Cause-specific Research Articles

Asbestos exposure and asbestosis mortality in Italian cement-asbestos cohorts: Dose-response relationship and the role of competing death causes.

In Italy, asbestos was used intensively until its ban in 1992, which was extended for asbestos cement factories until 1994. The aim of this study was to evaluate the dose-response between asbestos exposure and asbestosis mortality across a pool of Italian occupational cohorts, taking into account the presence of competing risks. Cohorts were followed for vital status and the cause of death was ascertained by a linkage with mortality registers. Cause-specific (CS) Cox-regression models were used to evaluate the dose-exposure relationship between asbestosis mortality and the time-dependent cumulative exposure index (CEI) to asbestos. Fine and Gray regression models were computed to assess the effect of competing risks of death. The cohort included 12,963 asbestos cement workers. During the follow-up period (1960-2012), of a total of 6961 deaths, we observed 416 deaths attributed to asbestosis, 879 to lung cancer, 400 to primary pleural cancer, 135 to peritoneal cancer, and 1825 to diseases of the circulatory system. The CS model showed a strong association between CEI and asbestosis mortality. Dose-response models estimated an increasing trend in mortality even below a CEI of 25 ff/mL-years. Lung cancer and circulatory diseases were the main competing causes of death. Asbestos exposure among Italian asbestos-cement workers has led to a very high number of deaths from asbestosis and asbestos-related diseases. The increasing risk trend associated with excess deaths, even at low exposure levels, suggests that the proposed limit values would not have been adequate to prevent disability and mortality from asbestosis.

A comprehensive prognostic analysis of cause-specific mortality in patients with ovarian serous cystadenocarcinoma using a competing-risks model: a case study of the SEER database.

This retrospective study employed a competing-risks analysis utilizing the Surveillance, Epidemiology, and End Results (SEER) database to identify precise prognostic factors associated with ovarian serous cystadenocarcinoma (OSCC) in patients. Patients with OSCC during 2004-2015 were identified in the SEER database, and their clinicopathological, demographic, and survival data were examined. Univariate analysis using Gray's test and the cumulative incidence function was used to evaluate the prognoses of events of interest. The multivariate analysis involved several models, including the Cox proportional hazards, Fine-Gray, and cause-specific (CS) hazard function models, to estimate the hazard functions of competing risks. Hazard ratios were analyzed to identify the reliability of the prognostic factors. Among the 10,400 individuals diagnosed with OSCC, 5,713 died from the illness, and 1,125 died from other causes. The cumulative incidence rate of events of interest was found to be significant for ethnicity, age at diagnosis, histological grade, American Joint Committee on Cancer (AJCC) stage, chemotherapy and surgery status, tumor size, marital status, and local lymph node metastases (p<0.05). The multivariate analysis revealed that ethnicity, histological grade, surgery and chemotherapy status, age at diagnosis, AJCC stage, marital status, and distant metastases were independent prognostic factors in the Cox model (p<0.05). Finally, the Fine-Gray and CS models demonstrated that ethnicity, histological grade, surgery and chemotherapy status, age at diagnosis, AJCC stage, tumor size, marital status, and combination summary stage were all identified as independent prognostic factors (p<0.05). This study determined the risk factors for OSCC using a competing risk analysis model established by the SEER database. The findings can help clinicians understand OSCC better and provide more accurate medical support to affected patients.

Very APBI in 1 or 2 Days: Late Toxicity and Early Oncological Outcomes of the GEC-ESTRO Cohort

To analyze late toxicity after very accelerated partial breast irradiation (VAPBI) for low-risk breast cancer. In this retrospective observational international multicenter study (HDH F20220713143949) from 7 European centers, patients with low-risk breast cancer underwent lumpectomy + adjuvant VAPBI based on high-dose rate (HDR) multicatheter interstitial brachytherapy (MIB). VAPBI was performed with 4 (4 × 6.2 Gy/2 d), 3 (3 × 7.45 Gy/2 d) or 1 fraction (1 × 16 Gy or 1 × 18 Gy/1 d). Primary endpoint was late toxicity. Secondary endpoints were oncological outcome based on cumulative incidence of breast cancer local relapse (LR) and distant metastasis disease (DMD) and cause-specific (CSS) and overall (OS) survival. Prognostic factors for late toxicity were analyzed. From 01/2012 to 06/2022, the GEC-ESTRO VAPBI cohort included 516 pts with an early breast cancer. Median follow-up was 42 months [95% CI = 39 - 44]. Median age was 71 years [40 - 100]. Median tumor size was 12 mm [1 - 46]. Tumor was mainly invasive ductal carcinoma (78%), pN0 (88.5%), with positive hormonal receptors (98.5%) and negative HER2 overexpression (96%). Patients underwent hormonal and chemo-therapy in 93.8% and 2.3% respectively. Catheter placement was performed peri or post-operatively in 50.2% and 49.8% respectively. Median time interval between surgery and VABPI was 10 days [6 - 65]. VAPBI delivered 1, 3 and 4 fractions for 205 pts (39.7%), 167 pts (32.4%) and 144 pts (28%) respectively. Median CTV was 40.7 cc [95% CI = 26.6 - 72], median V100%, V150%, D90% and Dose non-uniformity ratio (DNR) were 90.2% [95% CI = 84.1 - 97.2], 24.2% [95% CI = 18.9 - 31.6], 103.8% [95% CI = 100.1 - 107.4] and 0.28 [95% CI = 0.23 - 0.33] respectively, 211 late toxicity events were observed in 168 pts (32.6%). Fibrosis, dyschromia, pain and telangiectasia were observed in 26.7%, 7.9%, 7.2% and 0.4 respectively. Grade 2 and 3 late toxicities were observed in 7.2 and 0.6% respectively (no G4). Grade ≥2 late toxicity was observed in 8.1%, 16.7% and 3.7% after 1, 3 and 4 fractions, respectively (p = 0.004). CTV > 50 cc (p = 0.007) and V150 > 40% (p = 0.027) were prognostic factors for G≥2 late toxicity. Regarding oncological outcome, 4-year cumulative incidence of LR, RR and DMD were 2% [95% CI = 0 - 3], 1% [95% CI = 0 - 2] and 1% [95% CI = 0 - 2] respectively. CSS and OS were 98% [95% CI = 96 - 100] and 93% [95% CI = 90 - 96] respectively. No significant difference was observed in terms of oncological outcome between the 3-fractionation groups. VAPBI based on 1 or 2 days of HDR MIB represents an attractive de-escalation irradiation approach for low-risk breast cancer. Late toxicity profile appears acceptable while early oncological outcome shows excellent local control. Brachytherapy technique remains a key component of clinical outcome. Longer follow-up is warranted in order to confirm these encouraging preliminary results.

