Lower Cause-specific Survival Research Articles

An Immune Gene Expression Risk Score for Distant Metastases after Radiotherapy for Cervical Cancer.

To develop an immune-based gene expression risk score to identify patients with cervical cancer at increased risk of distant metastases (DM). Tumor biopsies were obtained from 81 patients prior to chemoradiotherapy. Whole-transcriptome RNA sequencing was performed (Illumina NextSeq500). Beginning with 4,723 immune-related genes, a 55-gene risk score for DM was derived using Cox modeling and principal component analysis. It was validated in independent cohorts of 274 patients treated at the Norwegian Radium Hospital (NRH) and 206 patients from The Cancer Genome Atlas (TCGA). The risk score was predictive of DM (HR, 2.7; P < 0.0001) and lower cause-specific survival (CSS) by univariate analysis (HR, 2.0; P = 0.0003) and multivariate analysis adjusted for clinical factors (DM HR, 3.0; P < 0.0001; CSS HR, 2.2; P = 0.0004). The risk score predicted DM (HR, 1.4; P = 0.05) and CSS (HR, 1.48; P = 0.013) in the NRH cohort and CSS (HR, 1.4; P = 0.03) in TCGA cohort. Higher risk scores were associated with lower CIBERSORT estimates of tumor-infiltrating immune cells, including CD8 T cells and M1 and M2 macrophages (all P < 0.001). Higher risk scores were associated with lower expression (all P < 0.001) of important chemokines (CXCL12, CXCR4), IFN-regulated genes (IRF1, STAT1, IDO1), and immune checkpoint regulators (PD-1, PD-L1, CTLA-4). The immune metastatic risk score addresses important challenges in the treatment of cervical cancer-identifying patients at high risk of DM after radiotherapy. The findings of this study indicate that high tumor mutational burden and a "cold," immune-excluded tumor microenvironment influence distant metastatic recurrence. Further validation of the risk score is needed.

Significance of histology and nodal status on the survival of women with early-stage cervical cancer: validation of the 2018 FIGO cervical cancer staging system.

ObjectiveTo assess the efficacy of the FIGO 2018 classification system for nodal-specific classifications for early-stage cervical cancer; specifically, to examine the impact of nodal metastasis on survival and the effect of postoperative treatments, according to histological subtypes.MethodsThis society-based retrospective observational study in Japan examined 16,539 women with the 2009 FIGO stage IB1 cervical cancer who underwent primary surgical treatment from 2004 to 2015. Associations of cause-specific survival (CSS) with nodal metastasis and postoperative adjuvant therapy were examined according to histology type (squamous cell carcinoma [SCC], n=10,315; and non-SCC, n=6,224).ResultsThe nodal metastasis rate for SCC was higher than that for non-SCC (10.7% vs. 8.3%, p<0.001). In multivariable analysis, the impact of nodal metastasis on CSS was greater for non-SCC tumors (adjusted-hazard ratio [HR], 3.11; 95% confidence interval [CI], 2.40–4.02) than for SCC tumors (adjusted-HR, 2.20; 95% CI, 1.70–2.84; p<0.001). Propensity score matching analysis showed significantly lower CSS rates for women with pelvic nodal metastasis from non-SCC tumors than from SCC tumors (5-year CSS rate, 75.4% vs. 90.3%, p<0.001). The CSS rates for women with nodal metastasis in SCC histology were similar between the postoperative concurrent chemoradiotherapy/radiotherapy and chemotherapy groups (89.2% vs. 86.1%, p=0.42), whereas those in non-SCC histology who received postoperative chemotherapy improved the CSS (74.1% vs. 67.7%, p=0.043).ConclusionThe node-specific staging system in the 2018 FIGO cervical cancer classification is applicable to both non-SCC tumors and SCC tumors; however, the prognostic significance of nodal metastases and efficacy of postoperative therapies vary according to histology.

Survival trends for patients with primary metastatic prostate cancer before and after the introduction of new antitumor drugs.

