Treatment of FIGO 2018 stage IIIC cervical cancer with different local tumor factors.

BACKGROUND: To compare the oncological outcomes of patients with FIGO 2018 stage IIIC cervical cancer (CC) involving different local tumor factors who underwent abdominal radical hysterectomy (ARH), neoadjuvant chemotherapy and radical surgery (NACT), or radical chemoradiotherapy (R-CT). METHODS: Based on tumor staging, patients with stage IIIC were divided into T1, T2a, T2b, and T3 groups. Kaplan-Meier and Cox proportional hazards regression analysis were used to compare their overall survival (OS) and disease-free survival (DFS) of 5 years. RESULTS: We included 4,086 patients (1,117, 1,019, 869, and 1,081 in the T1, T2a, T2b, and T3 groups, respectively). In the T1 group, NACT was correlated with a decrease in OS (hazard ratio [HR] = 1.631, 95% confidence interval [CI]: 1.150-2.315, P = 0.006) and DFS (HR = 1.665, 95% CI: 1.255-2.182, P < 0.001) than ARH. ARH and NACT were not correlated with OS (P = 0.226 and P = 0.921) or DFS (P = 0.343 and P = 0.535) than R-CT. In the T2a group, NACT was correlated with a decrease in OS (HR = 1.454, 95% CI: 1.057-2.000, P = 0.021) and DFS (HR = 1.529, 95% CI: 1.185-1.974, P = 0.001) than ARH. ARH and NACT were not correlated with OS (P = 0.736 and P = 0.267) or DFS (P = 0.714 and P = 0.087) than R-CT. In the T2b group, NACT was correlated with a decrease in DFS (HR = 1.847, 95% CI: 1.347-2.532, P < 0.001) than R-CT nevertheless was not correlated with OS (P = 0.146); ARH was not correlated with OS (P = 0.056) and DFS (P = 0.676). In the T3 group, the OS rates of ARH (n = 10), NACT (n = 18), and R-CT (n = 1053) were 67.5%, 53.1%, and 64.7% (P = 0.941), and the DFS rates were 68.6%, 45.5%, and 61.1%, respectively (P = 0.761). CONCLUSION: R-CT oncological outcomes were not entirely superior to those of NACT or ARH under different local tumor factors with stage IIIC. NACT is not suitable for stage T1, T2a, and T2b. Nevertheless ARH is potentially applicable to stage T1, T2a, T2b and T3. The results of stage T3 require confirmation through further research due to disparity in case numbers in each subgroup.

Rationality of FIGO 2018 IIIC restaging of cervical cancer according to local tumor size: A cohort study.

INTRODUCTION: FIGO 2018 IIIC remains controversial for the heterogeneity of its prognoses. To ensure a better management of cervical cancer patients in Stage IIIC, a revision of the FIGO IIIC version classification is required according to local tumor size. MATERIAL AND METHODS: We retrospectively enrolled cervical cancer patients of FIGO 2018 Stages I-IIIC who had undergone radical surgery or chemoradiotherapy. Based on the tumor factors from the Tumor Node Metastasis staging system, IIIC cases were divided into IIIC-T1, IIIC-T2a, IIIC-T2b, and IIIC-(T3a+T3b). Oncologcial outcomes of all stages were compared. RESULTS: A total of 63 926 cervical cancer cases were identified, among which 9452 fulfilled the inclusion criteria and were included in this study. Kaplan-Meier pairwise analysis showed that: the oncology outcomes of I and IIA were significantly better than of IIB, IIIA+IIIB, and IIIC; the oncology outcome of IIIC-(T1-T2b) was significantly better than of IIIA+IIIB and IIIC-(T3a+T3b); no significant difference was noted between IIB and IIIC-(T1-T2b), or IIIC-(T3a+T3b) and IIIA+IIIB. Multivariate analysis indicated that, compared with IIIC-T1, Stages T2a, T2b, IIIA+IIIB and IIIC-(T3a+T3b) were associated with a higher risk of death and recurrence/death. There was no significant difference in the risk of death or recurrence/death between patients with IIIC-(T1-T2b) and IIB. Also, compared with IIB, IIIC-(T3a+T3b) was associated with a higher risk of death and recurrence/death. No significant differences in the risk of death and recurrence/death were noted between IIIC-(T3a+T3b) and IIIA+IIIB. CONCLUSIONS: In terms of oncology outcomes of the study, FIGO 2018 Stage IIIC of cervical cancer is unreasonable. Stages IIIC-T1, T2a, and T2b may be integrated as IIC, and it might be unnecessary for T3a/T3b cases to be subdivided by lymph node status.

Prognostic analysis of patients with stage IIIC1p cervical cancer treated by surgery.