Outcomes following oropharyngeal squamous cell carcinoma resection and bilateral neck dissection with or without contralateral postoperative radiotherapy of the pathologically node-negative neck

PurposeThere are no consensus guidelines regarding the postoperative treatment of the contralateral pathologically node-negative neck in oropharyngeal squamous cell carcinoma. This study aimed to determine if omission of postoperative irradiation of the contralateral pathologically node-negative neck affects oncological outcomes.MethodsWe retrospectively identified 84 patients with primary surgical treatment including bilateral neck dissection and postoperative (chemo-)radiotherapy (PO(C)RT). Survival was analyzed using the log-rank test and the Kaplan–Meier method.ResultsPatients showed no decrease in tumor-free, cause-specific (CSS), or overall survival (OS) when PO(C)RT of the contralateral pathologically node-negative neck was omitted. Increased OS was found in patients with unilateral PO(C)RT and especially an increased OS and CSS was found in unilateral PO(C)RT and in tumors arising from lymphoepithelial tissue.ConclusionsOmitting the contralateral pathologically node-negative neck appears to be safe in terms of survival and our retrospective study advocates further prospective randomized control de-escalation trials.

Salvage vs. Primary Total Laryngectomy in Patients with Locally Advanced Laryngeal or Hypopharyngeal Carcinoma: Oncologic Outcomes and Their Predictive Factors

The aims of this study were to compare the survival outcomes of salvage vs. primary total laryngectomy (TL) in patients with locally advanced laryngeal or hypopharyngeal carcinoma and to determine their predictive factors. Overall (OS), cause-specific (CSS) and recurrence-free survival (RFS) of primary vs. salvage TL were compared in univariate and multivariate analysis taking into account other potential predictive factors (tumor site, tumor stage, comorbidity level etc.). A total of 234 patients were included in this study. Five-year OS was 53% and 25% for the primary and salvage TL groups, respectively. Multivariate analysis confirmed the independent negative impact of salvage TL on OS (p = 0.0008), CSS (p < 0.0001) and RFS (p < 0.0001). Hypopharyngeal tumor site, ASA score ≥ 3, N-stage ≥ 2a and positive surgical margins were the main other predictors of oncologic outcomes. Salvage TL is associated with significantly worse survival rates than primary TL highlighting the need for careful selection of patients who are candidates for larynx preservation. The predictive factors of survival outcomes identified here should be considered in the therapeutic decision-making, especially in the setting of salvage TL, given the poor prognosis of these patients.

Second Conservative Treatment for Ipsilateral Breast Cancer Recurrence: First 10-Year Oncological Outcome Report