During the past two decades, new antitumor drugs (Abiraterone, Enzalutamide, Radium-223, Cabazitaxel, and Docetaxel) have been introduced for treatment of prostate cancer with distant metastases (mPCa). Each drug have demonstrated a survival gain in studies, but little is known about the impact in a general population of mPCa patients. In this study we assessed survival before and after introduction of the new drugs for Norwegian mPCa patients. Survival was assessed in 5542 patients with primary mPCa. The patients were diagnosed between 2004 and 2018, identified in the Norwegian Cancer Registry. We also analyzed a subgroup of 2738 patients possibly eligible for treatment with new drugs (age <80 years, WHO performance status ≤2 and not dead within 3 months from diagnosis). We estimated overall (OS) and cause-specific survival (CSS) across three diagnostic time periods reflecting to the drugs' introduction in Norway: Before (2004-2009), "in between" (2010-2014) and after the introduction (2015-2018). We used Kaplan-Meier survival analysis and multivariable Cox regression. Median OS increased from 2.3 years in 2004-2009 to 3.3 years in 2015-2018. 3-year OS improved from 41% in 2004-2009 to 51% in 2015-2018. An earlier diagnostic period, a more advanced T stage, higher ISUP grade group, lower WHO status and higher PSA levels were associated with a lower CSS. Similar results was found for the subgroup. Median OS of mPCa has increased by one year since 2004 for mPCa patients in Norway. Survival improvement persisted after adjustment for recognized prognostic factors and may be related to the introduction of new drugs in Norway.

Risk stratification in differentiated thyroid cancer with RAI-avid lung metastases.

ObjectiveRadioactive iodine (RAI) therapy is effective for differentiated thyroid cancer (DTC) patients with lung metastasis. However, some patients have a poor prognosis despite the RAI accumulation. The utility of inflammatory biomarkers, including neutrophil-to-lymphocyte ratio (NLR), has been reported as a prognostic factor for many carcinomas. This study aimed to investigate the risk factors related to DTC patient survival with RAI-avid lung metastasis and to attempt risk stratification.Design and methodsThis retrospective study included 123 patients with RAI-accumulating lung metastatic DTC. The cause-specific survival (CSS) rate from the time of detection of lung metastasis was tested using the Kaplan–Meier log-rank test, and the multivariate analysis was calculated using the Cox proportional hazards model. NLR was retrospectively calculated using the blood sample collected before initial RAI treatment. The NLR cutoff value was 2.6 on the ROC curve.ResultsAge ≥ 55 years at the time of operative treatment, follicular carcinoma, lung metastasis tumor ≥ 10 mm in diameter, age ≥ 55 years at the time of detection of lung metastasis, age ≥ 55 years at the time of RAI treatment, and NLR ≥ 2.6 at the initial RAI treatment were predictive of decreased CSS. Multivariate analysis identified that the independent prognostic factors were lung metastatic tumor ≥ 10 mm in diameter and NLR ≥ 2.6. Patients in the high-risk group with both factors had significantly lower CSS rates than those in the low- and intermediate-risk groups with one or none of these factors.ConclusionsThe high-risk group patients had significantly poorer survival, and these patients could be considered as future candidates for tyrosine kinase inhibitor therapy.

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

ObjectivesTo compare survival and progression outcomes between 2 nodal assessment approaches in patients with nonbulky stage IIIC endometrial cancer (EC). MethodsPatients 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. ResultsThe 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. ConclusionsIn 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.

Impact on survival with adjuvant radiotherapy for clear cell, mucinous, and endometriod ovarian cancer: the SEER experience from 2004 to 2011.

ObjectiveEvaluate the impact of radiotherapy on cause specific survival (CSS) and overall survival (OS) for stage (I–III) clear cell, mucinous, and endometriod ovarian cancer.MethodsWe analyzed incidence, survival, and treatments from the Surveillance, Epidemiology, and End Results (SEER) Program from 2004 to 2011 for clear cell, mucinous, and endometriod histologies of the ovary for stages (I–III). We examined CSS and OS for all three histologies combined and each histology with relation to the use of adjuvant radiation therapy (RT). Survival analysis was calculated by Kaplan-Meier and log-rank analysis.ResultsCSS was higher in individuals not receiving RT at 5 years (81% vs. 74%) and 10 years (74% vs. 65%, p=0.003). OS was higher in individuals not receiving RT at 5 years (76% vs. 73%) and 10 years (64% vs. 59%, p=0.039). Stage III patients receiving RT had a higher OS at 5 years (54% vs. 44%) and 10 year intervals (36% vs. 30%, p=0.037). Stage III patients with mucinous histology receiving RT had a higher OS at 5 years (50% vs. 36%) and 10 years (45% vs. 26%, p=0.052).ConclusionThose receiving RT had a lower CSS and OS at 5 and 10 years. However, subgroup analysis revealed a benefit of RT in terms of OS for all stage III patients and for stage III patients with mucinous histology.

Comparing outcomes in poorly-differentiated versus anaplastic thyroid cancers treated with radiation: a surveillance, epidemiology, and end results analysis.

