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1.
J Clin Oncol ; 40(28): 3289-3300, 2022 10 01.
Article in English | MEDLINE | ID: mdl-35658479

ABSTRACT

PURPOSE: The status of p53 in a tumor can be inferred by next-generation sequencing (NGS) or by immunohistochemistry (IHC). We examined the association between p53 IHC and sequence and whether p53 IHC alone, or integrated with TP53 NGS, predicts the outcome. METHODS: From GOG-86P, a randomized phase II study of chemotherapy combined with either bevacizumab or temsirolimus in advanced endometrial cancer, 213 cases had p53 protein expression data measured by IHC and TP53 NGS data. An analysis was designed to integrate p53 expression by IHC with the presence or absence of a TP53 mutation. These variables were further correlated with progression-free survival (PFS) and overall survival (OS) in the chemotherapy plus bevacizumab arms versus the chemotherapy plus temsirolimus arm. RESULTS: In the analysis of p53 IHC, the most striking treatment effect favoring bevacizumab was in cases where p53 was overexpressed (PFS hazard ratio [HR]: 0.46, 95% CI, 0.26 to 0.88; OS HR: 0.31, 95% CI, 0.16 to 0.62). On integrated analysis, patients with TP53 missense mutations and p53 protein overexpression had a similar treatment effect on PFS (HR: 0.41, 95% CI, 0.22 to 0.83) and OS (HR: 0.28, 95% CI, 0.14 to 0.59) favoring bevacizumab plus chemotherapy relative to temsirolimus plus chemotherapy. Concordance between TP53 NGS and p53 IHC was 88%. Concordance was 92% when cases with TP53 mutations and POLE mutations or mismatch repair deficiency were removed. CONCLUSION: IHC for p53 alone or when integrated with sequencing for TP53 identifies a specific, high-risk tumor genotype/phenotype for which bevacizumab is particularly beneficial in improving outcomes when combined with chemotherapy.


Subject(s)
Endometrial Neoplasms , Tumor Suppressor Protein p53 , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Bevacizumab/adverse effects , Endometrial Neoplasms/drug therapy , Endometrial Neoplasms/genetics , Endometrial Neoplasms/pathology , Female , Humans , Immunohistochemistry , Mutation , Sirolimus/analogs & derivatives , Tumor Suppressor Protein p53/genetics
2.
Gynecol Oncol ; 164(3): 481-491, 2022 03.
Article in English | MEDLINE | ID: mdl-35063278

ABSTRACT

BACKGROUND: Blocking the PI3K/AKT/mTOR pathway decreases resistance to hormonal therapy in endometrial carcinoma (EC). OBJECTIVE: In this study, the aim was to assess the efficacy and tolerability of everolimus(E)/letrozole (L) or medroxyprogesterone acetate(M)/tamoxifen(T) in the treatment of metastatic EC. STUDY DESIGN: This single stage, open-label two arm randomized phase II trial accrued women with advanced/persistent/recurrent EC. Treatment with E (10 mg daily) and L (2.5 mg daily) or T (20 mg twice daily) and M (200 mg daily alternating weeks) was randomly assigned, and stratified by prior adjuvant therapy. Treatments were administered orally. Primary endpoint was response rate. RESULTS: Between February 2015 and April 2016, everolimus/letrozole (n = 37) or MT (n = 37) was assigned to 74 patients. Median follow-up was 37 months. Eight (22%; 95% CI 11% to 37%) patients responded on EL (one CR) and nine (25%; 95% CI 14% to 41%) patients responded on MT (three CRs). Median PFS for EL and MT arms was 6 months and 4 months, respectively. On EL, chemo-nave patients demonstrated a 28 month median PFS; prior chemotherapy patients had a 4-month median PFS. On MT, patients without prior therapy had a 5-month median PFS; those with prior chemotherapy demonstrated a 3-month PFS. Common grade 3 adverse events were anemia (9 [24%] patients EL vs 2 [6%] MT) and mucositis (2 [5%] vs 0 [0%]). Grade 3/4 thromboembolic events were observed with MT but not with EL (0 [0%] vs 4 [11%]). CONCLUSIONS: EL and MT demonstrated clinically meaningful efficacy in recurrent EC patients. The higher PFS observed in chemo-naïve patients is worthy of confirmation in future studies.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols , Endometrial Neoplasms , Neoplasm Recurrence, Local , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Drug Combinations , Endometrial Neoplasms/drug therapy , Endometrial Neoplasms/pathology , Estradiol , Estriol , Estrone , Everolimus/therapeutic use , Female , Humans , Letrozole/therapeutic use , Neoplasm Recurrence, Local/drug therapy , Neoplasm Recurrence, Local/pathology , Phosphatidylinositol 3-Kinases
3.
J Clin Oncol ; 40(9): 968-977, 2022 03 20.
Article in English | MEDLINE | ID: mdl-35007153

ABSTRACT

PURPOSE: This phase III randomized trial (NCT00954174) tested the null hypothesis that paclitaxel and carboplatin (PC) is inferior to paclitaxel and ifosfamide (PI) for treating uterine carcinosarcoma (UCS). PATIENTS AND METHODS: Adults with chemotherapy-naïve UCS or ovarian carcinosarcoma (OCS) were randomly assigned to PC or PI with 3-week cycles for 6-10 cycles. With 264 events in patients with UCS, the power for an overall survival (OS) hybrid noninferiority design was 80% for a null hazard ratio (HR) of 1.2 against a 13% greater death rate on PI with a type I error of 5% for a one-tailed test. RESULTS: The study enrolled 536 patients with UCS and 101 patients with OCS, with 449 and 90 eligible, respectively. Primary analysis was on patients with UCS, distributed as follows: 40% stage I, 6% stage II, 31% stage III, 15% stage IV, and 8% recurrent. Among eligible patients with UCS, PC was assigned to 228 and PI to 221. PC was not inferior to PI. The median OS was 37 versus 29 months (HR = 0.87; 90% CI, 0.70 to 1.075; P < .01 for noninferiority, P > .1 for superiority). The median progression-free survival was 16 versus 12 months (HR = 0.73; P = < 0.01 for noninferiority, P < .01 for superiority). Toxicities were similar, except that more patients in the PC arm had hematologic toxicity and more patients in the PI arm had confusion and genitourinary hemorrhage. Among 90 eligible patients with OCS, those in the PC arm had longer OS (30 v 25 months) and progression-free survival (15 v 10 months) than those in the PI arm, but with limited precision, these differences were not statistically significant. CONCLUSION: PC was not inferior to the active regimen PI and should be standard treatment for UCS.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols , Carcinosarcoma , Ovarian Neoplasms , Uterine Neoplasms , Adult , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Carboplatin/therapeutic use , Carcinosarcoma/drug therapy , Disease-Free Survival , Female , Humans , Ifosfamide/therapeutic use , Ovarian Neoplasms/drug therapy , Paclitaxel/therapeutic use , Uterine Neoplasms/drug therapy
4.
Appl Immunohistochem Mol Morphol ; 30(1): 27-35, 2022 01 01.
Article in English | MEDLINE | ID: mdl-34224438