BACKGROUND: Cervical cancer (CC) is one of the most common gynaecologic malignancies. The prognosis of stage IIIC1p cervical cancer patients treated by surgery is heterogeneous. Therefore, the aim of this study was to analyse the factors influencing the prognosis in such patients. METHODS: From January 2012 to December 2017, 102 patients with cervical cancer who underwent surgical treatment in the Department of Gynaecology and Tumours, Changzhou Maternal and Child Health Hospital, and had pelvic lymph node metastasis confirmed by pathology were analysed retrospectively. All patients underwent radical hysterectomy with/without oophorectomy with pelvic lymphadenectomy with/without para-aortic lymphadenectomy. Clinical data was collected including age, surgical method, ovarian status, intraoperative blood loss, perioperative complications, tumour size, pathological type, depth of stromal invasion (DSI), whether the lymphatic vascular space was infiltrated, number of pelvic lymph node metastases, location of pelvic lymph node metastases, total number of lymph nodes resected, lymph node ratio (LNR), nature of vaginal margin, whether parametrium was involved, postoperative adjuvant therapy, preoperative neutrophil-lymphocyte ratio (NLR) and prognostic information of patients. Survival curves for overall survival (OS) and disease-free survival (DFS) were plotted using the Kaplan-Meier method, and the difference between the survival curves was tested using the log-rank test. Univariate and multivariate COX regression models were used to assess the factors associated with overall survival and disease-free survival in patients with stage IIIC1p cervical cancer. Nomogram plots were constructed to predict OS and DFS, and the predictive accuracy of the nomograms was measured by Harrell's C-index and calibration curves. RESULTS: A total of 102 patients with stage IIIC1p cervical cancer were included in the study, and the median follow-up time was 63 months (range from 6 to 130 months). The 5-year OS was 64.7%, and the 5-year DFS was 62.7%. Multivariate analysis showed that no postoperative adjuvant therapy, LNR > 0.3 and NLR > 3.8 were independent risk factors for OS and DFS in patients with stage IIIC1p cervical cancer. CONCLUSIONS: Patients with stage IIIC1p cervical cancer have a poor prognosis. Lower OS and DFS were associated with no postoperative adjuvant therapy, LNR > 0.3 and NLR > 3.8.

Survival and Surgical Approach among Women with Advanced Ovarian Cancer Treated with Neoadjuvant Chemotherapy.

STUDY OBJECTIVE: To evaluate the effect of surgical approach on overall survival (OS) for women with advanced, epithelial ovarian cancer (EOC) after neoadjuvant chemotherapy (NACT) and determine the sociodemographic and clinical factors associated with surgical approach. DESIGN: The primary exposure was surgical approach to interval cytoreduction, minimally invasive versus open, and was evaluated by intention to treat. Primary outcome was OS. Associations were examined using Chi-squared tests, Wilcoxon rank sum tests, and multivariate logistic regression. Survival analysis was performed with Kaplan-Meier methods and Cox proportional hazards. SETTING: The National Cander Database was used to identify eligible patients. PATIENTS: Women diagnosed with stage IIIC/IV EOC from 2010-2016. INTERVENTIONS: Patients were included if they were treated with NACT within 90 days of diagnosis before interval cytoreductive surgery (CRS). MEASUREMENTS AND MAIN RESULTS: A total of 8085 women were identified; 6713 (83%) underwent open interval CRS, and 1372 (17%) underwent minimally invasive interval CRS. The proportion undergoing minimally invasive CRS after NACT increased from 2% in 2010 to 11% in 2016, a nearly 6-fold increase. There was no difference in OS between women who underwent minimally invasive and open interval CRS (median OS 36.5 vs 35.2 months, HR 0.94, 95% CI, 0.86-1.04). After adjusting for demographic and clinical variables, including age, race, ethnicity, income, and Charlson/Deyo score, no difference in OS was observed (HR 0.95, 95% CI, 0.86-1.04). Women of older age (OR 1.35, 95% CI, 1.05-1.74) and Hispanic ethnicity (OR 1.46, 95% CI, 1.14-1.88) had increased odds of receiving minimally invasive CRS after NACT, whereas low income (<$38000/year) women had decreased odds (OR 0.76, 95% CI, 0.60-0.97, p = .03). Length of stay differed for patients undergoing minimally invasive versus open interval CRS (3 vs 5 days, p <.01), but there was no difference in need for postoperative readmission. CONCLUSIONS: Minimally invasive CRS has similar survival outcomes to open CRS among women with EOC who have undergone NACT.

The tumor-stroma ratio is an independent predictor of survival in patients with 2018 FIGO stage IIIC squamous cell carcinoma of the cervix following primary radical surgery.

