mutation were considerably resistant to both treatment modalities. Collectively, our results demonstrate the clinical feasibility of prospective genetic sequencing to facilitate personalized treatment opportunities for patients with EOC.

Randomized multicenter phase II trial of prophylactic irradiation of para-aortic lymph nodes in advanced cervical cancer according to tumor hypoxia: Korean Radiation Oncology Group (KROG 07-01) study.

We conducted a prospective phase II study on whether extended-field irradiation (EFI) confers survival benefits depending on hypoxic markers in locally advanced uterine cervical cancer (LAUCC). RNA-seq was performed to identify immune and hypoxic gene signatures. A total of 288 patients were randomized to either EFI or pelvic radiotherapy (PRT). All patients completed chemoradiotherapy. Overall, significantly higher 5-year para-aortic recurrence free survival (PARFS) rate occurred in EFI (97.6%) than in PRT group (87.2%), with marginal tendency to improve disease-free survival (DFS; 78% vs 70%, P = .066). Subgroup analyses were performed based on carbonic anhydrase 9 (CA9)-only positive, CA9/hypoxia-inducible factor (HIF) double positive and CA9 negative. In the CA9-only positive, EFI successfully increased 5-year PARFS (100% vs 76.4%, P = .010), resulting in significantly improved long-term DFS (85.7% vs 54.7%, P = .023) compared to the PRT, while there was no such benefit of EFI in the CA9/HIFs double positive. RNA-seq analysis identified distinct immunehigh subgroup with negative correlation with hypoxia gene signatures (R = -.37, P < .01), which showed a higher 5-year DFS than the immunelow (P = .032). Hypoxia-related genes were upregulated in the CA9/HIFs double positive compared to CA9 negative (P < .05). Only 17.4% of patients in CA9-negative group showed immunelow signatures, while 40.0% of patients in the double-positive group exhibited immunelow signatures. In conclusion, EFI improved PARFS significantly in all patients, but therapeutic efficacy of EFI in terms of improved DFS was solely observed in CA9-only positive LAUCC, and not in CA9/HIFs double-positive subgroup. RNA-seq analysis suggested that hypoxia-induced immunosuppression may be related to treatment resistance in LAUCC.

A predictive model based on site-specific risk factors of recurrence regions in endometrial cancer patients.

OBJECTIVE: This study investigated site-specific differences in clinical factors for recurrence in patients who were newly diagnosed and treated for endometrial cancer. A model for predicting recurrence sites was generated. METHODS: Electronic medical records' data were retrieved from January 2006 to December 2018 for patients who were diagnosed with endometrial cancer at the National cancer center in Korea. Recurrence sites were classified as local, regional, or distant. We used multinomial logistic regression models that modeled the log-odds for the three recurrence sites relative to non-recurrence as a linear combination of possible risk factors for the recurrence of endometrial cancer. RESULTS: The data of 611 patients were selected for analysis; there were 20, 12, and 25 cases of local, regional, and distant recurrence, respectively, and 554 patients had no recurrence. High-grade disease was associated with local recurrence; non-endometrioid histology and parametrial invasion were risk factors for regional recurrence; additionally, parametrial invasion and no lymphadenectomy were associated with distant metastasis. CONCLUSION: We identified different risk factors specific for each type of recurrence site. Using these risk factors, we suggest that individually tailored adjuvant treatments be introduced for patients.

Surgical outcomes of ureteral reconstruction during cytoreductive surgery for ovarian cancer: a retrospective cohort study.