ABSTRACT

We performed a pilot study in anticipation of using long-aged precut formalin-fixed paraffin-embedded tissue sections stored in real-world conditions for translational biomarker studies of topoisomerase 2A (TOP2A), Ki67, and human epidermal growth factor receptor 2 (HER2) in endometrial cancer. Formalin-fixed paraffin-embedded tissue blocks or unstained slides or both from GOG-0177 were collected centrally (1999-2000) and stored at room temperature. During 2004 to 2011 specimens were stored at 4°C. Matched pairs of stored slides and freshly cut slides from stored blocks were analyzed for TOP2A (KiS1), Ki67 (MIB1), and HER2 (HercepTest) proteins. To assess DNA stability (HER2 PathVision), fluorescence in situ hybridization (FISH) was repeated on stored slides from 21 cases previously shown to be HER2 amplified. Immunohistochemistry (IHC) staining intensity and extent, mean FISH copies/cell, and copy number ratios were compared using the κ statistic for concordance or signed rank test for differences in old cut versus new cut slides. IHC results reflected some protein degradation in stored slides. The proportion of cells with TOP2A staining was lower on average by 12% in older sections (P=0.03). The proportion of Ki67-positive cells was lower in stored slides by an average of 10% (P<0.01). Too few cases in the IHC cohort were FISH positive for any conclusions. HER2 amplification by FISH was unaffected by slide storage. We conclude that use of aged stored slides for proliferation markers TOP2A and Ki67 is feasible but may modestly underestimate true values in endometrial cancer. Pilot studies for particular storage conditions/durations/antigens to be used in translational studies are warranted.


Subject(s)
Breast Neoplasms , Endometrial Neoplasms , Aged , Endometrial Neoplasms/diagnosis , Female , Humans , Immunohistochemistry , In Situ Hybridization, Fluorescence , Pilot Projects , Receptor, ErbB-2/metabolism
5.
Gynecol Oncol ; 164(2): 428-436, 2022 02.
Article in English | MEDLINE | ID: mdl-34903380

ABSTRACT

INTRODUCTION: Chemotherapy plus radiation (Cis-RT + CP) did not demonstrate superiority in prolonging relapse-free survival compared to chemotherapy alone in patients with stage III or IVA endometrial carcinoma. The impact of treatment on quality of life (QOL), neurotoxicity (NTX) and psychometric properties of the gastrointestinal (GI) symptoms subscale during treatment and up to 1 year are described herein. METHODS: QOL assessments were scheduled at baseline, 6 weeks (post completion of RT (Cis-RT + CP) or prior to cycle 3 (CP)), then 18 weeks (end of treatment) and 70 weeks (1 year after the end of treatment) after starting treatment. QOL instruments included the FACT-En TOI, FACT/GOG-neurotoxicity (Ntx) subscale (short), and the gastrointestinal (GI) symptoms subscale. RESULTS: At the end of treatment, patients receiving Cis-RT + CP reported a statistically significant decreased QOL when compared to CP. The decline in QOL was reflected in physical well-being, functional well-being, and endometrial cancer specific concerns, but the minimally important differences (MID) were not considered clinically meaningful. Patients in both groups reported increased chemotherapy-induced Ntx symptoms with the CP group having worse scores and reaching peak symptoms at the time of chemotherapy completion. Patients on Cis-RT + CP reported statistically significantly worse GI symptoms after radiation therapy compared to patients on CP, this occurred across assessment intervals, though the MID was not meaningful. Psychometric evaluations indicated that the GI symptom scale is reliable, valid, and responsive to change. CONCLUSIONS: PROs indicate that the chemoradiotherapy group experienced worse HRQoL and GI toxicity compared to patients randomized to chemotherapy alone for locally advanced endometrial cancer though based on the MID, these were not clinically meaningful differences. The GI symptom subscale was a reliable and valid scale that has value for future trials. TRIAL REGISTRATION: NCT00942357.


Subject(s)
Chemoradiotherapy, Adjuvant , Chemotherapy, Adjuvant , Endometrial Neoplasms/therapy , Gastrointestinal Diseases/physiopathology , Peripheral Nervous System Diseases/physiopathology , Quality of Life , Carboplatin/administration & dosage , Cisplatin/administration & dosage , Disease-Free Survival , Endometrial Neoplasms/pathology , Female , Functional Status , Gastrointestinal Diseases/epidemiology , Humans , Neoplasm Staging , Paclitaxel/administration & dosage , Patient Reported Outcome Measures , Peripheral Nervous System Diseases/chemically induced , Peripheral Nervous System Diseases/epidemiology
6.
Clin Cancer Res ; 27(10): 2734-2741, 2021 05 15.
Article in English | MEDLINE | ID: mdl-33766814