OBJECTIVE: To determine the value of the tumor-stroma ratio (TSR) while identifying prognostic factors in patients with 2018 International Federation of Gynecology and Obstetrics (FIGO) stage IIIC squamous cell carcinoma of the cervix following primary radical surgery. METHODS: Three hundred eighty-four patients with node-positive squamous cell carcinoma of the cervix (2018 FIGO stage IIIC) who underwent radical surgery between January 2005 and December 2016 were included in this retrospective study. The TSRs were assessed on hematoxylin and eosin-stained tumor slides and classified as stroma-low (<50% stroma) or stroma-high (≥50% stroma). RESULTS: Sixty-seven patients were categorized as stroma-high; they had shorter disease-free survival (DFS) and overall survival (OS) periods than did their stroma-low counterparts. On multivariate analysis, a tumor size ≥4 cm, ≥3 metastatic lymph nodes, and stroma-high status were independent predictors of shorter DFS and OS. These factors were incorporated into a prognostic scoring system in which patients were categorized into low- (score 0), intermediate- (score 1), and high-risk (scores 2-3) groups. The scoring system differentiated DFS and OS well (C-index = 0.65, 95% confidence interval, 0.59-0.72; and C-index = 0.65, 95% confidence interval, 0.59-0.72, respectively). CONCLUSIONS: The TSR is an independent prognostic factor, and our prognostic scoring system that incorporates this parameter exhibits good discriminative ability for both recurrence and survival in patients with 2018 FIGO stage IIIC cervical cancer after radical surgery. The TSR is a potentially novel clinicopathological variable for predicting the prognoses of these patients contingent on the validation of our findings.

Ultrastaging of negative pelvic lymph nodes to decrease the true prevalence of isolated paraaortic dissemination in endometrial cancer.

OBJECTIVE: This study aimed to determine the prevalence of occult pelvic lymph node metastasis in patients with endometrial cancer (EC) with isolated paraaortic dissemination who underwent pelvic and paraaortic lymphadenectomy. METHODS: From 2004 to 2008, patients undergoing surgery for EC at our institution were prospectively treated according to a validated surgical algorithm relying on intraoperative frozen section. For the current study, we re-reviewed pathologic slides obtained at the time of diagnosis and performed ultrastaging of all negative pelvic lymph nodes to assess the prevalence of occult pelvic lymph node metastasis. RESULTS: Of 466 patients at risk for lymphatic dissemination, 394 (84.5%) underwent both pelvic and paraaortic lymphadenectomy. Of them, 10 (2.5%) had isolated paraaortic metastasis. Pathologic review of hematoxylin-eosin-stained slides identified 1 patient with micrometastasis in 1 of 18 pelvic lymph nodes removed. Ultrastaging of 296 pelvic lymph nodes removed from the 9 other patients (median [range], 32 [20-50] nodes per patient) identified 2 additional cases (1 with micrometastasis and 1 with isolated tumor cells), for a total of 3/10 patients (30%) having occult pelvic dissemination. CONCLUSIONS: Ultrastaging and pathologic review of negative pelvic lymph nodes of patients with presumed isolated paraaortic metastasis can identify occult pelvic dissemination and reduce the prevalence of true isolated paraaortic disease. In the era of the sentinel lymph node (SLN) algorithm for EC staging, which incorporates ultrastaging of the SLNs removed, these findings demonstrate that use of the SLN algorithm can further mitigate the concern of missing cases of isolated paraaortic dissemination.

Adjuvant combined-modality therapy for stage IIIC endometrioid and non-endometrioid endometrial cancer.

OBJECTIVE: To identify the optimal adjuvant treatment regimen for patients with endometrioid and non-endometrioid node-positive endometrial cancer. METHODS: We retrospectively identified 249 women with FIGO 2009 stage IIIC endometrial cancer at our institution who underwent surgical staging from 1985 to 2015 followed by external beam radiotherapy (RT), chemotherapy (CT), or a combination of CT + RT. Survival rates were calculated using the Kaplan-Meier method. RESULTS: The 5-year disease-specific survival (DSS) rate for all patients was 65%. Adjuvant CT + RT conferred higher rates of 5-year DSS as compared to CT alone in patients with grade 3 endometrioid and non-endometrioid tumors (61% vs. 27%, P = 0.04 and 67% vs. 38%, P = 0.02, respectively). Among patients with non-endometrioid tumors, treatment with concurrent chemoradiotherapy followed by additional sequential chemotherapy had higher 5-year DSS rates than with concurrent chemoradiotherapy alone (74% vs. 50%, P = 0.02). The 3-year pelvic recurrence rate was 5% with RT ±â€¯CT and 35% with CT alone (P < 0.001) for all patients. No paraaortic nodal failures were observed following extended-field RT, but 14% of patients who received pelvic-only RT or CT alone developed recurrences in the paraaortic nodes (P < 0.001). CONCLUSIONS: Combined-modality therapy including adjuvant external beam pelvic radiotherapy yields excellent outcomes for patients with all subtypes of node-positive endometrial cancer. The most pronounced DSS advantage from adjuvant chemoradiotherapy was evident in women with non-endometrioid endometrial cancer.

Role of lymphadenectomy in endometrial cancer with nonbulky lymph node metastasis: Comparison of comprehensive surgical staging and sentinel lymph node algorithm.