BACKGROUND: Ureteral reconstruction is required after surgical resection of the tumor invading the urinary tract in ovarian cancer with low incidence. There are no currently reported surgical outcomes of ureteral reconstruction during cytoreductive surgery. The aim of the study is to investigate the clinical features and surgical outcomes of ureteral reconstruction during primary, interval and secondary cytoreductive surgery for ovarian cancer.  METHODS: A total of 3226 patients who underwent primary, interval or secondary cytoreductive surgery for ovarian cancer between January 2000 and May 2021 were reviewed. Fifty-six patients who underwent ureteral reconstruction during cytoreductive surgery were included in the analysis.  RESULTS: Ureteral reconstruction was required in 1.7% (56/3226) of ovarian cancer patients. Of the 56 patients who underwent ureteral reconstruction during cytoreductive surgery, 35 (62.5%) had primary ovarian cancer, and 21 (37.5%) had recurrent ovarian cancer. The median tumor size invading the lower urinary tract was 2.0 cm (range, 0.4-9.5 cm). Ureteroneocystostomy with direct implantation (51.8%) and psoas hitch (8.9%), transureteroureterostomy (7.1%), and ureteroureterostomy (32.1%) were required as part of cytoreductive surgery. Complete cytoreduction with ureteral reconstruction was achieved in 83.9% (47/56) and the rest of the patient population (16.1%) achieved a gross residual tumor size of less than 1 cm. All complications, including hydronephrosis (33.9%), were managed, none resulting in long-term sequelae. In primary ovarian cancer, the 5-year disease-free survival and overall survival were 50.0% and 89.5%, respectively. In patients with recurrent ovarian cancer, the 5-year disease-free survival and overall survival were 23.6% and 64.0%, respectively. CONCLUSIONS: Ureteral reconstruction as a part of cytoreductive surgery for ovarian cancer could be performed with acceptable morbidities. Complete cytoreduction by a multidisciplinary surgical team, including urologic oncologists, should be pursued for the surgical management of ovarian cancer. TRIAL REGISTRATION: Retrospectively registered.

Predicting the risk of the distant recurrence of cervical cancer after concurrent chemoradiation: A validation study of the Korean Gynecologic Oncologic Group (KGOG)-1024 model.

BACKGROUND: This study aimed to validate the performance of the Korean Gynecologic Oncologic Group (KGOG)-1024 risk model in predicting the risk of distant failure after chemoradiation in patients with locally advanced cervical cancer (LACC). METHODS: In a retrospective cohort of 297 patients who received concurrent chemoradiation for advanced cervical cancer, individual risk was calculated using the KGOG-1024 risk model. The cohort was categorized into three risk groups (low-, intermediate-, and high-risk groups) according to the calculated risk. The means of the calculated and observed risks were compared within each group. RESULTS: The study population was classified into low-, intermediate-, and high-risk groups according to the KGOG-1024 risk model (27.2%, 49.3%, and 23.5% of patients, respectively). The calculated and observed 5-year cumulative incidence rates were 12.4% vs. 16.4% in the low-risk group, 23.2% vs. 25.9% in the intermediate-risk group, and 50.7% vs. 36.3% in the high-risk group. Overall, the calculated and observed risk was 26.7% vs. 25.6%. CONCLUSIONS: The KGOG-1024 risk assessment model accurately predicted distant recurrence after chemoradiation in patients with LACC, especially in the low- and intermediate-risk groups. The model may be helpful for identifying patients for future trials assessing the possible benefit of adjuvant systemic treatment after chemoradiation.

Clinical outcomes of BRCA1/2 pathogenic variants in ovarian cancer cluster region in patients with primary peritoneal, epithelial ovarian, and fallopian tube cancer.

OBJECTIVE: An "ovarian cancer cluster region" (OCCR) has been reported in both BRCA1 and BRCA2. However, the clinical significance of the OCCR of BRCA1/2 has not yet been investigated. METHODS: The medical records of 991 patients with epithelial ovarian, primary peritoneal, and fallopian tube cancer who underwent genetic testing for BRCA1 and/or BRCA2 from January 1, 2006, to August 31, 2019, were retrospectively reviewed. Sanger and next-generation sequencing analyses were used to test the BRCA1 and BRCA2 mutation status. Progression-free survival (PFS) and overall survival (OS) were compared according to the mutation location (OCCR vs. non-OCCR region). Survival outcomes were determined using Kaplan-Meier survival analysis. RESULTS: A total of 162 patients had BRCA1 pathogenic variants (PVs), and 76 had BRCA2 PVs. Patients with BRCA1 PV that in the OCCR region showed shorter PFS than those with BRCA1 PV outside the OCCR (22.6 months vs. 27.6 months, P = 0.038). In the platinum-sensitive subgroup of BRCA1, patients with BRCA1 PV in the OCCR region showed shorter PFS than those in the non-OCCR group (P = 0.0197). On the other hand, BRCA2 variants did not exhibit any particular trend (32.8 months vs. 27.9 months, P = 0.468). However, no significant differences were detected in OS between patients with BRCA1/2 PVs, regardless of the location of the variants. CONCLUSIONS: Patients with BRCA1 PV in the OCCR had shorter PFS than those outside the OCCR. This tendency was more pronounced in the platinum-sensitive subgroup. To our knowledge, this is the first study of BRCA1/2 mutations based on the OCCR.