ABSTRACT

PURPOSE: This surgical window of opportunity (window) study assessed the short-term effect of medroxyprogesterone acetate (MPA) alone versus MPA plus the histone deacetylase (HDAC) inhibitor entinostat on regulation of progesterone receptor (PR) in women with newly diagnosed endometrioid endometrial adenocarcinoma. PATIENTS AND METHODS: This multisite, randomized, open-label surgical window study treated women intramuscularly on day 1 with 400 mg MPA. Entinostat given 5 mg by mouth on days 1, 8, and 15 was randomly assigned with equal probability. Surgery followed on days 21-24. Pretreatment and posttreatment tissue was assessed for PR H-scores, Ki-67 levels, and histologic response. RESULTS: Fifty patients were accrued in 4 months; 22 and 20 participants had PR evaluable pretreatment and posttreatment slides in the MPA and MPA/entinostat arms, respectively. Median posttreatment PR H-scores were significantly lower than pretreatment H-scores in both arms but did not differ significantly (MPA: 247 vs. 27, MPA/entinostat 260 vs. 23, respectively, P = 0.87). Decreased Ki-67 was shown in 90% treated with MPA/entinostat compared with 68% treated with MPA alone (P = 0.13). Median PR H-score decreases were larger when Ki-67 was decreased (208) versus not decreased (45). The decrease in PR pretreatment versus posttreatment was associated with loss of Ki-67 nuclear staining, consistent with reduced cellular proliferation (P < 0.008). CONCLUSIONS: This surgical window trial rapidly accrued in a multisite setting and evaluated PR as its primary endpoint and Ki-67 as secondary endpoint. Despite no immediate effect of entinostat on PR in this short-term study, lessons learned can inform future window and treatment trials.


Subject(s)
Antineoplastic Agents, Hormonal/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Endometrial Neoplasms/therapy , Hysterectomy , Medroxyprogesterone Acetate/therapeutic use , Adult , Aged , Aged, 80 and over , Antineoplastic Agents, Hormonal/administration & dosage , Antineoplastic Agents, Hormonal/adverse effects , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Benzamides/administration & dosage , Clinical Decision-Making , Disease Management , Endometrial Neoplasms/diagnosis , Endometrial Neoplasms/etiology , Female , Humans , Hysterectomy/methods , Medroxyprogesterone Acetate/administration & dosage , Medroxyprogesterone Acetate/adverse effects , Middle Aged , Pyridines/administration & dosage , Time-to-Treatment , Treatment Outcome
7.
Gynecol Oncol ; 161(1): 113-121, 2021 04.
Article in English | MEDLINE | ID: mdl-33541735

ABSTRACT

BACKGROUND: Successfully combining targeted agents with chemotherapy is an important future goal for cancer therapy. However, an improvement in patient outcomes requires an enhanced understanding of the tumor biomarkers that predict for drug sensitivity. NRG Oncology/Gynecologic Oncology Group (GOG) Study GOG-86P was one of the first attempts to combine targeted agents (bevacizumab or temsirolimus) with chemotherapy in patients with advanced endometrial cancer. Herein we performed exploratory analyses to examine the relationship between mutations in TP53, the most commonly mutated gene in cancer, with outcomes on GOG-86P. METHODS: TP53 mutational status was determined and correlated with progression-free survival (PFS) and overall survival (OS) on GOG-86P. RESULTS: Mutations in TP53 were associated with improved PFS and OS for patients that received bevacizumab as compared to temsirolimus (PFS: HR 0.48, 95% CI 0.31, 0.75; OS: HR: 0.61, 95% CI 0.38, 0.98). By contrast, there was no statistically significant difference in PFS or OS between arms for cases with WT TP53. CONCLUSIONS: This exploratory study suggests that combining chemotherapy with bevacizumab, but not temsirolimus, may enhance PFS and OS for patients whose tumors harbor mutant p53. These data set the stage for larger clinical studies evaluating the potential of TP53 mutational status as a biomarker to guide choice of treatment for endometrial cancer patients. Clintrials.gov: NCT00977574.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Endometrial Neoplasms/drug therapy , Endometrial Neoplasms/genetics , Mutation , Neoplasm Recurrence, Local/drug therapy , Neoplasm Recurrence, Local/genetics , Tumor Suppressor Protein p53/genetics , Angiogenesis Inhibitors/administration & dosage , Bevacizumab/administration & dosage , Carboplatin/administration & dosage , Clinical Trials, Phase II as Topic , Endometrial Neoplasms/pathology , Epothilones/administration & dosage , Female , Genes, p53 , Humans , Neoplasm Recurrence, Local/pathology , Neoplasm Staging , Paclitaxel/administration & dosage , Progression-Free Survival , Randomized Controlled Trials as Topic , Sirolimus/administration & dosage , Sirolimus/analogs & derivatives , Survival Rate , Treatment Outcome
8.
J Clin Oncol ; 38(33): 3841-3850, 2020 11 20.
Article in English | MEDLINE | ID: mdl-33078978

ABSTRACT

PURPOSE: Limitations of the paclitaxel-doxorubicin-cisplatin (TAP) regimen in the treatment of endometrial cancer include tolerability and cumbersome scheduling. The Gynecologic Oncology Group studied carboplatin plus paclitaxel (TC) as a noninferior alternative to TAP. METHODS: GOG0209 was a phase III, randomized, noninferiority, open-label trial. Inclusion criteria were stage III, stage IV, and recurrent endometrial cancers; performance status 0-2; and adequate renal, hepatic, and marrow function. Prior radiotherapy and/or hormonal therapy were permitted, but chemotherapy, including radiosensitization, was not. Patients were treated with doxorubicin 45 mg/m2 and cisplatin 50 mg/m2 (day 1), followed by paclitaxel 160 mg/m2 (day 2) with granulocyte colony-stimulating factor or paclitaxel 175 mg/m2 and carboplatin area under the curve 6 (day 1) every 21 days for seven cycles. The primary endpoint was overall survival (OS; modified intention to treat). Progression-free survival (PFS), health-related quality of life (HRQoL), and toxicity were secondary endpoints. RESULTS: From 2003 to 2009, 1,381 women were enrolled. Noninferiority of TC to TAP was concluded for OS (median, 37 v 41 months, respectively; hazard ratio [HR], 1.002; 90% CI, 0.9 to 1.12), and PFS (median, 13 v 14 months; HR, 1.032; 90% CI, 0.93 to 1.15). Neutropenic fever was reported in 7% of patients receiving TAP and 6% of those receiving TC. Grade > 2 sensory neuropathy was recorded in 26% of patients receiving TAP and 20% receiving TC (P = .40). More grade ≥ 3 thrombocytopenia (23% v 12%), vomiting (7% v 4%), diarrhea (6% v 2%), and metabolic (14% v 8%) toxicities were reported with TAP. Neutropenia (52% v 80%) was more common with TC. Small HRQoL differences favored TC. CONCLUSION: With demonstrated noninferiority to TAP, TC is the global first-line standard for advanced endometrial cancer.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Endometrial Neoplasms/drug therapy , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Carboplatin/administration & dosage , Carboplatin/adverse effects , Cisplatin/administration & dosage , Cisplatin/adverse effects , Endometrial Neoplasms/mortality , Female , Filgrastim/administration & dosage , Filgrastim/adverse effects , Humans , Middle Aged , Paclitaxel/administration & dosage , Paclitaxel/adverse effects , Paclitaxel/therapeutic use , Progression-Free Survival , Quality of Life , Treatment Outcome
9.
Support Care Cancer ; 27(2): 531-538, 2019 Feb.
Article in English | MEDLINE | ID: mdl-30003341