OBJECTIVES: To compare survival and progression outcomes between 2 nodal assessment approaches in patients with nonbulky stage IIIC endometrial cancer (EC). METHODS: Patients with stage IIIC EC treated at 2 institutions were retrospectively identified. At 1 institution, a historical series (2004-2008) was treated with systematic pelvic and para-aortic lymphadenectomy (LND cohort). At the other institution, more contemporary patients (2006-2013) were treated using a sentinel lymph node algorithm (SLN cohort). Outcomes (hazard ratios [HRs]) within the first 5 years after surgery were compared between cohorts using Cox models adjusted for type of adjuvant therapy. RESULTS: The study included 104 patients (48 LND, 56 SLN). The use of chemoradiotherapy was similar in the 2 cohorts (46% LND vs 50% SLN), but the use of chemotherapy alone (19% vs 36%) or radiotherapy alone (15% vs 2%) differed. Although there was evidence of higher risk of cause-specific death (HR, 2.10; 95% CI, 0.79-5.58; P = 0.14) and lower risk of para-aortic progression (HR, 0.27; 95% CI, 0.05-1.42; P = 0.12) for the LND group, the associations did not meet statistical significance. The risk of progression was not significantly different between the groups (HR, 1.27; 95% CI, 0.60-2.67; P =0 .53). In parsimonious multivariable models, high-risk tumor characteristics and nonendometrioid type were independently associated with lower cause-specific survival and progression-free survival. CONCLUSIONS: In EC patients with nonbulky positive lymph nodes, use of the SLN algorithm with limited nodal dissection does not compromise survival compared with LND. Aggressive pathologic features of the primary tumor are the strongest determinants of prognosis.

Burden of lymphatic disease predicts efficacy of adjuvant radiation and chemotherapy in FIGO 2018 stage IIICp cervical cancer.

OBJECTIVE: Nodal involvement is one of the most important prognostic factors in cervical cancer patients. We aimed to assess the prognostic role in relation to the burden of nodal disease in stage IIICp cervical cancer. METHODS: Data on all consecutive patients diagnosed with cervical cancer undergoing primary surgery (radical hysterectomy plus lymphadenectomy) or neoadjuvant chemotherapy followed by radical hysterectomy plus lymphadenectomy, between January 1980 and December 2017, were collected in a dedicated database. Exclusion criteria were: (1) consent withdrawal; (2) synchronous malignancies (within 5 years). Survival outcomes were assessed using Kaplan-Meier and Cox models. RESULTS: Overall, 177 (14.1%) of 1257 patients with cervical cancer were diagnosed with positive lymph nodes. After a median follow-up of 58 (range 4-175) months, 66 (37.3%) and 37 (20.9%) patients developed recurrent disease and died of disease, respectively. Via multivariate analysis, positive para-aortic nodes (HR 2.62, 95% CI 1.12 to 6.11; p=0.025) and the number of positive nodes (HR 1.06, 95% CI 1.02 to 1.11; p=0.002) correlated with worse disease-free survival. Furthermore, the number of positive nodes (HR 1.06, 95% CI 1.01 to 1.12; p=0.021) correlated with worse overall survival. Number of positive nodes (1, 2 or ≥3) strongly correlated with both disease-free survival (p<0.001, log-rank test) and overall survival (p=0.001, log-rank test). Focusing on patients receiving adjuvant radiation and chemotherapy, the number of positive lymph nodes was associated with response to treatment (p<0.001). Median disease-free survival was 100, 42, and 12 months for patients with one, two, or three or more positive lymph node(s), respectively (p<0.001, log-rank test). CONCLUSIONS: In stage IIICp cervical cancer, adjuvant radiation and chemotherapy provides adequate overall survival in patients diagnosed with only one metastatic node, while survival outcomes are poor in patients with two or more metastatic nodes. This highlights the need for innovative treatments in patients with a high burden of lymphatic disease.

Patterns of FIRST recurrence of stage IIIC1 endometrial cancer with no PARAAORTIC nodal assessment.

OBJECTIVE: To assess the rates and distribution of first recurrence in patients with FIGO stage IIIC1 endometrial cancer (EC) who did not undergo paraaortic dissection at surgical staging. METHODS: We retrospectively selected all (n = 207) stage IIIC1 patients treated at a single institution from 5/1993-1/2017. Sites of first recurrence were identified, disease-free (DFS) and overall survival (OS) calculated, multivariate logistic regression performed to identify factors associated with recurrence. RESULTS: Three-year DFS and OS were 66.5% and 85.7%, respectively. The most common histology was endometroid (64.2%). Three-year DFS was 81% (SE±3.8%) endometrioid vs. 39.5% (SE±6.6%) non-endometrioid (P < 0.001). Three-year OS was 96.9% (SE±1.8%) endometrioid vs. 65.6% (SE±6.7%) non-endometrioid (P < 0.001). Sixty-two (30.1%) patients recurred. Patterns of recurrence were: 14 (8.3%) multiple sites, 17 (8.2%) abdominal, 14 (6.8%) extra-abdominal, 17 (8.3%) isolated nodal (8 of these (3.9%) paraaortic). Patients with isolated tumor cells (ITCs) in lymph nodes only had 12/71 (17%) recurrence rate vs. 50/135 (37%) for patients with micro-/macrometastasis. On univariate analysis, grade (HR 4.67 95%CI 1.5-14.5, P = 0.008), histology (HR 4.9 95%CI 2.6-9.3, P < 0.001), myometrial invasion (HR 1.9 95%CI 1.04-3.5, P = 0.04), pelvic washing (HR 2.2 95%CI 1.1-4.5, P = 0.03), tumor volume in pelvic LNs (ITC vs. micro-/macrometastasis; HR 0.3 95%CI 0.2-0.7, P = 0.003) were associated with recurrence. On multivariate analysis, only histology was associated with recurrence (HR 7.88 95%CI 3.43-18.13, P < 0.001). CONCLUSIONS: Isolated paraaortic recurrence in stage IIIC1 EC is uncommon. Micro-/macrometastasis were associated with twice the recurrence rate compared to ITC. These data will help clinicians counsel patients with stage IIIC1 EC regarding paraaortic assessment.