How Do Patients Value the Benefit of Minimally Invasive Surgery in Cancer Treatment?

OBJECTIVES: Due to the increasing cost of cancer treatment, the demand for value-based healthcare is increasing. Although several value frameworks have been developed recently in the field of oncology, the nononcological benefits of minimally invasive surgery have not been addressed. This study aimed to estimate how patients value nononcological benefits in minimally invasive cancer surgery. METHODS: The value that patients placed on various benefits of cancer surgery was termed throughout the study as patient value (PV). To quantize PVs for the benefits of cancer surgery, a one-tiered analytic hierarchy process model was constructed. The model includes 6 well-known surgical outcomes, including nononcological benefits. The study participants included 303 patients with cancer and family caregivers who participated in a questionnaire survey. RESULTS: The PVs for "decreased operation time," "reduced length of hospital stay," and "improved cosmetic results" were 0.050, 0.044, and 0.045, respectively, whereas the PVs for "increased survival," "prevention of disease recurrence," and "avoidance of complications" were 0.366, 0.292, and 0.203, respectively. The PV placed on nononcological benefits from minimally invasive surgery was one-tenth (10.2%) of the total value. CONCLUSIONS: Nononcological benefits arising from minimally invasive surgery were relatively small but nonnegligible. This value should be considered in the process of developing a value framework for cancer surgery and shared decision making.

How to manage synchronous endometrial and ovarian cancer patients?

BACKGROUNDS: We aimed to evaluate the prognosis in patients with synchronous endometrial and ovarian cancer (SEOC) by comparing the differences between double primary cancer (DPC) and metastatic cancer (MC). METHODS: The medical records of 47 patients diagnosed synchronously with endometrial and ovarian cancer between January 2006 and December 2018 were retrospectively reviewed. Twenty-eight and 19 patients were diagnosed with DPC and MC, respectively. Demographics, recurrence-free survival (RFS), and 5-year overall survival (OS) were compared. The clinical factors affecting survival were evaluated using univariate and multivariate analyses. RESULTS: The demographics were not different between both groups. Endometrioid histology and the International Federation of Gynecology and Obstetrics grade were higher in the MC group than in the DPC group (42.1% vs. 10.7%; P = 0.018, P = 0.002, respectively). The ratio of post-operative adjuvant therapy was not different in both groups. Recurrence occurred in five patients with DPC and seven with MC. The difference in RFS was not significantly different (P = 0.131) but the OS was different between both groups (P = 0.020). Histology and para-aortic lymph node metastasis were associated wtih RFS in univariate analysis, but no difference was found in multivariate analysis. CONCLUSIONS: Although DPC patients had longer OS, multivariate analysis did not identify any influential factors. Focus should be placed on defining the appropriate adjuvant treatment for high-risk patients, which will improve prognosis, rather than on discriminating between DPC and MC.

Is Korean society prepared for the financial burden of novel anticancer drugs? A survey of willingness to pay among National Health Insurance beneficiaries.

PURPOSE: Since South Korea's 5-year policy of increasing National Health Insurance (NHI) coverage began in 2017, related pharmaceutical expenditures have increased by 41%. Thus, there is a critical need to examine society's willingness to pay (WTP) for increased premiums to include new anticancer drugs in NHI coverage. METHODS: Participants aged 20-65 were invited to a web-based online survey. The acceptable effectiveness threshold for a new anticancer drug to be included in NHI coverage and the WTP for an anticancer drug with modest effectiveness were determined by open-ended questions. RESULTS: A total of 1817 respondents completed the survey. Participants with a family history of cancer or a higher perceived risk of getting cancer had significantly higher WTPs (RR [relative risk] = 1.17 and 1.21, both P = 0.012). Participants who agreed on adding coverage for new anticancer drugs with a life gain of 3 months had a higher WTP (RR = 1.70, P < 0.0001). These associations were greater among the employed and low-income groups. The adjusted mean of acceptable effectiveness for a new anticancer drug was 21.5 months (interquartile range [IQR] = 19.3 to 24.0, median = 21.9). The WTP for a new anticancer drug with a life gain of 3 months was $5.2 (IQR = 4.0 to 6.0, median = 4.6). CONCLUSION: The unrealistic expectations in Korean society for new anticancer agents may provoke challenging issues of fairness and equity. Although Korean society is willing to accept premium increases, our data suggest that such increases would benefit only a small proportion of advanced cancer patients.