ABSTRACT

PURPOSE: Social determinants may influence health-related quality of life (HRQOL) among women with ovarian cancer, potentially creating disparities in clinical outcomes. We investigated the relationship between HRQOL and social determinants of health, including travel distance to access cancer care and health insurance type, among women participating in a randomized trial of primary adjuvant treatment for advanced ovarian cancer. METHODS: The Functional Assessment of Cancer Therapy-Ovarian (FACT-O) questionnaire captured HRQOL (physical well-being, functional well-being, ovarian-specific, and trial outcome index [TOI]) prior to chemotherapy (baseline), during the trial, and 84 weeks after initiation of chemotherapy for women with advanced epithelial ovarian, primary peritoneal, or fallopian tube cancer. We constructed bivariate and multivariable linear mixed effects models examining the associations of social determinants of health (individual-level and contextual factors) with HRQOL scores at 84 weeks, clustering participants (n = 993) within treatment centers, and Census regions and controlling for baseline HRQOL. RESULTS: Most individual-level (race, age, cancer stage, adverse events) and contextual (travel distance to treatment center, community socioeconomic status) factors were not statistically significantly associated with HRQOL. Compared to participants with private health insurance, other participants had lower mean HRQOL (physical well-being: public insurance, - 1.00 (standard error[SE] = 0.49) points, uninsured, - 1.93 (SE = 0.63) points; functional well-being: public, - 1.29 (SE = 0.59), uninsured, - 1.98 (SE = 0.76); ovarian cancer-specific: public, - 1.60 (SE = 0.59), uninsured, - 1.66 (SE = 0.75); TOI: public, - 3.81 (SE = 1.46), uninsured, - 5.51 (SE = 1.86); all p < .05). CONCLUSIONS: Private health insurance was associated with improved HRQOL at the completion of treatment for advanced stage ovarian cancer. Implications of health insurance on HRQOL should be further investigated, particularly among women with ovarian cancer who receive standard of care treatment.


Subject(s)
Health Status Disparities , Ovarian Neoplasms/epidemiology , Ovarian Neoplasms/therapy , Quality of Life , Social Determinants of Health , Adult , Aged , Aged, 80 and over , Carcinoma, Ovarian Epithelial/economics , Carcinoma, Ovarian Epithelial/epidemiology , Carcinoma, Ovarian Epithelial/pathology , Carcinoma, Ovarian Epithelial/therapy , Disease Progression , Female , Health Services Accessibility/economics , Health Services Accessibility/statistics & numerical data , Humans , Individuality , Insurance, Health/statistics & numerical data , Middle Aged , Neoplasm Staging , Ovarian Neoplasms/economics , Ovarian Neoplasms/pathology , Social Class , Social Determinants of Health/economics , Social Determinants of Health/statistics & numerical data , Surveys and Questionnaires , Young Adult
10.
Gynecol Oncol ; 145(3): 519-525, 2017 06.
Article in English | MEDLINE | ID: mdl-28392124

ABSTRACT

OBJECTIVE: To report clinical and pathologic relationships with disease spread in endometrial cancer patients. METHODS: Surgical candidates with uterine cancer (adenocarcinoma or carcinosarcoma) who were eligible to participate in a surgical pathological study to create a clinically annotated tissue biorepository to support translational and clinical research studies. All patients were to undergo a hysterectomy, bilateral salpingo-oophorectomy, and bilateral pelvic and para-aortic lymphadenectomy. From 2003-2007, open eligibility enrollment was conducted, and from 2007-2011, eligibility was restricted to enrich underrepresented patients or those at high risk. RESULTS: This report details clinical pathological relationships associated with extra uterine disease spread of 5866 evaluable patients including those with endometrioid histology as well as papillary serous, clear cell and carcinosarcoma histologies. Review of unrestricted enrollment was constructed in an effort to capture a cross-section population representative of endometrial cancers seen by the GOG participating members. Evaluation of this group of patients suggested the more natural incidence of different surgical pathological findings as well as demographic information. The addition of 2151 patients enrolled during the restricted time interval allowed a total of 1630 poor histotype patients available for further analysis. As expected, endometrioid (E) cancers represented the largest enrollment and particularly E grade 1 and 2 (G1 and 2) were more frequently confined to the uterus. Grade 3 (G3) endometrioid cancers as well as the poor histotype (papillary serous, clear cell and carcinosarcoma) had a much greater propensity for extant disease. CONCLUSIONS: This study confirms the previously reported surgical pathological findings for endometrioid cancers but in addition, using a large database of papillary serous, clear cell and carcinosarcoma, surgical pathological findings substantiate the categorization of poor histotypes for these cancers.