Prognostic factors and patterns of recurrence in lymphovascular space invasion positive women with stage IIIC endometriod endometrial cancer.

AIM: The purpose of this study was to determine the prognostic factors and patterns of failure in lymphovascular space invasion (LVSI)-positive women with stage IIIC endometrioid endometrial cancer (EC). METHODS: A multicenter, retrospective, department database review was performed to identify LVSI-positive patients with stage IIIC endometrioid EC at five gynecological oncology centers in Turkey. Demographic, clinicopathological and survival data were collected. RESULTS: We identified 172 LVSI-positive women with stage IIIC endometrioid EC during the study period; 75 (43.6%) were classified as Stage IIIC1 and 97 (56.4%) as Stage IIIC2 . The median age at diagnosis was 59 years, and the median duration of follow up was 34.5 months. The total number of recurrences was 46 (26.7%). We observed 14 (8.1%) locoregional recurrences, 12 (7.0%) retroperitoneal failures and 20 (11.6%) distant relapses. For the entire study cohort, 5-year progression-free survival (PFS) was 67.4%, while the 5-year overall survival (OS) rate was 75.1%. Grade 3 histology (hazard ratio [HR] 2.62, 95% confidence interval [CI] 1.34-5.12; P = 0.005), cervical stromal invasion (HR 2.33, 95% CI 1.09-4.99; P = 0.028) and myometrial invasion (MMI) ≥50% (HR 4.0, 95% CI 1.16-13.69; P = 0.028) were found to be independent prognostic factors for decreased OS. CONCLUSION: Uterine factors such as grade 3 disease, cervical stromal invasion and deep MMI seem to be independently associated with decreased OS in LVSI-positive women with stage IIIC endometrioid EC. The high distant recurrence rate in this subgroup of patients warrants further studies in order to identify the most effective treatment strategy for those patients.

Role of adjuvant radiotherapy in FIGO stage IIIC endometrial carcinoma: Treatment outcomes and prognostic factors in 52 irradiated patients.

BACKGROUND: To retrospectively review the postoperative radiotherapy treatment outcomes and the prognostic factors for the International Federation of Gynecology and Obstetrics (FIGO) stage IIIC endometrial carcinoma. METHODS: Fifty-two patients who were newly diagnosed and previously untreated FIGO stage IIIC endometrial carcinoma over a 33-year period (September 1983 to April 2015) were retrospectively reviewed. They had received radical surgery followed by adjuvant radiotherapy with or without adjuvant chemotherapy. Those excluded patients had initial distant metastasis disease, palliative intent or incomplete adjuvant radiotherapy. Different subgroups of the stage III patients were compared statistically in terms of their rates of overall survival (OS), loco-regional recurrence-free survival (LRRFS) and distant metastasis-free survival (DMFS). RESULTS: The median follow up duration was 51.5 months (range, 5-298). The loco-regional recurrence was found in 4 patients and distant metastasis in 15 patients. Comparing stage IIIC1 vs. IIIC2 patients, their 5-year OS were 69.9% vs. 55% (p = 0.0954), LRRFS 90.3% vs. 94.4% (p = 0.6151), and DMFS 82.5% vs. 53.3% (p = 0.0080). The FIGO stage was a significant factor for DMFS (hazard ratio [HR], 5.440, 95% confidence interval [95% CI] 1.379-21.451, p = 0.0155), but only marginal for OS (HR, 2.137, 95% CI 0.930-4.913, p = 0.0738). The ECOG performance status was marginal significant for DMFS (HR, 4.777, 95% CI 0.976-23.378, p = 0.0536). CONCLUSION: Adjuvant radiotherapy decreased loco-regional recurrence and had good local control in FIGO stage IIIC endometrial carcinoma. The stage IIIC2 patients showed a greater tendency of distant metastases and poorer overall survival rate when compared to patients of stage IIIC1.

Vemurafenib plus cobimetinib in unresectable stage IIIc or stage IV melanoma: response monitoring and resistance prediction with positron emission tomography and tumor characteristics (REPOSIT): study protocol of a phase II, open-label, multicenter study.