The impact of depressive symptoms on health value in patients with gynecologic cancer: A comparison with physical symptoms and performance status.

OBJECTIVE: The importance of managing depressive symptoms is frequently underestimated in the clinic. In this study, the effects of depressive symptoms on health utility value (HUV) in gynecologic cancer patients are evaluated. In addition, the effects were compared with those of performance status and physical symptoms. METHODS: Patient-reported outcome data from 274 gynecologic cancer patients were prospectively collected. HUV was measured using the 3-level version of the EuroQoL 5-dimension descriptive system (EQ-5D-3L) and the EuroQoL visual analog scale (EQ-VAS). The Patient Health Questionnaire-9 (PHQ-9) was used to measure the severity of depressive symptoms. The impact of depressive symptoms on HUV was analyzed using the generalized linear model. RESULTS: Moderate-severe depressive symptoms were significantly associated with a decrease in HUV in gynecologic cancer patients (p < 0.0001 for the EQ-5D-3L and EQ-VAS). Severe fatigue and severe pain were also associated with a decrease in HUV (p = 0.018 and p < 0.0001 for the EQ-5D-3L and EQ-VAS; p < 0.0001 for the EQ-5D-3L, respectively), and the effect sizes were comparable to that of moderate-severe depressive symptoms. In addition to the patients with moderate-severe depressive symptoms, the patients with mild depressive symptoms also experienced a significant decrease in HUV (p < 0.0001 for the EQ-5D-3L and EQ-VAS). The effect size for mild depressive symptoms was comparable to those for mild fatigue or mild pain. CONCLUSIONS: Even mild depressive symptoms may significantly compromise HUV in gynecologic cancer patients, and the effect is comparable to that of performance status or physical symptoms. Gynecologic oncologists should put more effort into properly preventing, detecting, and managing depressive symptoms.

Effect of addition of bevacizumab to chemoradiotherapy in newly diagnosed stage IVB cervical cancer: a single institution experience in Korea.

OBJECTIVE: The aim of this study was to compare the clinical outcomes of chemoradiotherapy with or without bevacizumab in patients with newly diagnosed International Federation of Gynecology and Obstetrics (FIGO) stage IVB cervical cancer. METHODS: 41 patients with stage IVB cervical cancer who underwent chemoradiotherapy between August 2015 and December 2017 were retrospectively analyzed. This study included 11 patients who received bevacizumab before or after radiotherapy (group A) and 30 patients who received conventional chemoradiotherapy without bevacizumab (group B). We excluded the following patients: those with dual primary cancers; those whose pathologic diagnosis was neither squamous cell carcinoma nor adenocarcinoma; those who did not undergo radiotherapy; or those from whom follow-up data could not be collected. We analyzed the treatment responses, toxicities, progression-free survival, and overall survival rates. RESULTS: A total of 41 patients were included in the analysis. The median follow-up was 19 months (range 3-108). The response rates at 3 months after treatment were 90.9% in group A and 83.3% in group B (p=0.54). After completing all treatments, the complete response rates were 81.8% in group A and 47% in group B (p=0.04). Grade ≥3 gastrointestinal toxicities, including bleeding, fistula, perforation, and obstruction, were more frequent in group A (54.5%) than in group B (6.7%) (p=0.003). The 12 month progression-free survival and overall survival rates were similar in both arms (12 month progression-free survival: 45.5% vs 46.7%, respectively, p=0.22; 12 month overall survival: 81.8% vs 72.9%, respectively, p=0.57). Patients with node-only metastasis had better 12 month progression-free survival in group B than in group A (59.1% vs 42.9%, respectively, p=0.04). However, the responses to both treatments did not differ in patients with organ metastasis. CONCLUSIONS: Bevacizumab for stage IVB cervical cancer is associated with higher complete response rates. However, patients treated with bevacizumab experienced more bowel toxicities. Bevacizumab did not improve progression-free survival among patients with node-only metastasis.