<h3>Purpose/Objective(s)</h3> To analyze long-term oncological outcome after 2^nd conservative treatment (2^ndCT) for patients with ipsilateral 2^nd breast cancer event (2^ndBCE). <h3>Materials/Methods</h3> In this retrospective observational single institution study (Health-data-hub N°F20210402152843), patients with 2^ndBCE underwent 2^ndCT based on lumpectomy plus re-irradiation of the tumor bed with multicatheter interstitial brachytherapy (MIB). Oncological outcome was investigated based on 3^rd breast cancer event (3^rdBCE-FS) and metastatic disease (MD-FS) -free survivals as well as disease-free (DFS), cause-specific (CSS) and overall (OS) survival. Prognostic factors were analyzed. Late toxicity was reported. <h3>Results</h3> From 09/2000 to 05/2013, 113 pts presented a 2^ndBCE managed by 2^ndCT. Median relapse age was 64.8 years [31 - 85]. Median time interval between 1^st and 2^ndBCE was 162 months [24 - 420]. 2^ndIBE occurred in or close to the primary tumor bed in 47.8% and 31% respectively. Median 2^ndBCE size was 11.3 mm [1 - 40] while histological type was invasive ductal or lobular carcinoma in 77% and 13.3% respectively. Regarding APBI classification, patients were low, intermediate and high-risk in 37.2%, 44.4% and 18.6% respectively. Regarding molecular classification, patients were HR+/Her2-, Her2+ and triple negative in 88.8%, 5.1% and 6.1% respectively. New axillary lymph node dissection was performed in 5 pts (4.4%). Low and high-dose rate MIB were used for 27 (24%) and 86 pts (76%) respectively. Median HDR dose was 32 Gy [32 - 34]. Systemic treatments were hormonal (83.2%) and chemo- (13.3%) therapies. With a MFU of 121.5 months [48 – 129.6], 10-y 3^rdBCE-FS, MDFS, DFS, CSS and OS were 89% [83 - 96], 89% [83 - 96], 78% [70 - 87], 95% [91 - 100] and 94% [90 – 99] respectively. In univariate analysis, APBI classification was prognostic factor for 3^rdBCE (LR: 4.8%, IR: 12% and HR: 23.8%; p = 0.02) with a trend for DFS (LR: 19%, IR: 24% and HR: 42.9%; p = 0.055). Ninety-seven complications occurred in 73 pts (G1: 55.7%; G2: 38.1%; G3: 5.2%; G4: 1%) with cutaneous (36.1%) and sub-cutaneous (27.8%) fibrosis, telangiectasia (13.4%) and hyperpigmentation (4.1%). Cosmetic outcome was excellent, good, fair and poor in 70 pts (61.9%), 33 pts (29.2%), fair 9 pts (8%) and 1 pt (0.9%) respectively. <h3>Conclusion</h3> With long-term follow-up, 2^ndBCE managed with lumpectomy and tumor bed re-irradiation (MIB) allows the patient to avoid salvage mastectomy without compromise in oncological outcome. With about 5% of G≥3 late toxicity, final cosmetic outcome remains acceptable. Larger patient cohorts are needed to refine eligibility criteria for 2^ndCT while the place of systemic therapy remains under debate.

Prostate Brachytherapy Boost in the Elderly: Results of a Comparative Study

<h3>Purpose/Objective(s)</h3> To analyze the oncological outcome and toxicity profile in elderly (> 70 years) prostate cancer after high-dose rate brachytherapy (HDB) boost. <h3>Materials/Methods</h3> In this retrospective observational single institution study (Health-data-hub N°F20201008194116), patients with intermediate (IR) and high-risk (HR) prostate cancer underwent external beam radiation therapy (EBRT) followed by HDB boost with or without androgen deprivation therapy (ADT). The impact of patient age (≤ 70 y vs. > 70 y) was investigated. Oncological outcome focused on biochemical (BRFS), local (LRFS), regional (RRFS) and metastatic relapse-free survival (MRFS) as well as Disease-free (DFS), Cause-specific (CSS) and overall survival (OS). Late genito-urinary (GU) and gastro-intestinal (GI) toxicities were investigated. <h3>Results</h3> From 02/09 to 12/21, 519 pts received a HDB boost. Among them, 387 were analyzed (≤70y: 180 pts [47%] vs. >70y: 207 pts [53%]). Regarding NCCN classification, 98 pts (≤70y: 53 pts; >70y: 45 pts; p = NS) and 289 pts (≤70y: 127 pts; >70y: 162 pts; p = NS) were IR and HR pts respectively. Intensity modulated RT was used in 241 pts (62.6%) with pelvic irradiation in 336 pts (86.2%) for a median dose of 45.5 Gy [35 – 57.5] in 23 fractions [15 - 25]. HDB boost was performed under general/spinal anesthesia delivering a single fraction of 14 or 15 Gy for 307 pts (79.3%). ADT was used in 309 pts (≤70y: 133 pts; >70y: 176 pts; p = 0.009) for a median time of 17.1 months [3 - 41] (IR: 6 months; HR: 18.8 months). With a median follow-up (MFU) of 72.3 months [64.6 – 81.1] for the whole cohort, 5-y BRFS, 5-y LRFS, 5-y RRFS and 5-y MRFS were 88% [84 - 92], 97% [95 - 99], 99% [98 - 1], 95% [93 - 98] respectively with 5-y DFS, 5-y CSS and 5-y OS of 84% [80-88], 99% [97-100] and 94% [92 - 97]. With the same MFU of 60 months in both age groups, oncological outcome was not statically different except for the 5-y CSS (≤70y: 97% [94 - 100] vs. >70y: 100%; p=0.05). Late GU toxicity was observed in 124 pts (32.1%) with 9 G3 pts (7.2%). Late GI toxicity was observed in 41 pts (10.2%) with no G3. However, in a subgroup analysis comparing 70y< pts ≤80y vs. >80y pts, a significant difference was noticed in terms of late GU toxicity (29.7% vs. 61.9%; p = 0.006). <h3>Conclusion</h3> For IR and HR prostate cancers, HDB boost leads to high rates of disease control with less than 3% of late G3 GU/GI toxicities. For elderly pts (>70y), HDB boost remains warranted in order to achieve optimal oncological outcome mainly in HR pts, although competing comorbidity factors will significantly impact the OS. However, HDB boost should be carefully discussed in the super senior pts (> 80 y). Due to the increase in life expectancy, the management of prostate cancer in the elderly is a real challenge for patients, clinicians, health care providers and payers. Except for unfit men, elderly patients remain candidates for optimal curative treatment (i.e., regardless of age) after oncogeriatric assessment.