BACKGROUND: In patients with BRAFV600 mutated unresectable stage IIIc or metastatic melanoma, molecular targeted therapy with combined BRAF/MEK-inhibitor vemurafenib plus cobimetinib has shown a significantly improved progression-free survival and overall survival compared to treatment with vemurafenib alone. Nevertheless, the majority of BRAFV600 mutation-positive melanoma patients will eventually develop resistance to treatment. Molecular imaging with 18F-Fluorodeoxyglucose (18F-FDG) PET has been used to monitor response to vemurafenib in some BRAFV600 mutated metastatic melanoma patients, showing a rapid decline of 18F-FDG uptake within 2 weeks following treatment. Furthermore, preliminary results suggest that metabolic alterations might predict the development of resistance to treatment. 18F-Fluoro-3'-deoxy-3'L-fluorothymidine (18F-FLT), a PET-tracer visualizing proliferation, might be more suitable to predict response or resistance to therapy than 18F-FDG. METHODS: This phase II, open-label, multicenter study evaluates whether metabolic response to treatment with vemurafenib plus cobimetinib in the first 7 weeks as assessed by 18F-FDG/18F-FLT PET can predict progression-free survival and whether early changes in 18F-FDG/18F-FLT can be used for early detection of treatment response compared to standard response assessment with RECISTv1.1 ceCT at 7 weeks. Ninety patients with BRAFV600E/K mutated unresectable stage IIIc/IV melanoma will be included. Prior to and during treatment all patients will undergo 18F-FDG PET/CT and in 25 patients additional 18F-FLT PET/CT is performed. Histopathological tumor characterization is assessed in a subset of 40 patients to unravel mechanisms of resistance. Furthermore, in all patients, blood samples are taken for pharmacokinetic analysis of vemurafenib/cobimetinib. Outcomes are correlated with PET/CT-imaging and therapy response. DISCUSSION: The results of this study will help in linking PET measured metabolic alterations induced by targeted therapy of BRAFV600 mutated melanoma to molecular changes within the tumor. We will be able to correlate both 18F-FDG and 18F-FLT PET to outcome and decide on the best modality to predict long-term remissions to combined BRAF/MEK-inhibitors. Results coming from this study may help in identifying responders from non-responders early after the initiation of therapy and reveal early development of resistance to vemurafenib/cobimetinib. Furthermore, we believe that the results can be fundamental for further optimizing individual patient treatment. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT02414750. Registered 10 April 2015, retrospectively registered.

Clinical prognostic markers in stage IIIC melanoma.

BACKGROUND: Although the EORTC 18071-trial has shown a clear survival benefit for adjuvant ipilimumab, accurately selecting patients for this toxic adjuvant therapy is important. We aimed to identify prognostic factors for death and disease recurrence in AJCC stage IIIC melanoma patients. PATIENTS AND METHODS: Retrospective analysis of patients who underwent lymph node dissection (LND) for stage IIIC melanoma in our institution between 2000 and 2016. Baseline characteristics, melanoma-specific survival (MSS), and disease-free survival (DFS) were assessed, and prognostic factors for recurrence and survival were analyzed using uni- and multivariable analysis. RESULTS: A total of 205 patients were included. Median follow-up was 20 months (interquartile range 11-43 months), median MSS was 28 months, and median DFS was 11 months. Five-year MSS was 33% and 5-year DFS was 23%. N3 (≥4 involved lymph nodes) and extracapsular extension (ECE) carried an increased risk of disease recurrence after LND and death by melanoma. Patients with both N3 and ECE had virtually no long-term survival. CONCLUSIONS: Although survival for patients with stage IIIC is poor in general, patients with both N3 disease and ECE constitute the group with the worst prognosis and should be considered for adjuvant therapy with ipilimumab or any other future effective adjuvant therapy (study).

The role of para-aortic lymphadenectomy in stage IIIC endometrial cancer: A single-institute study.

The therapeutic value of para-aortic lymphadenectomy (PAL) in women with endometrial cancer (EC) remains uncertain. We retrospectively analysed 25 patients with stage IIIc EC (17 stage IIIC1; 8 IIIC2) who were treated in our institution. All subjects had undergone pelvic lymphadenectomies in which para-aortic nodes were sampled, or removed only when these nodes were enlarged. Sampling of para-aortic nodes or PAL was performed in all patients with stage IIIC2 disease and one of 17 with stage IIIC1 disease. Para-aortic lymph nodes were the most frequent site of recurrence in stage IIIC1 patients, but no such recurrences occurred in stage IIIC2 patients. Overall survival tended to be shorter in stage IIIC1 patients than stage IIIC2 patients. Our findings indicate that PAL improves the outcomes of patients with EC and high risk of para-aortic lymph node metastasis, such as those with positive pelvic lymph nodes or enlargement of para-aortic lymph nodes. Impact statement Para-aortic lymph node (PALN) metastases are important prognostic factors in endometrial cancer. Overall survival of patients with stage IIIC1 disease is generally longer than for those with stage IIIC2 disease. Retrospective studies - but no prospective studies - have suggested that para-aortic lymphadenectomy (PAL) provides a survival benefit. In our institution, we had performed PAL or para-aortic sampling for patients with enlarged PALNs; therefore, as most IIIC1 patients had no enlarged PALNs, they underwent pelvic lymphadenectomy only, whereas all IIIC2 patients had enlarged PALNs and underwent pelvic lymphadenectomy and PAL or PALN sampling in addition to pelvic lymphadenectomy. However, under this policy, survival of stage IIIC1 patients was not better than for stage IIIC2 patients. Our retrospective study indicates a survival benefit for PAL in patients with pelvic node-positive or enlarged PALN. PAL warrants a prospective randomised trial to see whether it should be a standard treatment in these patients.