Real-world effectiveness of bevacizumab based on AURELIA in platinum-resistant recurrent ovarian cancer (REBECA): A Korean Gynecologic Oncology Group study (KGOG 3041).

PURPOSE: To evaluate the effectiveness of bevacizumab with single-agent chemotherapy for platinum-resistant ovarian cancer in a real-world setting. PATIENTS AND METHODS: We enrolled recurrent platinum-resistant ovarian cancer patients from 27 institutions. All had received bevacizumab with single-agent chemotherapy (weekly paclitaxel, pegylated liposomal doxorubicin (PLD), topotecan) between 2015 and 2017 for second- or third-line chemotherapy in routine clinical practice. The primary endpoint was progression-free survival (PFS) and safety. Secondary endpoints included the objective response rate (ORR), PFS2, overall survival, duration of chemotherapy, and reasons for discontinuing chemotherapy. RESULTS: Of 391 patients, 259 (66.2%) received bevacizumab with PLD, 94 (24.0%) with topotecan, and 38 (9.7%) with weekly paclitaxel. The median PFS was 6.1 months with all forms of bevacizumab-containing therapy. Although the cohort with weekly paclitaxel had a better PFS than the PLD cohort (P = 0.028), this finding was not found in patients with a previous platinum-free interval of less than three months. The median duration of therapy was five cycles (range, one to 20 cycles), and 29 patients (7.4%) discontinued treatment because of adverse events from bevacizumab-containing regimens. The PLD cohort had fewer grade ≥ 3 adverse events than the other regimens (PLD, 35.8%; weekly paclitaxel, 52.6%; topotecan, 51.1%; P = 0.012), especially events of hematologic toxicities. CONCLUSION: In Korean ovarian cancer patients, the safety and effectiveness of chemotherapy with bevacizumab in a real-world setting was consistent with the results from a randomized controlled study. The effectiveness and toxicity profiles varied among the chemotherapy regimens, and this finding should be considered in practice. CLINICAL TRIALS REGISTRATION: NCT03367182.

Phase I/II clinical trial of modulated electro-hyperthermia treatment in patients with relapsed, refractory or progressive heavily treated ovarian cancer.

OBJECTIVE: To determine the maximal tolerated dose (MTD) of modulated electro-hyperthermia (mEHT) treatment and to reveal whether mEHT treatment is feasible and effective as second-line therapy in recurrent and progressive ovarian cancer. METHODS: Patients were treated with mEHT with dose escalation during the first cycle (two sessions each week for three weeks) to determine the MTD. Additional cycles were carried out with the determined dose. Dose limiting toxicity (DLT) was defined grade ≥ 2: skin burns and inability to endure the hyperthermic state of the study. The Fact-O quality of life scale was used to assess health-related well-being. RESULTS: Nineteen patients with recurrent and progressive ovarian cancer were enrolled. In the first cycle of mEHT treatment, no patient developed DLT with applied power up to 110 W, 130 W, and 150 W/day; the 150 W was the maximal applied power. Stable disease was observed in only one patient (12.5%). With median progression of 4.0 months (range, 2-17 months), 18 patients (95%) demonstrated disease progression. With median overall survival of 8.0 months (range, 2-32 months), 18 patients (95%) had died. Physical well-being scores were significantly decreased over the study period, although social, emotional, and functional well-being scores did not significantly change. CONCLUSIONS: The mEHT treatment was feasible in patients with recurrent or progressive ovarian cancer without any complication and optimal dose of mEHT treatment was up to 150 W for 1 hour/day.

Gene Expression Signature-Based Prediction of Lymph Node Metastasis in Patients With Endometrioid Endometrial Cancer.