Poorly differentiated thyroid carcinoma (PDTC) and anaplastic thyroid carcinoma (ATC) are considered the most aggressive cancers of the head and neck. The aim of the study was to evaluate and compare survival outcomes in PDTC and ATC in a large population-based cohort. Patients with PDTC and ATC diagnosed from 1973 to 2008 were obtained from Surveillance, Epidemiology, and End RESULTS database. Kaplan-Meier survival analysis and log-rank analyses were performed to evaluate (1) The effect of histology on cause-specific survival (CSS) and (2) the influence of factors such as treatment, treatment sequence, race, sex, and age on CSS. Multivariate analysis was performed to assess the independent effect of these factors on CSS. A total of 1352 patients with PDTC and ATC were identified. PDTC constituted 52.4% of patients versus 47.6% for ATC. Median CSS was similar in the two histology groups (P = 0.14). Both PDTC and ATC patients receiving radioisotopes showed a significantly better CSS compared to external beam radiation (P < 0.0001). PDTC and ATC Patients receiving radiation prior to surgery demonstrated a significantly lower CSS compared to patients receiving radiation postoperatively (P < 0.0001). Female gender and black/nonwhite race tended to improve CSS in PDTC and ATC patients (P = 0.29 and P = 0.03, for gender and race, respectively). However, multivariate analysis revealed only type of radiation treatment and age to be independently associated with CSS. This is the first large population-based study evaluating PDTC and ATC outcomes in patients who received radiation treatment. Radioisotope use and timing of radiotherapy (postoperative vs. preoperative) were associated with improved CSS in both histologies.

Long-term outcomes of prostate cancer patients with Gleason pattern 5 treated with combined brachytherapy and external beam radiotherapy

Recent reports have suggested relatively poor prognosis for prostate cancer patients with Gleason pattern 5 treated with dose-escalated external beam radiotherapy (XRT) and androgen deprivation therapy (ADT). We present the largest series of men with high-risk, Gleason pattern 5 prostate cancer treated with permanent interstitial brachytherapy and XRT. Between April 1995 and December 2008, 329 consecutive patients with National Comprehensive Cancer Network high-risk disease were treated with permanent interstitial brachytherapy. Most received XRT and ADT. Median followup was 7.2 years. The cause of death was determined for each deceased patient. Multiple clinical, treatment, and dosimetric parameters were evaluated for impact on the evaluated survival parameters. At 10 years, biochemical progression-free survival, cause-specific survival (CSS), and overall survival for the group of high-risk patients as a whole was 91.1%, 95.5%, and 72.5%, respectively. There was no difference in biochemical progression-free survival between men with and without Gleason pattern 5 (89.7% vs. 91.8%; p=0.56). However, men with Gleason pattern 5 had lower prostate cancer CSS (90.3% vs. 98.1%; p=0.011). There was no difference in overall survival comparing men with and without Gleason pattern 5 disease (67.7% vs. 75.4%; p=0.14). Men with high-risk, Gleason pattern 5 histology treated with brachytherapy and XRT have excellent long-term outcomes, which compare favorably to dose-escalated XRT/ADT series without brachytherapy. Nonetheless, Gleason pattern 5 results in lower CSS than high-risk disease without Gleason pattern5.