Efficacy of contemporary chemotherapy in stage IIIC endometrial cancer: a histologic dichotomy.

BACKGROUND: Treatment failures in stage IIIC endometrial carcinoma (EC) are predominantly due to occult extrapelvic metastases (EPM). The impact of chemotherapy on occult EPM was investigated according to grade (G), G1/2EC vs G3EC. METHODS: All surgical-stage IIIC EC cases from January 1, 1999, through December 31, 2008, from Mayo Clinic were included. Patient-, disease-, and treatment-specific risk factors were assessed for association with overall survival, cause-specific survival, and extrapelvic disease-free survival (DFS) using Cox proportional hazards regression. RESULTS: 109 cases met criteria, with 92 (84%) having systematic lymphadenectomy (>10 pelvic and >5 paraaortic lymph nodes resected). In patients with documented recurrence sites, occult EPM accounted for 88%. Among G1/2EC cases (n=48), the sole independent predictor of extrapelvic DFS was grade 2 histology (hazard ratio [HR], 0.28; 95% CI, 0.08-0.91; P=.03) while receipt of adjuvant chemotherapy approached significance (HR 0.13; 95% CI, 0.02, 1.01; P=.0511). The 5-year extrapelvic DFS with and without adjuvant chemotherapy was 93% and 54%, respectively (log-rank, P=.02). Among G3EC (n=61), the sole independent predictor of extrapelvic DFS was lymphovascular space involvement (HR, 2.63; 95% CI, 1.16-5.97; P=.02). Adjuvant chemotherapy did not affect occult EPM in G3EC; the 5-year extrapelvic DFS for G3EC with and without adjuvant chemotherapy was 43% and 42%, respectively (log-rank, P=.91). CONCLUSIONS: Chemotherapy improves extrapelvic DFS for stage IIIC G1/2EC but not stage IIIC G3EC. Future efforts should focus on prospectively assessing the impact of chemotherapy on DFS in G3EC and developing innovative phase I and II trials of novel systemic therapies for advanced G3EC.

Effect of different treatment modalities on the prognosis of patients with stage IIIC cervical cancer.

Objective: To compare the effects of different treatments on the prognosis of patients with stage IIIC cervical cancer and to identify the main influencing factors to predict the outcomes of patients. Methods: In this study, a total of 1763 patients with stage IIIC cervical cancer from 2010-2015 were retrospectively analyzed, and these patients were divided into the radical radiotherapy ± chemotherapy group (877 patients) and the radical surgery + radiotherapy ± chemotherapy group (886 patients) according to the treatment methods. The survival differences between the two groups were compared using the Kaplan-Meier method. Unifactorial and multifactorial COX analyses screened the clinical factors affecting the prognosis. The nomogram was constructed, and the accuracy of the line graph was verified using the C-index, calibration, and ROC (receiver operator characteristic curve, ROC). Results: Age, race, T-stage, pathologic type, mass size, whether or not they underwent surgery, and whether or not they received radiotherapy were independent factors affecting Overall Survival (OS). For all patients with TxN1M0 in cervical cancer stage IIIC, radical synchronized radiotherapy was better than the radical surgery group (p<0.0001). After comparing the tumor size breakdown, it could be found that in the T1N1M0, T2N1M0, and T3N1M0 groups, none of the OS in the surgical group achieved an improvement in OS compared with that in the non-surgical group (p>0.05). Conclusion: In patients with stage IIIC cervical cancer, OS did not improve in the radical surgery group compared with the radical simultaneous radiotherapy group. And surgery did not benefit patients' survival regardless of tumor size.

Prognostic analysis of stage IIIC1p cervical cancer patients.

Background: Stage IIIC1p cervical cancer is characterized by marked heterogeneity and considerable variability in the postoperative prognosis. This study aimed to identify the clinical and pathological characteristics affecting the survival of patients diagnosed with stage IIIC1p cervical cancer. Methods: We retrospectively analyzed patients diagnosed with stage IIIC1p cervical cancer who underwent radical hysterectomy and lymph node dissection between March 2012 and March 2022. Overall survival (OS) was estimated using Kaplan-Meier survival curves. Univariate and multivariate Cox proportional hazards models were used to evaluate prognostic factors for OS and forest plots were used to visualize these findings. Nomogram charts were created to forecast survival rates at 3 and 5 years, and the accuracy of predictions was evaluated using Harrell's concordance index (C-index) and calibration curves. Results: The study cohort comprised 186 women diagnosed with stage IIIC1p cervical cancer. The median follow-up duration was 51.1 months (range, 30-91 months), and the estimated 5-year OS rate was 71.5%. Multivariate analysis revealed that concurrent chemoradiotherapy plus adjuvant chemotherapy (CCRT + AC), monocyte-lymphocyte ratio (MLR), ratio of lymph node metastasis (LNM), and squamous cell carcinoma antigen (SCCA) levels independently predicted OS. Conclusions: Significant prognostic disparities exist among patients diagnosed with stage IIIC1p cervical cancer. MLR, ratio of LNM, and SCCA were associated with poor OS. In contrast, the CCRT + AC treatment regimen appeared to confer a survival advantage.