OBJECTIVE: This study aimed to develop a prediction model for lymph node metastasis using a gene expression signature in patients with endometrioid-type endometrial cancer. METHODS: Newly diagnosed endometrioid-type endometrial cancer cases in which the patients had undergone lymphadenectomy during a surgical staging procedure were identified from a national dataset (N = 330). Clinical and pathologic data were extracted from patient medical records, and gene expression datasets of their tumors were used to create a 12-gene predictive model for lymph node metastasis. We used principal components analysis on a training set (n = 110) to develop multivariate logistic models to predict low-risk patients having a probability of lymph node metastasis of less than 4%. The model with the highest prediction performance was selected for an evaluation set (n = 112), which, in turn, was validated in an independent validation set (n = 108). RESULTS: The model applied to the evaluation set showed 100% sensitivity (90% confidence interval [CI], 74%-100%) and 42% specificity (90% CI, 34%-51%), which resulted in 100% negative predictive value (90% CI, 89%-100%). In the validation set, we confirmed that the model consistently showed 100% sensitivity (90% CI, 88%-100%), 42% specificity (90% CI, 32%-50%), and 100% negative predictive value (90% CI, 88%-100%). CONCLUSIONS: Our 12-gene signature model is a useful tool for the identification of patients with endometrioid-type endometrial cancer at low risk of lymph node metastasis, particularly given that it can be used to analyze histologic tissue before surgery and used to tailor surgical options.

Preoperative assessment of lymph node metastasis in endometrial cancer: A Korean Gynecologic Oncology Group study.

BACKGROUND: Previously proposed criteria for preoperatively identifying endometrial cancer patients at low risk for lymph node metastasis remain to be verified. For this purpose, a prospective, multicenter observational study was performed. METHODS: Eligible patients with histologically confirmed endometrial cancer underwent magnetic resonance imaging (MRI) and serum cancer antigen 125 (CA 125) testing before surgery. The following criteria were used to identify low-risk patients: 1) endometrioid-type cancer, 2) no evidence of deep myometrial invasion on MRI, 3) no enlarged lymph nodes on MRI, 4) no suspicious metastasis out of the uterine corpus, and 5) serum CA 125 levels less than 35 U/mL. Systematic pelvic and/or para-aortic lymphadenectomy was performed for all patients. The primary endpoint was estimation of the negative predictive value (NPV). RESULTS: From January 2012 to December 2014, 529 patients from 20 hospitals in 3 Asian countries were consecutively enrolled. According to our criteria, 272 patients (51.4%) were categorized into the low-risk group. Fifty-three of the 529 patients (10.0%) had lymph node metastases; these patients included 8 (2.9%) falsely categorized as low-risk. The sensitivity and specificity of the criteria were 84.9% and 55.5%, respectively. The NPV of 97.1% was higher than the predefined target endpoint of 96%. CONCLUSIONS: The low-risk criteria based on preoperative tests were confirmed to be reliable and accurate for identifying patients at low risk for lymph node metastasis. These criteria may facilitate patient counseling and surgical decision making. Cancer 2017;123:263-272. © 2016 American Cancer Society.

Phase I study of oral ridaforolimus in combination with paclitaxel and carboplatin in patients with solid tumor cancers.

BACKGROUND: Ridaforolimus is a mammalian target of rapamycin inhibitor that has activity in solid tumors. Paclitaxel and carboplatin have broad antineoplastic activity in many cancers. This phase I trial was conducted to determine the safety profile, maximal tolerated dose, and recommended phase II dose and schedule of oral ridaforolimus combined with paclitaxel and carboplatin in patients with solid tumor cancers. METHODS: Eligible patients with advanced solid tumor cancers received oral 10 to 30 mg ridaforolimus daily for 5 consecutive days per week combined with intravenous paclitaxel (175 mg/m2) and carboplatin (area under the curve [AUC] 5-6 mg/mL/min) in 3-week cycles. A standard 3 + 3 design was used to escalate doses, with predefined changes to an alternate dosing schedule and/or changes in carboplatin AUC doses based on dose-limiting toxicity (DLT). Secondary information was collected regarding response and time to progression. Patients were continued on treatment if therapy was tolerated and if stable disease or better was demonstrated. RESULTS: Thirty-one patients were consented, 28 patients were screened, and 24 patients met eligibility requirements and received treatment. Two patients were replaced for events unrelated to drug-related toxicity, resulting in 22 DLT-evaluable patients. Two grade 4 DLTs due to neutropenia were observed at dose level 1. The next cohort was changed to a predefined alternate dosing schedule (days 1-5 and 8-12). DLTs were neutropenia, sepsis, mucositis, and thrombocytopenia. The most common adverse events were neutropenia, anemia, thrombocytopenia, fatigue, alopecia, nausea, pain, and leukopenia. Twenty-four patients received a median of 4 cycles (range, 1-12). Evaluable patients for response (n = 18) demonstrated a median tumor measurement decrease of 25%. The best response in these 18 patients included 9 patients with partial response (50%), 6 with stable disease (33%), and 3 with progressive disease (17%). Thirteen of these patients received treatment for 4 or more cycles. CONCLUSIONS: Treatment with ridaforolimus combined with paclitaxel and carboplatin had no unanticipated toxicities and showed antineoplastic activity. The recommended phase II dose and schedule is ridaforolimus 30 mg (days 1-5 and 8-12) plus day 1 paclitaxel (175 mg/m2) and carboplatin (AUC 5 mg/mL/min) on a 21-day cycle. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01256268 (trial registration date: December 1, 2010).