Single Fraction HDR Brachytherapy for Prostate Cancer: SiFEPI Phase II Trial Results

<h3>Purpose/Objective(s)</h3> To report the results of the <i>Single Fraction Early Prostate Irradiation</i> (SiFEPI) phase 2 prospective trial. <h3>Materials/Methods</h3> The SiFEPI trial (NCT02104362) evaluated a single fraction of high-dose rate brachytherapy (HDB) for low- (LR) and low-intermediate (LIR) risk prostate cancers. After injection of 10 ml of macromolecular hyaluronic acid (rectal spacer), needles were implanted under endorectal ultrasound guidance. After post-implant CT scan, a single fraction of 20 Gy was delivered to the prostate taking into account the dose constraints for CTV and organs at risk (urethra, rectum, anus). Oncological outcome (biochemical (bRFS), local (lRFS), and metastatic (mRFS) relapses and disease-free (DFS), cause-specific (CSS) and overall (OS) survivals), toxicity profile (acute [d30, d90, d180] and late [> 6 months] genito-urinary (GU), gastro-intestinal (GI) and sexual (S) toxicities) were investigated as well as quality of life (QLQ-C30 and QLQ-PR25). <h3>Results</h3> From March 2014 to October 2017, 35 pts were enrolled. Among them, 33 were evaluable. With a median age of 66 y [46 - 79], 25 (76%) and 8 (24%) pts were LR and FIR respectively. Median MRI prostatic volume was 41 cc [19 - 84]. Median peak-urinary flow and post-void residual volume were 17 ml/s [8 - 25] and 19 cc [0 - 165] while 30 pts (91%) had an IIEF score between 16 and 25. Median CTV, D90% and V100% were 50 cc [29 - 92], 106% [104 - 109], and 98% [96 - 99] respectively. With a MFU of 72.8 months [64 - 86], 6y-bRFS, lRFS and mRFS were 62% [45 - 85], 61% [44 - 85] and 93% [85 - 100] respectively while 6y-DFS, CSS and OS were 54% [37 - 77], 100% and 89% [77 - 100]. Acute GU, GI and S toxicities were observed in 27 pts (82%; 36 G1 & 8 G2), 5 pts (15%; 7 G1 & 3 G2) and 5 pts (15%; 3 G1 & 2 G2) respectively and no acute G3 toxicity was observed. Late GU, GI and S toxicities were observed in 11 pts (33%; 18 G1), 4 pts (12%; 4 G1) and 7 pts (21%; 1 G1, 5 G2 & 1 G3) respectively. QLQ-C30 and QLQ-PR25 will be reported later. Biochemical relapse (BR) was observed in 11 pts (33%; 7 LR & 4 FIR) with a median time interval between HDB and BR of 51 months [24 – 69]. Among them, 9 pts (82%) presented a histologically proven isolated local recurrence and underwent salvage prostate re-irradiation delivering a median dose of 78 Gy [73 – 78] (2 Gy/f). With a MFU from salvage EBRT of 27 months [3 – 59], 2^nd bRFS rate was 100%. One pt presented a G3 GU toxicity (hematuria) while no G≥3 GI complication was observed. <h3>Conclusion</h3> Long-term results of the SiFEPI phase 2 prospective trial showed that a single fraction of 20 Gy (HDB) leads to a sub-optimal biochemical control for LR and LIR prostate cancers. The reported oncological outcome is in line with the previous series of HDB single fraction protocols. However, late GU and GI toxicity profile is encouraging (especially compared to iodine implant series), leading to consideration of HDB as a safe irradiation technique. Salvage EBRT appears feasible with an acceptable risk of complications.

Prognostic factors for squamous cervical carcinoma identified by competing-risks analysis: A study based on the SEER database.

Cervical cancer has a high incidence of malignant tumors and a high mortality rate, with squamous cervical carcinoma (SCC) accounting for 80% of cases. A competing-risks model is recommended as being more feasible for evaluating the prognosis and guiding clinical practice in the future compared to Cox regression. Data originating from the Surveillance, epidemiology, and end results (SEER) database during 2004 to 2013 were analyzed. Univariate analysis with the cumulative incidence function was performed to assess the potential risk of each covariate. Significant covariates (P < .05) were extracted for inclusion in a Cox regression analysis and a competing-risks model that included a cause-specific (CS) hazard function model and a sub-distribution (SD) hazard function model. A total of 5591 SCC patients met the inclusion criteria. The three methods (Cox regression analysis, CS analysis, and SD analysis) showed that age, metastasis, American Joint Committee on Cancer stage, surgery, chemotherapy, radiation sequence with surgery, lymph node dissection, tumor size, and tumor grade were prognostic factors affecting survival in patients with SCC. In contrast, race and radiation status were prognostic factors affecting survival in the Cox regression and CS analysis, but the results were different in the SD analysis. Being separated, divorced, or widowed was an independent prognostic factor in the Cox regression analysis, but the results were different in the CS and SD analyses. A competing-risks model was used as a new statistical method to more accurately identify prognostic factors than conventional Cox regression analysis leading to bias in the results. This study found that the SD model may be better suited to estimate the clinical prognosis of a patient, and that the results of an SD model analysis were close to those of a CS analysis.