Subject(s)
Carcinoma, Endometrioid/pathology , Carcinoma, Endometrioid/surgery , Endometrial Neoplasms/pathology , Endometrial Neoplasms/surgery , Adult , Aged , Aged, 80 and over , Carcinoma, Endometrioid/epidemiology , Carcinoma, Endometrioid/ethnology , Cross-Sectional Studies , Endometrial Neoplasms/epidemiology , Endometrial Neoplasms/ethnology , Female , Humans , Middle Aged , Neoplasm Grading , Neoplasm Staging , United States/epidemiology
11.
Cancer ; 123(7): 1144-1155, 2017 04 01.
Article in English | MEDLINE | ID: mdl-27926776

ABSTRACT

BACKGROUND: Synuclein-γ (SNCG) is highly expressed in advanced solid tumors, including uterine serous carcinoma (USC). The objective of the current study was to determine whether SNCG protein was associated with survival and clinical covariates using the largest existing collection of USCs from the Gynecologic Oncology Group (GOG-8023). METHODS: High-density tissue microarrays (TMAs) of tumor tissues from 313 patients with USC were stained by immunohistochemistry for SNCG, p53, p16, FOLR1, pERK, pAKT, ER, PR, and HER2/neu. Associations of SNCG and other tumor markers with overall and progression-free survival were assessed using log-rank tests and Cox proportional-hazards models, which also were adjusted for age, race, and stage. RESULTS: The overall survival at 5 years was 46% for women with high SNCG expression and 62% for those with low SNCG expression (log-rank P = .021; hazard ratio [HR], 1.31; 95% confidence interval [CI], 0.91-1.9 in adjusted Cox model). The progression-free survival rate at 5 years was worse for women who had high SNCG expression, at 40%, compared with 56% for those who had low SNCG expression (log-rank P = .0081; HR, 1.36; 95% CI, 0.96-1.92 in adjusted Cox model). High levels of both p53 and p16 were significantly associated with worse overall survival (p53: HR, 4.20 [95% CI, 1.54-11.45]; p16: HR, 1.95 [95% CI, 1.01-3.75]) and progression-free survival (p53: HR, 2.16 [95% CI, 1.09-4.27]; p16: HR, 1.53 [95% CI, 0.87-2.69]) compared with low levels. CONCLUSIONS: This largest collection of USCs to date demonstrates that SNCG was associated with poor survival in univariate analyses. SNCG does not predict survival outcome independent of p53 and p16 in models that jointly consider multiple markers. Cancer 2017;123:1144-1155. © 2016 American Cancer Society.


Subject(s)
Biomarkers, Tumor , Cystadenocarcinoma, Serous/metabolism , Cystadenocarcinoma, Serous/mortality , Uterine Neoplasms/metabolism , Uterine Neoplasms/mortality , gamma-Synuclein/metabolism , Aged , Aged, 80 and over , Cystadenocarcinoma, Serous/pathology , Cystadenocarcinoma, Serous/therapy , Female , Gene Expression , Humans , Immunohistochemistry , Kaplan-Meier Estimate , Middle Aged , Neoplasm Metastasis , Neoplasm Staging , Prognosis , Uterine Neoplasms/pathology , Uterine Neoplasms/therapy , gamma-Synuclein/genetics
12.
Obstet Gynecol ; 128(3): 535-542, 2016 Sep.
Article in English | MEDLINE | ID: mdl-27500329

ABSTRACT

OBJECTIVE: To evaluate the efficacy and safety of second uterine curettage in lieu of chemotherapy for patients with low-risk, nonmetastatic gestational trophoblastic neoplasia (GTN) and to evaluate whether response to second curettage is independent of patient age, World Health Organization (WHO) risk score, registration human chorionic gonadotropin (hCG) level, lesion size, and depth of myometrial invasion measured on ultrasound examination. METHODS: This was a cooperative group multicenter prospective phase II study. Prestudy testing included quantitative hCG level, pelvic ultrasonography, and chest radiography. Patients were categorized according to WHO risk scoring criteria (low risk with a score of 0-6). RESULTS: Sixty-four women with newly diagnosed low-risk, nonmetastatic GTN were enrolled. Four patients were excluded. Twenty-four patients (40%) (lower 95% confidence limit 27.6%) were cured after second curettage. An additional two patients (3%) achieved a complete response but did not complete follow-up. Overall, 26 of 60 patients were able to avoid chemotherapy. Surgical failure was observed in 34 women (59%) and was more common in women 19 years old or younger or 40 years old or older. One case of grade 1 uterine perforation was successfully managed by observation. Four grade 1 and one grade 3 uterine hemorrhages were reported. New metastatic disease (lung) was identified in one of these women after second curettage. In three patients (surgical failures), the second curettage pathology was placental site trophoblastic tumor, and it was placental nodule in one additional patient. CONCLUSION: Second uterine curettage as initial treatment for low-risk, nonmetastatic GTN cures 40% of patients without significant morbidity. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, https://clinicaltrials.gov/, NCT00521118.


Subject(s)
Curettage , Gestational Trophoblastic Disease , Reoperation , Adolescent , Adult , Chorionic Gonadotropin/analysis , Curettage/adverse effects , Curettage/methods , Curettage/statistics & numerical data , Female , Gestational Trophoblastic Disease/blood , Gestational Trophoblastic Disease/diagnosis , Gestational Trophoblastic Disease/epidemiology , Gestational Trophoblastic Disease/pathology , Humans , Middle Aged , Neoplasm Invasiveness , Neoplasm Staging , Pregnancy , Prognosis , Prospective Studies , Reoperation/methods , Reoperation/statistics & numerical data , Risk Assessment , Risk Factors , Ultrasonography/methods , United States/epidemiology
13.
Gynecol Oncol ; 141(1): 43-8, 2016 Apr.
Article in English | MEDLINE | ID: mdl-27016228

ABSTRACT

OBJECTIVE: Rapamycin analogs have reproducible but modest efficacy in endometrial cancer (EC). Identification of molecular biomarkers that predict benefit could guide clinical development. METHODS: Fixed primary tissue and whole blood were collected prospectively from patients enrolled on GOG 248. DNA was isolated from macro-dissected tumors and blood; next-generation sequence analysis was performed on a panel of cancer related genes. Associations between clinical outcomes [response rate (RR) 20%; progression-free survival (PFS) median 4.9months] and mutations (PTEN, PIK3CA, PIK3R1, KRAS, CTNNB1, AKT1, TSC1, TSC2, NF1, FBXW7) were explored. RESULTS: Sequencing data was obtained from tumors of 55 of the 73 enrolled pts. Mutation rates were consistent with published reports: mutations in PTEN (45%), PIK3CA (29%), PIK3R1 (24%), K-RAS (16%), CTNNB1 (18%) were common and mutations in AKT1 (4%), TSC1 (2%), TSC2 (2%), NF1 (9%) and FBXW7 (4%) were less common. Increased PFS (HR 0.16; 95% CI 0.01-0.78) and RR (response difference 0.83; 95% CI 0.03-0.99) were noted for AKT1 mutation. An increase in PFS (HR 0.46; 95% CI 0.20-0.97) but not RR (response difference 0.00, 95% CI -0.34-0.34) was identified for CTNNB1 mutation. Both patients with TSC mutations had an objective response. There were no statistically significant associations between mutations in PIK3CA, PTEN, PIK3R1, or KRAS and PFS or RR. CONCLUSIONS: Mutations in AKT1, TSC1 and TSC2 are rare, but may predict clinical benefit from temsirolimus. CTNNB1 mutations were associated with longer PFS on temsirolimus.