Comparison of Lower Extremity Edema in Locally Advanced Cervical Cancer: Pretreatment Laparoscopic Surgical Staging with Tailored Radiotherapy Versus Primary Radiotherapy.

BACKGROUND: This study investigated the clinical manifestations of lower extremity edema (LEE) in locally advanced cervical cancer patients treated with two different strategies. METHODS: In total, 79 cervical cancer survivors with International Federation of Gynecology and Obstetrics stage IB2-IIB were included. Six survivors with stage IB1 and who had been suspicious for lymph node metastasis on pretreatment image also were included. Forty-two patients received radiotherapy after pretreatment laparoscopic surgical staging (Group 1), and 43 patients received primary radiotherapy (Group 2). The patients' medical records and survey results of the Korean version of the Gynecologic Cancer Lymphedema Questionnaire (GCLQ-K) were analyzed. RESULTS: The incidence of LEE was higher in Group 1 than in Group 2 (69.0 vs. 11.6 %; P < 0.001). The duration of LEE was longer in Group 1 (mean 77.3 vs. 9.4 months). At the time of survey, 47.6 % of the patients in Group 1 were clinically diagnosed with lymphedema compared with no patients in Group 2. In GCLQ-K, the mean symptom cluster scores for general swelling (0.74 vs. 0.09; P < 0.001), limb swelling (0.22 vs. 0.00; P = 0.006), and heaviness (0.45 vs. 0.23; P = 0.033) were significantly higher in Group 1. One patient in Group 1 developed lymphedema-related angiosarcoma that was diagnosed at 7.8 years after surgery. CONCLUSIONS: Patients with cervical cancer who underwent radiotherapy after laparoscopic surgical staging more commonly experienced LEE and related symptoms than patients who underwent primary radiotherapy. As LEE decreases patients' quality of life, it should be considered during patient consultation and surveillance.

Postoperative Lower Extremity Edema in Patients with Primary Endometrial Cancer.

PURPOSE: The goal of this study was to investigate clinical manifestations of lower extremity edema (LEE) after lymph node dissection in patients with primary endometrial cancer. METHODS: Women with primary endometrial cancer who underwent staging surgery between November 2001 and March 2011 were included in the study. Medical records and/or responses to the Gynecologic Cancer Lymphedema Questionnaire (GCLQ) were used for LEE evaluation. RESULTS: All 154 patients underwent pelvic lymph node dissection, and 126 patients (81.8 %) underwent paraaortic LN dissection. The median age of the patients was 52 years, the majority had stage I cancer (78.6 %), and most had endometrioid histology (90.9 %). The most frequent GCLQ responses were "experienced swelling" (35.7 %), "experienced numbness" (30.5 %), "experienced heaviness" (29.9 %), and "experienced aching" (29.9 %). Sixty-four patients (41.6 %) had previous (9/64, 14.1 %) and/or current (55/64, 85.9 %) patient-reported LEE. Most patients developed LEE within 12 months after surgery (39/56, 69.6 %), and LEE lasted for more than 12 months in most patients (45/56, 80.4 %). Three patients reported recurrent LEE after recovery. Multivariate logistic regression identified the number of dissected pelvic lymph node (≥21) as a risk factor for LEE [odds ratio (OR) 3.28; 95 % confidence interval (CI) 1.058-10.136] and postoperative radiotherapy (OR 3.81, 95 % CI 1.67-8.69). CONCLUSIONS: LEE developed in more than one-third of patients with endometrial cancer after surgery, and LEE lasted for more than 12 months in most patients. A high number of dissected pelvic lymph nodes and postoperative radiotherapy is associated with LEE.