Abstract 6315: Are a subset of patients at higher risk for mortality in stage III colon cancer: An analysis of the SEER database

Abstract Background: High-risk features (HRF) increase mortality for Stage II colon cancer (CC). These HRF include pathologic T4 disease, perineural invasion (PNI), lymphovascular invasion (LVI), an inadequate lymphadenectomy (less than 12 lymph nodes harvested) and poorly differentiated tumors. The presence of two or more HRF has an additive impact on survival for patients with Stage II CC. While T4 and disease greater than N1a raise the risk of mortality in Stage III CC, the effect of the other accepted HRF in patients with Stage III CC has not been studied. Materials and Methods: Surveillance, Epidemiology and End Results (SEER) (2010 - 2017) was used to identify patients with Stage III and IV CC. Patients with Stage III CC were then further classified by the presence of zero, 1, or 2 or more of the following HRF: pathologic T4, PNI, inadequate lymphadenectomy, or poor differentiation. Overall (OS) and cause-specific (CS) survival were calculated. Results: 57,640 patients with Stage III or IV CC were identified. 35,760 (62%) patients had Stage III disease and 21,880 (38%) had Stage IV disease. Among patients with Stage III disease, 16,733 (46.8%) had no HRF, 12,703 (35.5%) had 1 HRF and 6,324 (17.7%) had 2 or more HRF. For patients with 1 HRF, 4,610 (36.3%) had poor differentiation, 2,339 (18.4%) had PNI, 3,673 (28.9%) had T4 disease, and 2,078 (16.4%) had an inadequate nodal harvest. Patients with Stage III CC without HRF had the best OS (73.3%) and CS (81.4%,). This was followed by Stage III with 1 HRF (OS 63.7%, CS 71.6%) and Stage III with 2 or more HRF (OS 44%, CS 51%). Patients with Stage IV disease had the worst OS (18.1%) and CS (20.4%) (p&amp;lt;0.05). For patients with 1 HRF, pathologic T4 conferred worse OS (57.2%) and CS (63.2%), compared to PNI (OS 66.4%, CS 73.7%), inadequate lymphadenectomy (OS 64.6%, CS 74.9%) and poor differentiation (OS 66.6%, CS 75.4%) (p&amp;lt;0.01). Conclusion: HRF have a cumulative influence on OS and CS in patients with Stage III CC. The presence of multiple HRF should be considered higher risk for patients with Stage III disease. Citation Format: Luv N. Hajirawala, Yong Yi, Michelle A. Bergeron, Danielle A. Dooley, Guy R. Orangio, Elyse R. Bevier-Rawls, Kurt G. Davis, Jeffrey S. Barton. Are a subset of patients at higher risk for mortality in stage III colon cancer: An analysis of the SEER database [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6315.

High-dose-rate brachytherapy boost for elderly patients with intermediate to high-risk prostate cancer: 5-year clinical outcome of the PROSTAGE cohort

PurposeTo analyze the oncological outcome in elderly (>70 years) prostate cancer after high-dose rate brachytherapy (HDB) boost. Materials/methodsIn this retrospective study, patients with intermediate (IR) and high-risk (HR) prostate cancer underwent external beam radiation therapy (EBRT) followed by HDB boost with/without androgen deprivation therapy (ADT). The impact of age (≤70y vs. > 70y) was investigated. Oncological outcome focused on biochemical relapse-free survival (bRFS), cause-specific (CSS) and overall survival (OS). Late genito-urinary (GU) and gastro-intestinal (GI) toxicities were investigated. ResultsFrom 07/08 to 01/22, 518 pts received a HDB boost, and 380 were analyzed (≤70y:177pts [46.6%] vs. > 70y:203pts [53.4%]). Regarding NCCN classification, 98 pts (≤70y: 53pts; >70y: 45pts; p = 0.107) and 282 pts (≤70y: 124pts; >70y: 158pts; p = NS) were IR and HR pts respectively. Median EBRT dose was 46 Gy [37.5–46] in 23 fractions [14–25]. HDB boost delivered a single fraction of 14/15 Gy (79%). ADT was used in 302 pts (≤70y: 130pts; >70y: 172pts; p = 0.01). With MFU of 72.6 months [67–83] for the whole cohort, 5-y bRFS, 5-y CSS and 5-y OS were 88% [85–92], 99% [97–100] and 94% [92–97] respectively; there was no statistical difference between the two age groups except for 5-y CSS (p = 0.05). Late GU and GI toxicity rates were 32.4% (G ≥ 3 7.3%) and 10.1% (no G3) respectively. ConclusionsFor IR and HR prostate cancers, HDB boost leads to high rates of disease control with few late G ≥ 3 GU/GI toxicities. For elderly pts, HDB boost remains warranted mainly in HR pts, while competing comorbidity factors influence OS.