Subject(s)
Endometrial Neoplasms/genetics , Megestrol Acetate/administration & dosage , Mutation , Sirolimus/analogs & derivatives , Tamoxifen/administration & dosage , Class I Phosphatidylinositol 3-Kinases , Endometrial Neoplasms/drug therapy , Endometrial Neoplasms/mortality , Female , Humans , PTEN Phosphohydrolase/genetics , Phosphatidylinositol 3-Kinases/genetics , Prospective Studies , Proto-Oncogene Proteins c-akt/genetics , Sirolimus/administration & dosage , Sirolimus/therapeutic use , Tuberous Sclerosis Complex 1 Protein , Tumor Suppressor Proteins/genetics
14.
Gynecol Oncol ; 138(1): 24-9, 2015 Jul.
Article in English | MEDLINE | ID: mdl-25888978

ABSTRACT

OBJECTIVE: This two-stage phase II study assessed activity of single agent dalantercept in patients with recurrent/persistent endometrial carcinoma (EMC). METHODS: Eligible patients had persistent/recurrent EMC after 1-2 prior cytotoxic regimens, measurable disease (RECIST 1.1), and GOG performance≤2. Dalantercept 1.2mg/kg subcutaneous was administered once every 3weeks until disease progression (PD)/development of prohibitory toxicity. Primary objectives were to estimate the proportion of patients with persistent/recurrent EMC, who survive progression-free without receiving non-protocol therapy (TPFS) for at least 6months and to estimate the proportion having objective tumor response. RESULTS: All 28 enrolled patients were eligible and evaluable. Median age: 62years. Most common histologies: 32% Grade 1/2 endometrioid and 54% serous tumors. Prior treatment: 1 or 2 regimens in 82% and 18% of patients, respectively. Eighteen patients received prior radiation therapy. Patients received 1-12 cycles of dalantercept, and 46% of patients received ≤2cycles. The most common adverse events (AE) were fatigue, anemia, constipation and peripheral edema. Grade 3/4 AEs occurred in 39% and 4% of patients. One grade 5 gastric hemorrhage in a patient with a history of radiation fibrosis/small bowel obstruction was deemed possibly dalantercept-related. All patients are off study: 86% for PD. No ORs were observed; 57% had stable disease and 11% had TPFS>6 mos. Median progression-free and overall survival: 2.1months (90% CI: 1.4-3.2) and 14.5months (90% CI: 7.0-17.5), respectively. CONCLUSIONS: Dalantercept has insufficient single agent activity in recurrent EMC to warrant further investigation at this dose level and schedule.


Subject(s)
Activin Receptors, Type II/therapeutic use , Endometrial Neoplasms/drug therapy , Immunoglobulin Fc Fragments/therapeutic use , Recombinant Fusion Proteins/therapeutic use , Activin Receptors, Type II/adverse effects , Adult , Aged , Disease-Free Survival , Endometrial Neoplasms/blood supply , Endometrial Neoplasms/pathology , Female , Humans , Immunoglobulin Fc Fragments/adverse effects , Middle Aged , Neoplasm Recurrence, Local/blood supply , Neoplasm Recurrence, Local/drug therapy , Neoplasm Recurrence, Local/pathology , Neovascularization, Pathologic/drug therapy , Recombinant Fusion Proteins/adverse effects
15.
Gynecol Oncol ; 132(3): 585-92, 2014 Mar.
Article in English | MEDLINE | ID: mdl-24456823

ABSTRACT

OBJECTIVES: To determine the response, toxicities, and progression free survival of a regimen of temsirolimus with or without hormonal therapy in the treatment of advanced, or recurrent endometrial carcinoma. BACKGROUND: Preclinical evidence suggested that blockade of the PI3K/AKT/mTOR pathway might overcome resistance to hormonal therapy. METHODS: We performed a randomized phase II trial of intravenous temsirolimus 25mg weekly versus the combination of weekly temsirolimus with a regimen of megestrol acetate 80 mg bid for three weeks alternating with tamoxifen 20mg bid for three weeks in women with recurrent or metastatic endometrial carcinoma. RESULTS: There were 71 eligible patients who received at least one dose of therapy with 21 of these treated on the combination arm which was closed early because of an excess of venous thrombosis, with 5 episodes of deep venous thrombosis (DVT) and 2 pulmonary emboli. There were three responses observed in that arm (14%). A total of 50 eligible patients were treated on the single agent arm with 3 episodes of DVT and 11 responses (22%). Response rates were similar in patients with prior chemotherapy (7 of 29; 24%) and those with no prior chemotherapy (4 of 21; 19%). Two of four patients with clear cell carcinoma responded. CONCLUSIONS: Adding the combination of megestrol acetate and tamoxifen to temsirolimus therapy did not enhance activity and the combination was associated with an excess of venous thrombosis. Temsirolimus activity was preserved in patients with prior adjuvant chemotherapy.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Endometrial Neoplasms/drug therapy , Sirolimus/analogs & derivatives , Adult , Aged , Aged, 80 and over , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Disease-Free Survival , Drug Administration Schedule , Endometrial Neoplasms/metabolism , Endometrial Neoplasms/pathology , Female , Humans , Immunohistochemistry , Megestrol Acetate/administration & dosage , Megestrol Acetate/adverse effects , Middle Aged , Neoplasm Metastasis , Neoplasm Recurrence, Local/drug therapy , Neoplasm Recurrence, Local/metabolism , Neoplasm Recurrence, Local/pathology , Sirolimus/administration & dosage , Sirolimus/adverse effects , Sirolimus/therapeutic use , Tamoxifen/administration & dosage , Tamoxifen/adverse effects
16.
Gynecol Oncol ; 125(1): 87-93, 2012 Apr.
Article in English | MEDLINE | ID: mdl-22155678