Population attributable risks of modifiable reproductive factors for breast and ovarian cancers in Korea.

BACKGROUND: Breast and ovarian cancers are predominant female cancers with increasing prevalence. The purpose of this study was to estimate the population attributable risks (PARs) of breast and ovarian cancer occurrence based on the relative risks (RRs) of modifiable reproductive factors and population-specific exposure prevalence. METHODS: The PAR was calculated by using the 1990 standardized prevalence rates, the 2010 national cancer incidence with a 20 year lag period, the meta-analyzed RRs from studies conducted in the Korean population for breast cancer, and the meta-analyzed RRs from a Korean epithelial ovarian cancer study and a prior meta-analysis, and ovarian cancer cohort results up to 2012. For oral contraceptive and hormone replacement therapy use, we did not consider lag period. RESULTS: The summary PARs for modifiable reproductive factors were 16.7% (95% CI 15.8-17.6) for breast cancer (2404 cases) and 81.9% (95% CI 55.0-100.0) for ovarian cancer (1579 cases). The modifiable reproductive factors included pregnancy/age at first birth (8.0%), total period of breastfeeding (3.1%), oral contraceptive use (5.3%), and hormone replacement therapy use (0.3%) for breast cancer and included breastfeeding experience (2.9%), pregnancy (1.2%), tubal ligation (24.5%), and oral contraceptive use (53.3%) for ovarian cancer. CONCLUSIONS: Despite inherent uncertainties in the risk factors for breast and ovarian cancers, we suggest that appropriate long-term control of modifiable reproductive factors could reduce breast and ovarian cancer incidences and their related burdens by 16.7% and 81.9%, respectively.

Predictors of Radiation Field Failure After Definitive Chemoradiation in Patients With Locally Advanced Cervical Cancer.

PURPOSE: We identified the predictive factors for locoregional failure after definitive chemoradiation in patients with locally advanced cervical cancer. METHODS: Altogether, 397 patients with locally advanced cervical cancer (stage IB2-IVA) were treated with definitive chemoradiation between June 2001 and February 2010. Platinum-based concurrent chemotherapy was given to all patients with median radiation dose of external beam radiotherapy 50.4 Gy in 28 fractions and intracavitary radiotherapy 30 Gy in 6 fractions. Competing risk regression analysis was used to reveal the predictive factors for locoregional failure. RESULTS: During the median follow-up of 7.2 years, locoregional failure occurred in 51 (12.9%) patients. The estimated 3-year rate of locoregional control was 89%, whereas the overall survival rate was 82%. After univariate and multivariate analyses, large tumor size (>5 cm), young age (≤40 years), nonsquamous histology, positive lymph node on magnetic resonance imaging, and advanced stage (III-IV) were identified as risk factors for locoregional failure (P = 0.003, P = 0.075, P = 0.005, P = 0.055, and P < 0.001, respectively). After risk grouping according to the coefficients from the multivariate model, we identified a high-risk group for locoregional failure after treatment with definitive chemoradiation as follows: (1) tumor size larger than 5 cm, and at least 1 other risk factor or (2) tumor size 5 cm or less, and at least 3 other risk factors. The cumulated estimated 3-year rate of locoregional failure of the high-risk group was 26%, which was significantly higher than that of the low-risk group (7%, P < 0.001). The 3-year overall survival rates of the 2 groups were also significantly different (57% vs 86%, P < 0.001). CONCLUSIONS: Large tumor size (>5 cm), young age (≤40 years), nonsquamous histology, positive lymph node on magnetic resonance imaging, and advanced stage are all risk factors for locoregional failure after definitive platinum-based chemoradiation in patients with locally advanced cervical cancer. In the high-risk group, further clinical trials are warranted to improve the locoregional control rate.