Five-year cause-specific survival after meningioma surgery. A nationwide population-based study

BackgroundSurvival after meningioma surgery is often reported with inadequate allowance for competing causes of death. MethodsWe processed the French administrative medical database (Système National des Données de Santé: SNDS), to retrieve appropriate cases of surgically treated meningioma. Cause-specific survival in meningioma-related death was analyzed with the Fine & Gray (F&G) and cause-specific (CS) Cox models to identify associated factors. ResultsFive-year cumulative incidence was 2.85% for meningioma-related death and 6.3% for unrelated death (P<0.001). In the adjusted F&G and cause-specific Cox regression models for meningioma-related death, gender, age at surgery, co-morbidities, neurofibromatosis type 2, tumor insertion, tumor grade, cerebrospinal fluid (CSF) shunt insertion, preoperative embolization and need for redo surgery for recurrence emerged as independent prognostic factors of cause-specific survival (CSS) in meningioma-related death. ConclusionAt 5 years, the risk of meningioma-unrelated death was 2.21-fold greater than the risk of dying from the meningioma disease. Five-year CSS after meningioma surgery was greater in younger adults with benign spinal meningioma with low comorbidity. Those with malignant cranial tumor requiring preoperative embolization or CSF shunting for associated hydrocephalus and with severely degraded overall health status showed a significantly increased risk of meningioma-related death. Redo surgery for recurrence failed to improve the risk of meningioma-related death. We recommend the use of net survival methods such as CSS in meningioma studies where unrelated mortality is predominant, as this approach results in more accurate estimates of disease risk and associated predictors.

Generation and validation of a PET radiomics model that predicts survival in diffuse large B cell lymphoma treated with R-CHOP14: A SAKK 38/07 trial post-hoc analysis.

Functional parameters from positron emission tomography (PET) seem promising biomarkers in various lymphoma subtypes. This study investigated the prognostic value of PET radiomics in diffuse large B-cell lymphoma (DLBCL) patients treated with R-CHOP given either every 14 (testing set) or 21 days (validation set). Using the PyRadiomics Python package, 107 radiomics features were extracted from baseline PET scans of 133 patients enrolled in the Swiss Group for Clinical Cancer Research 38/07 prospective clinical trial (SAKK 38/07) [ClinicalTrial.gov identifier: NCT00544219]. The international prognostic indices, the main clinical parameters and standard PET metrics, together with 52 radiomics uncorrelated features (selected using the Spearman correlation test) were included in a least absolute shrinkage and selection operator (LASSO) Cox regression to assess their impact on progression-free (PFS), cause-specific (CSS), and overall survival (OS). A linear combination of the resulting parameters generated a prognostic radiomics score (RS) whose area under the curve (AUC) was calculated by receiver operating characteristic analysis. The RS efficacy was validated in an independent cohort of 107 DLBCL patients. LASSO Cox regression identified four radiomics features predicting PFS in SAKK 38/07. The derived RS showed a significant capability to foresee PFS in both testing (AUC, 0.709; p<0.001) and validation (AUC, 0.706; p<0.001) sets. RS was significantly associated also with CSS and OS in testing (CSS: AUC, 0.721; p<0.001; OS: AUC, 0.740; p<0.001) and validation (CSS: AUC, 0.763; p<0.0001; OS: AUC, 0.703; p=0.004) sets. The RS allowed risk classification of patients with significantly different PFS, CSS, and OS in both cohorts showing better predictive accuracy respect to clinical international indices. PET-derived radiomics may improve the prediction of outcome in DLBCL patients.

Competing risk of mortality in association studies of non-fatal events.

In geriatric research of non-fatal events, participants often die during the study follow-up without having the non-fatal event of interest. Cause-specific (CS) hazard regression and Fine-Gray (FG) subdistribution hazard regression are the two most common estimation approaches addressing such competing risk. We explain how the conventional CS approach and the FG approach differ and why many FG estimates of associations are counter-intuitive. Additionally, we clarify the indirect link between models for hazard and models for cumulative incidence. The methodologies are contrasted on data from the Cardiovascular Health Study, a population-based study in adults aged 65 years and older.

Prognostic Value of the N1c in Stage III and IV Colorectal Cancer: A Propensity Score Matching Study Based on the Surveillance, Epidemiology, and End Results (SEER) Database

Introduction: The prognostic role of the N1c remains unclear in colorectal cancer (CRC). Our study aimed to determine the prognostic value of N1c. Methods: Patients diagnosed in 2010-2015 were accessed from the Surveillance, Epidemiology, and End Results (SEER) database. COX univariate and multivariate regression analysis and the Kaplan-Meier method were used to assess the impact of the N1c stage on the cause-specific (CSS) and overall survival (OS). Propensity score matching (PSM) was used to construct a matched group with similar propensity scores. Results: Kaplan-Meier analysis showed that the CSS and OS rates in N1a were significantly better than N1c in stage III and IV CRCs after reducing selection bias (CSS: P < 0.001 in stage III, P = 0.041 in stage IV; OS: P < 0.001 in stage III, P = 0.0079 in stage IV). There were no statistical differences in CSS and OS between N1b and N1c (CSS: P = 0.500 in stage III, P = 0.270 in stage IV; OS: P = 0.390 in stage III, P = 0.600 in stage IV). Further, the prognostic value of N1c with only one tumor deposit (TD) is equivalent to N1a based on the comparison of CSS and OS rates (CSS: P = 0.420; OS: P = 0.310). Whereas N1c with only one TD had significantly better CSS and OS than N1b (CSS: P = 0.039; OS: P = 0.037). Conclusion: The CSS and OS rates of N1c do not achieve a statistical difference with N1b in both stage III and IV CRCs. Significantly, higher CSS and OS rates were found in N1c with only one TD versus N1b stage in stage III CRC.