Analysis of the therapeutic effect of synchronous integrated intensity modulated radiotherapy combined with chemotherapy in stage IIIc of cervical cancer.

Objective: To explore the Therapeutic effect of synchronous Integrated intensity modulated radiotherapy combined with chemotherapy in stage IIIc of Cervical Cancer. Methods: A total of 58 patients with stage IIIC cervical cancer (KPS ≥ 80) were analyzed in this study. They were admitted to our hospital between August 2017 and August 2022. Synchronous integrated boost intensity-modulated radiotherapy (SIB-IMRT) and sequential boost intensity-modulated radiotherapy (LCB-IMRT) were used to treat pelvic and/or para-aortic metastatic lymph nodes, with 30 cases in the SIB group and 28 cases in the LCB group. Comparison of short-term and long-term efficacy. Comparison of recurrence and metastasis rates, radiation dose to organs at risk and incidence of adverse drug reactions. Result: 30 patients were treated with simultaneous integrated boost intensity-modulated radiotherapy (SIB-IMRT), and 28 patients were treated with sequential boost intensity-modulated radiotherapy (LCB-IMRT). At the completion of radiotherapy and 3 months after radiotherapy, there was no significant difference in clinical efficacy observed between the two treatment groups. The median overall survival (OS), progression-free survival (PFS), and disease-free survival (DMR) in the SIB-IMRT group were significantly higher compared to the LCB-IMRT group. The SIB-IMRT group demonstrated significantly lower rates compared to the LCB-IMRT group. Furthermore, within 3 years and 5 years, the rates of lymph node recurrence, cervical and vaginal local recurrence, and distant metastasis within the radiotherapy field were significantly lower in the SIB-IMRT group compared to the LCB-IMRT group. There were no significant differences observed between the two groups in terms of the maximum dose to the small intestine (Dmax), dose received by 2cc of the small intestine (D2cc), maximum dose to the rectum (Dmax), and dose received by 1cc of the bladder (D1cc). The incidence of bone marrow toxicity in the SIB-IMRT group was significantly lower compared to the LCB-IMRT group. Moreover, the occurrence of grade III and IV bone marrow toxicity was also significantly lower in the SIB-IMRT group compared to the LCB-IMRT group. Conclusion: The study has concluded that there is no significant differences in in terms of bladder associated adverse events and gastrointestinal toxicity in both Simultaneous Integrated Boost Intensity-Modulated Radiotherapy and Layered Conical Beam Intensity-Modulated Radiation Therapy.

Effects of Adjuvant Radiation Plus Chemotherapy on Survival Outcomes in Stage III C Endometrial Cancer According to Histology: Analysis of Data from the Surveillance, Epidemiology, and End Results Database.

Purpose: To evaluate the survival benefit of radiation plus chemotherapy in adult females with stage IIIC endometrial cancer and to investigate whether the benefit varies according to histology. Methods: Data from adult females with International Federation of Gynecology and Obstetrics (FIGO) stage IIIC endometrial cancer, who underwent at least total hysterectomy between 2010 and 2015, were obtained from the Surveillance, Epidemiology, and End Results (SEER) database. Adjuvant treatments were categorized as chemotherapy alone, chemotherapy with external beam radiation therapy (EBRT), chemotherapy with vaginal brachytherapy (VBT), or chemotherapy with EBRT+VBT. Multivariate Cox regression models, Kaplan-Meier curves, and log-rank tests were used to assess the association between treatment modality and overall survival (OS). Results: In total, 2138 cases were identified: stage IIIC1 (n = 1299 [60.8%]) and stage IIIC2 (n = 839 [39.2%]). Median OS for all patients was 48 (interquartile range [IQR] 28-70) months. Regarding adjuvant treatment, 40.5% of patients underwent chemotherapy only, followed by chemotherapy with EBRT (35.5%). Stage IIIC patients treated with chemotherapy plus radiation exhibited a significantly reduced risk for death from endometrial cancer in both univariate and multivariate analyses (P < 0.001). However, when stratified according to histology, OS also differed according to treatment modality when analyzing each histological type; combination therapy was no longer significantly different from chemotherapy alone for any histology (clear cell and carcinosarcoma). Combination therapy was associated with improved OS in patients with IIIC1 and IIIC2 disease. Similar associations were observed in patients with high-grade stage IIIC endometrioids. However, for low-grade tumors, combination therapy was no longer associated with reduced risk for death compared with chemotherapy alone. Conclusion: For patients with stage IIIC endometrial cancer, combined treatment with radiation and chemotherapy was associated with improved OS compared with chemotherapy alone. However, no survival benefit was found, and radiotherapy may be unnecessary in patients with low-grade endometrioids.