ABSTRACT

OBJECTIVE: To determine whether the number of positive pelvic nodes (PPN), cervical stromal involvement (CSI), and/or lymphovascular space involvement (LVSI) were prognostic factors among women with advanced endometrial carcinoma treated with adriamycin plus cisplatin (AP) or whole abdominal irradiation (WAI). METHODS: Data were abstracted from records of patients treated with adjuvant WAI or AP in a GOG randomized trial. Cox proportional hazards models were used to estimate the association of CSI and PPN with differences in PFS and OS while adjusting for treatment and previously studied factors. RESULTS: WAI was randomly allocated to 202 and AP to 194 eligible patients. CSI (n=93 total) was associated with a 44% increase in risk of progression and a 33% increase in risk of death. There was a trend for increasing number PPN being associated with a 7% per positive node increase in risk of progression/death. For CSI, the estimated unadjusted treatment hazard ratios (HRs) were: PFS 0.85 (0.53, 1.38); OS 0.81 (0.50, 1.33). For metastatic disease limited to a single PPN (n=25), the unadjusted HRs were: PFS 0.96 (0.34, 2.74); OS 0.73 (0.24, 2.18). The test of homogeneity of treatment effect (ie., AP vs WAI) across subgroups (CSI, number of positive pelvic nodes) was not statistically significant for either endpoint, thus supporting the superiority of chemotherapy as reported in the original manuscript. CONCLUSIONS: The presence of CSI and increasing number of PPN were associated with poor prognosis. On average, patients with CSI experienced improved PFS and OS when treated with AP relative to WAI.


Subject(s)
Cervix Uteri/pathology , Endometrial Neoplasms/pathology , Lymph Nodes/pathology , Antineoplastic Agents/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Chemotherapy, Adjuvant , Cisplatin/administration & dosage , Clinical Trials, Phase III as Topic , Doxorubicin/administration & dosage , Endometrial Neoplasms/mortality , Endometrial Neoplasms/therapy , Female , Gynecologic Surgical Procedures , Humans , Lymphatic Metastasis , Neoplasm Invasiveness , Pelvis , Prognosis , Radiotherapy, Adjuvant , Randomized Controlled Trials as Topic , Retrospective Studies , Survival Analysis , Treatment Outcome
17.
J Clin Oncol ; 28(16): 2727-31, 2010 Jun 01.
Article in English | MEDLINE | ID: mdl-20421537

ABSTRACT

PURPOSE: Platinum and taxane compounds have demonstrated activity in uterine carcinosarcoma (malignant mixed Mullerian tumor). Ifosfamide plus paclitaxel is the regimen with established superiority based on a randomized phase III trial conducted through the Gynecologic Oncology Group. However, the toxicity, multiday schedule, and limited activity of this regimen support further development of novel regimens. Our primary objective was to estimate the antitumor activity and toxicity of paclitaxel plus carboplatin in patients with uterine carcinosarcomas. PATIENTS AND METHODS: Eligible patients had advanced stage (III or IV), persistent or recurrent measurable disease, and no prior chemotherapy. Patients received paclitaxel at 175 mg/m(2) intravenously (IV) over 3 hours plus carboplatin (area under the serum concentration-time curve = 6) IV over 30 minutes every 3 weeks until disease progression or until adverse effects occurred. Common Terminology Criteria for Adverse Events v3.0 was used to grade adverse events. RESULTS: Fifty-five patients were entered onto the study with nine being excluded from analysis, leaving 46 evaluable for analysis. Treatment was well tolerated with expected hematologic toxicity and minimal nonhematologic grade 4 toxicity (one cardiovascular and two pain) with 59% of patients completing six or more cycles of chemotherapy. The proportions of patients with confirmed complete and partial responses were 13% and 41%, respectively, resulting in a total overall response rate of 54% (95% CI, 37% to 67%). CONCLUSION: Paclitaxel plus carboplatin demonstrates antitumor activity against uterine carcinosarcoma with acceptable toxicity and warrants further evaluation in phase III randomized trials.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Carcinosarcoma/drug therapy , Carcinosarcoma/mortality , Uterine Neoplasms/drug therapy , Uterine Neoplasms/mortality , Aged , Aged, 80 and over , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Biopsy, Needle , Carboplatin/administration & dosage , Carboplatin/adverse effects , Carcinosarcoma/pathology , Confidence Intervals , Disease-Free Survival , Dose-Response Relationship, Drug , Drug Administration Schedule , Female , Humans , Immunohistochemistry , Infusions, Intravenous , Kaplan-Meier Estimate , Maximum Tolerated Dose , Middle Aged , Neoplasm Invasiveness/pathology , Neoplasm Staging , Paclitaxel/administration & dosage , Paclitaxel/adverse effects , Probability , Prognosis , Program Evaluation , Risk Assessment , Survival Analysis , Treatment Outcome , Uterine Neoplasms/pathology
18.
Gynecol Oncol ; 106(1): 16-22, 2007 Jul.
Article in English | MEDLINE | ID: mdl-17574073