Improving the Policy Utility of Cause of Death Statistics in Sri Lanka: An Empirical Investigation of Causes of Out-of-Hospital Deaths Using Automated Verbal Autopsy Methods.

Background: Setting public health policies and effectively monitoring the impact of health interventions requires accurate, timely and complete cause of death (CoD) data for populations. In Sri Lanka, almost half of all deaths occur outside hospitals, with questionable diagnostic accuracy, thus limiting their information content for policy.Objectives: To ascertain whether SmartVA is applicable in improving the specificity of cause of death data for out-of-hospital deaths in Sri Lanka, and hence enhance the value of these routinely collected data for informing public policy debates.Methods: SmartVA was applied to 2610 VAs collected between January 2017 and March 2019 in 22 health-unit-areas clustered in six districts. Around 350 community-health-workers and 50 supervisory-staffs were trained. The resulting distribution of Cause-Specific-Mortality-Fractions (CSMFs) was compared to data from the Registrar-General's-Department (RGD) for out-of-hospital deaths for the same areas, and to the Global-Burden-of-Disease (GBD) estimates for Sri Lanka.Results: Using SmartVA, for only 15% of deaths could a specific-cause not be assigned, compared with around 40% of out-of-hospital deaths currently assigned garbage codes with “very high” or “high” severity. Stroke (M: 31.6%, F: 35.4%), Ischaemic Heart Disease (M: 13.5%, F: 13.0%) and Chronic Respiratory Diseases (M: 15.4%, F: 10.8%) were identified as the three leading causes of home deaths, consistent with the ranking of GBD-Study for Sri Lanka for all deaths, but with a notably higher CSMF for stroke.Conclusions: SmartVA showed greater diagnostic specificity, applicability, acceptability in the Sri Lankan context. Policy formulation in Sri Lanka would benefit substantially with national-wide implementation of VAs.

Theory development in servitization through the application of fsQCA and experiments

PurposeThe purpose of this study is to explain how the application of fuzzy-set qualitative comparative analysis (fsQCA) and experiments can advance theory development in the field of servitization by generating better causal explanations.Design/methodology/approachFsQCA and experiments are established research methods that are suited for developing causal explanations but are rarely utilized by servitization scholars. To support their application, we explain how fsQCA and experiments represent distinct ways of developing causal explanations, provide guidelines for their practical application and highlight potential application areas for a future research agenda in the servitization domain.FindingsFsQCA enables specification of cause–effects relationships that result in equifinal paths to an intended outcome. Experiments have the highest explanatory power and enable the drawing of direct causal conclusions through reliance on an interventionist logic. Together, these methods provide complementary ways of developing and testing theory when the research objective is to understand the causal pathways that lead to observed outcomes.Practical implicationsApplications of fsQCA help to explain to managers why there are numerous causal routes to attaining an intended outcome from servitization. Experiments support managerial decision-making by providing definitive “yes/no” answers to key managerial questions that address clearly specified cause–effect relationships.Originality/valueThe main contribution of this study is to help advance theory development in servitization by encouraging greater methodological plurality in a field that relies primarily on the qualitative case study methodology.

Effect of a Pay-for-Performance Program on Renal Outcomes Among Patients With Early-Stage Chronic Kidney Disease in Taiwan.

With the promising outcomes of the pre-ESRD (end-stage renal disease) pay-for-performance (P4P) program, the National Health Insurance Administration (NHIA) of Taiwan launched a P4P program for patients with early chronic kidney disease (CKD) in 2011, targeting CKD patients at stages 1, 2, and 3a. This study aimed to examine the long-term effect of the early-CKD P4P program on CKD progression. We conducted a matched cohort study using electronic medical records from a large healthcare delivery system in Taiwan. The outcome of interest was CKD progression to estimated glomerular filtration rate (eGFR) <45 mL/min/1.73 m2 between P4P program enrolees and non-enrolees. The difference in the cumulative incidence of CKD progression between the P4P and non-P4P groups was tested using Gray's test. We adopted a cause-specific (CS) hazard model to estimate the hazard in the P4P group as compared to non-P4P group, adjusting for age, sex, baseline renal function, and comorbidities. A subgroup analysis was further performed in CKD patients with diabetes to evaluate the interactive effects between the early-CKD P4P and diabetes P4P programs. The incidence per 100 person-months of disease progression was significantly lower in the P4P group than in the non-P4P group (0.44 vs. 0.69, P<.0001), and the CS hazard ratio (CS-HR) for P4P program enrolees compared with non-enrolees was 0.61 (95% CI: 0.58-0.64, P<.0001). The results of the subgroup analysis further revealed an additive effect of the diabetes P4P program on CKD progression; compared to none of both P4P enrolees, the CS-HR for CKD disease progression was 0.60 (95% CI: 0.54-0.67, P<.0001) for patients who were enrolled in both early-CKD P4P and diabetes P4P programs. The present study results suggest that the early-CKD P4P program is superior to usual care to decelerate CKD progression in patients with early-stage CKD.

Competitive Risk Analysis of Prognosis in Patients With Cecum Cancer: A Population-Based Study.

Background:The presence of competing risks means that the results obtained using the classic Cox proportional-hazards model for the factors affecting the prognosis of patients diagnosed with cecum cancer (CC) may be biased.Objective:The purpose of this study was to establish a competitive risk model for patients diagnosed with CC to evaluate the relevant factors affecting the prognosis of patients, and to compare the results with the classical COX proportional risk model.Methods:We extracted data on patients diagnosed with CC registered between 2004 and 2016 in the Surveillance, Epidemiology, and End Results (SEER) database. The univariate analysis utilized the cumulative incidence function and Gray’s test, while a multivariate analysis was performed using the Fine-Gray, cause-specific (CS), and Cox proportional-hazards models.Results:The 54463 eligible patients diagnosed with CC included 24387 who died: 12087 from CC and 12300 from other causes. The multivariate Fine-Gray analysis indicated that significant factors affecting the prognosis of patients diagnosed with CC include: age, race, AJCC stage, differentiation grade, tumor size, surgery, radiotherapy, chemotherapy and regional lymph nodes metastasis. Due to the presence of competitive risk events, COX model results could not provide accurate estimates of effects and false-negative results occurred. In addition, COX model misestimated the direction of association between regional lymph node metastasis and cumulative risk of death in patients diagnosed with CC. Competitive risk models tend to be more advantageous when analyzing clinical survival data with multiple endpoints.Conclusions:The present study can help clinicians to make better clinical decisions and provide patients diagnosed with CC with better support.

Sequencing of Adjuvant Chemoradiation for Advanced Stage Endometrial Cancer: Outcomes and Toxicity Profiles

Adjuvant radiation (RT) is frequently used in addition to adjuvant chemotherapy (C) for advanced stage endometrial cancer (EC) to improve outcomes, however little data is available to guide the sequencing of adjuvant therapy. We retrospectively reviewed patients with stage III-IVA EC treated at our institution and compared outcomes and toxicities of patients treated with “sandwich” CRT (consisting of C, then RT, then C) versus patients treated with any “other” sequence approach (C then RT, or RT then C, or concurrent CRT). We identified 107 patients with stage III-IVA EC treated at our institution from 2000-2018 who underwent surgical staging followed by both adjuvant C and RT. Only patients with complete treatment records and a minimum of six months follow up were included. Baseline characteristics and details of adjuvant treatment were recorded. Acute and chronic toxicities were defined as side effects < = 6 m and > 6 m after completion of adjuvant CRT, respectively. Toxicity was graded according to CTCAE v4.0. Local (LR), regional (RR), distant (DM), overall (OS), cause specific (CSS), and disease-free survival (DFS) were calculated using Kaplan Meier. Effects of adjuvant treatment order (sandwich vs other) on recurrence, survival, and toxicity were analyzed using t-tests for continuous variables, chi-squared for categorical variables, and Kaplan-Meier estimates. P-values < 0.05 were considered significant. Median age was 63 yrs (33-90) with a median follow up of 3.2 yrs (0.4-14). Histologies were 51% endometrioid, 26% serous, and 23% mixed, other, or unknown. Twenty-one percent were stage IIIA, 9% IIIB, 68% IIIC, and 2% IVA. Twenty-five percent had grade I disease, 27% grade 2, and 43% grade 3. Five yr outcomes were as follows: LR 7%, RR 15%, DM 33%, DFS 82%, and OS 68%. There were no significant differences in clinical outcomes or in the rates of acute toxicity by treatment sequence. Rates of chronic toxicity are shown below. The overall rates of chronic GI, GU, and GYN toxicity were significantly lower in the sandwich group. There were no grade 4 or 5 acute or chronic toxicities. Advanced stage EC is an aggressive disease and adjuvant C and RT are indicated. Clinical outcomes were similar amongst the different sequencing algorithms; however, sandwich therapy led to lower rates of chronic toxicity, offering an opportunity to improved quality of life in survivorship.Tabled 1Abstract 3072; TableToxicity (grade 1, 2, 3)SandwichOtherP-valueOverall26.7%, 15.6%, 0%31.8%, 22.7%, 27.3%<0.001Diarrhea7%, 2%, 0%23%, 0%, 0%0.135Constipation0%, 0%, 0%14%, 0%, 0%0.032Small bowel/colon obstruction0%, 0%, 0%4.5%, 0%, 0%0.328Urinary tract pain/dysuria0%, 0%, 0%13.5%, 4.5%, 0%0.013Frequency/Urgency7%, 0%, 0%23%, 4%, 0%0.051Pelvic pain0%, 0%, 0%27%, 0%, 0%0.001Vaginal Stenosis/Stricture9%, 9%, 0%27%, 14%, 18%0.001 Open table in a new tab