ABSTRACT

OBJECTIVES: To explore associations between histology and outcome in advanced or recurrent endometrial cancer patients participating in Gynecologic Oncology Group chemotherapy trials. METHODS: Age, race, performance status, histologic type (serous=S; clear cell=CC; endometrioid=E), disease stage, and prior radiation were evaluated using various analytic methods to evaluate the probability of response and identify independent predictors of progression-free survival (PFS) and overall survival (OS). RESULTS: Single agent or combination chemotherapy regimens including doxorubicin (A) (12%), doxorubicin/cisplatin (AP) (63%), doxorubicin/paclitaxel (AT) (13%), and paclitaxel/doxorubicin/cisplatin (TAP) (11%) were used among 1203 patients treated on 4 randomized clinical trials. Breakdown of disease stage was 7.8% stage III, 22.8% stage IV, and 69.4% recurrent disease. Histologic distribution was 18% S, 3.7% CC, 8.5% mixed, 51.7% E and 18.1% other. More S/CC patients enrolled on trials with advanced stage (III-IV) disease (as opposed to recurrent disease) compared to E patients (45% vs. 24%, p<0.05). Overall response rate was 42% (E=44%, S=44%, CC=32%). Histologic type was not an independent predictor of response. Independent predictors of PFS included race, performance status, disease stage, and CC histology. Histology was also an independent predictor of OS; the relative hazard ratio for S histology was 1.2 (1.02-1.4; p=0.03), and for CC was 1.51 (1.1-2.07; p=0.01). CONCLUSION: In patients with advanced/recurrent endometrial cancer treated with A, P and/or T, response was not associated with histology. This exploratory analysis does not support exclusion of S tumors in future trials. Poorer PFS and OS were observed in CC compared to other types, but a lack of benefit from chemotherapy was not shown, and as this histology represents such a small fraction, it does not seem feasible to have separate chemotherapy trials for CC.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Doxorubicin/therapeutic use , Endometrial Neoplasms/drug therapy , Endometrial Neoplasms/pathology , Neoplasm Recurrence, Local/drug therapy , Neoplasm Recurrence, Local/pathology , Adult , Aged , Aged, 80 and over , Cisplatin/administration & dosage , Disease-Free Survival , Doxorubicin/administration & dosage , Female , Humans , Middle Aged , Neoplasm Staging , Paclitaxel/administration & dosage , Treatment Outcome
19.
Cancer ; 107(6): 1280-6, 2006 Sep 15.
Article in English | MEDLINE | ID: mdl-16900525

ABSTRACT

BACKGROUND: The purpose of the study was to determine the activity and toxicity of pulse dactinomycin as salvage treatment of patients with low-risk gestational trophoblastic neoplasia (GTN) who failed methotrexate therapy. METHODS: Eligible patients had persistent/recurrent low-risk GTN defined by changes in serum human chorionic gonadotropin (hCG) levels (<10% fall over 3 consecutive weekly titers, >20% rise over the previous value, or a rise after attaining institutional normal [>5 mu/mL]); World Health Organization (WHO) score 2-6; Gynecologic Oncology Group (GOG) performance status 0-1; and previous treatment restricted to methotrexate. Dactinomycin administration was 1.25 mg/m2 intravenous (i.v.) every 2 weeks until documented complete response (CR) or treatment failure. CR was defined as an institutional normal serum hCG level sustained for >or=4 consecutive weeks; treatment failure was a <10% fall (3 assays over 4 weeks) or >20% rise (over previous value) in hCG serum level. Levels were monitored biweekly x 8 weeks beyond the first normal value, then monthly x 10. RESULTS: Five of 44 enrolled patients were ineligible due to choriocarcinoma and normal pretreatment serum hCG level (2 each), no history of methotrexate (1), and 1 patient with documented phantom hCG syndrome was unevaluable. In all, 28 of 38 (74%) evaluable patients attained CR. The median number of cycles was 4 (range, 2-10). Severe toxicity was minimal, causing no patient to discontinue therapy. All treatment failures achieved a CR after receiving subsequent chemotherapy; 3 patients also underwent hysterectomy. CONCLUSION: Pulse dactinomycin is an active regimen for patients with low-risk GTN who fail previous methotrexate therapy.


Subject(s)
Dactinomycin/therapeutic use , Gestational Trophoblastic Disease/drug therapy , Salvage Therapy , Adult , Antibiotics, Antineoplastic/administration & dosage , Antibiotics, Antineoplastic/adverse effects , Antibiotics, Antineoplastic/therapeutic use , Chorionic Gonadotropin/blood , Dactinomycin/administration & dosage , Dactinomycin/adverse effects , Drug Administration Schedule , Female , Gestational Trophoblastic Disease/blood , Gestational Trophoblastic Disease/pathology , Humans , Injections, Intravenous , Nausea/chemically induced , Neutropenia/chemically induced , Pregnancy , Pulse Therapy, Drug , Risk Factors , Treatment Outcome , Vomiting/chemically induced
20.
J Clin Oncol ; 24(1): 36-44, 2006 Jan 01.
Article in English | MEDLINE | ID: mdl-16330675

ABSTRACT

PURPOSE: To compare whole-abdominal irradiation (WAI) and doxorubicin-cisplatin (AP) chemotherapy in women with stage III or IV endometrial carcinoma having a maximum of 2 cm of postoperative residual disease. PATIENTS AND METHODS: Four hundred twenty-two patients were entered onto this trial. Of 396 assessable patients, 202 were randomly allocated to receive WAI, and 194 were allocated to receive AP. Irradiation dosage was 30 Gy in 20 fractions, with a 15-Gy boost. Chemotherapy consisted of doxorubicin 60 mg/m2 and cisplatin 50 mg/m2 every 3 weeks for seven cycles, followed by one cycle of cisplatin. RESULTS: Most patient and tumor characteristics were well balanced. The median patient age was 63 years; 50% had endometrioid tumors. Median follow-up time was 74 months. The hazard ratio for progression adjusted for stage was 0.71 favoring AP (95% CI, 0.55 to 0.91; P < .01). At 60 months, 50% of patients receiving AP were predicted to be alive and disease free when adjusting for stage compared with 38% of patients receiving WAI. The stage-adjusted death hazard ratio was 0.68 (95% CI, 0.52 to 0.89; P < .01) favoring AP. Moreover, at 60 months and adjusting for stage, 55% of AP patients were predicted to be alive compared with 42% of WAI patients. Greater acute toxicity was seen with AP. Treatment probably contributed to the deaths of eight patients (4%) on the AP arm and five patients (2%) on the WAI arm. CONCLUSION: Chemotherapy with AP significantly improved progression-free and overall survival compared with WAI. Nevertheless, further advances in efficacy and reduction in toxicity are clearly needed.


Subject(s)
Abdomen/radiation effects , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Endometrial Neoplasms/drug therapy , Endometrial Neoplasms/radiotherapy , Adult , Aged , Aged, 80 and over , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Cause of Death , Cisplatin/administration & dosage , Doxorubicin/administration & dosage , Endometrial Neoplasms/mortality , Endometrial Neoplasms/pathology , Female , Humans , Middle Aged , Neoplasm Staging , Prognosis , Radiotherapy Dosage , Treatment Failure , Treatment Outcome
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