Investigation on the Benefit of PMRT in Women With High Risk N0 Breast Cancer

Prior studies have shown that there are subsets of women with node-negative breast cancer with tumor-defined risk factors that portend a higher rate of locoregional recurrence (LR). These factors include lymph vascular invasion, tumor size, young age, close margins, or high tumor grade. Women who have ≥2 of these factors may benefit from post-mastectomy radiation therapy (PMRT). The general use of PMRT for women with node-negative (N0) breast cancer has been shown to be associated with decreased survival. However, providing PMRT to women at high risk of LR may result in a survival advantage. This study evaluates whether a survival benefit of PMRT can be observed in women under age 50 with high-risk N0 disease. The Surveillance, Epidemiology, and End Results database was searched for women age 20-49 diagnosed from 1990-2008 with N0 invasive breast cancer and treated with mastectomy. Multivariable proportional hazards survival analysis (MVA) assessed the association between cause specific survival (CSS) and the following factors: age, estrogen receptor (ER) or progesterone receptor (PR) expression, race, tumor size, histology, number of axillary lymph nodes removed, risk group, PMRT, and tumor grade. Risk groups were defined a priori according to number of factors associated with decreased survival on MVA as follows: high risk (tumor size >5.0cm, grade III-IV, and ER-negative and/or PR-negative, intermediate risk (1 or 2 high risk factors), and low risk (size ≤5cm, grade I-II, and ER- and PR-positive) groups. Interaction of PMRT and risk group was analyzed. A total of 7,226 patients were identified in the CSS analysis, of which 191 (2.6%) were high risk, 4,150 (57.4%) were intermediate risk, and 2,885 (40%) were low risk. Receipt of PMRT was 51.3%, 12.1%, and 7.8% in the risk groups, respectively. In the MVA, ER-negative (Hazard ratio [HR] = 1.31 [1.02-1.67] p = 0.03), PR-negative* (HR = 1.96[1.23-3.14] p = 0.005), black race (HR = 1.40 [1.10-1.78] p = 0.006) tumor size 2.1-5cm vs. ≤2cm (HR = 1.76 [1.46-2.11] p < 0.0001), tumor size >5cm vs. ≤2cm (HR = 2.00 [1.15-3.48] p = 0.01), and grade* (HR = 2.29 [1.32-3.98] p = 0.003) were associated with lower CSS (*PR-negative and grade were only associated with lower CSS after 2 years). In the interaction analysis of hazard ratios for risk, there is a lower survival for patients who had PMRT if they were intermediate risk (HR = 0.73 [0.55-0.97]). Patients in the low risk group had a trend toward lower survival with PMRT (HR = 0.59 [0.32-1.08]). Patients in the high-risk group had a trend toward improved survival with PMRT (HR = 2.13 [0.91-4.99]). Young women with N0 breast cancer who have large, high-grade tumors that do not express hormone receptors may benefit from PMRT.

High-dose radiation employing external beam radiotherapy and high-dose rate brachytherapy with and without neoadjuvant androgen deprivation for prostate cancer patients with intermediate- and high-risk features

The role of neoadjuvant androgen deprivation (NAD) in high-risk prostate cancer patients receiving high-dose radiotherapy (RT) remains unstudied. To evaluate the effect of a course of NAD, we reviewed the experiences of three institutions treating these patients with combined RT and high-dose rate brachytherapy (HDR). Of 1260 prostate cancer patients with high-risk features (pretreatment prostate-specific antigen (PSA) > or =10, Gleason Score (GS) > or =7, or T stage > or =T2b), 560 received no NAD (n=308) or NAD for < or =6 months (n=252). Median dose to the prostate from RT and HDR was 42 and 23 Gy, respectively. Average total biologic equivalent prostate dose was >100 Gy (alpha/beta=1.2). Median follow-up was 4.3 years. Pretreatment characteristics were similar on chi(2) tables for all 560 patients treated with or without NAD including pretreatment PSA (P=0.11), GS (P=0.4), and clinical T stage (P=0.2). Outcomes worsened for patients receiving NAD (5-year distant metastasis (DM) 10 vs 5% (P=0.04); cause-specific survival (CSS), 93 vs 98% (P=0.005)). Higher 5-year DM rates and lower CSS occurred in NAD patients with a GS between 8 and 10 (n=112 (P=0.03, P=0.02)), pretreatment PSA> or =15 (n=136 (P=0.03, P=0.008)), and palpable disease > or =T2a (n=434 (P=0.04, P=0.02)). The only two significant risk factors for DM on Cox multivariate analysis were GS (P=0.003, HR 2.8) and NAD (P=0.03, HR 2.7). AD given before definitive high-dose RT did not benefit prostate cancer patients with intermediate- and high-risk features. We favor the use of concurrent/adjuvant AD over prolonged NAD for prostate cancer patients for whom AD is clinically indicated.

Impact of Elapsed Treatment Time on Outcome of External-Beam Radiation Therapy for Localized Carcinoma of the Prostate

The purpose of this study was to evaluate the impact of elapsed treatment time in external-beam radiation therapy for localized prostate carcinoma. The medical records of 1083 patients with localized prostate carcinoma treated between 1970 and December 1999 with external irradiation alone were reviewed. Median follow-up was 6 years (range, 4-24 years). Since 1987, prostate-specific antigen levels were obtained in 687 patients before the initiation of radiation therapy, and all patients seen in follow-up had prostate-specific antigen determinations. There were 344 patients with T1c, 496 with T2, and 243 with T3 tumors. The elapsed treatment time was divided into < or = 7, 7.1-9, or > 9 weeks. Local tumor control was determined by rectal examination and cause-specific survival or prostate-specific antigen failure according to American Society of Therapeutic Radiology and Oncology consensus criteria. Because of dose-escalation studies, tumor dose levels ranged from 66-73.8 Gy, given in 1.8- to 2-Gy fractions. In patients with stage T1c, local failure ranged from 0% to 10% with doses < or = 72 Gy with; elapsed treatment time had no impact. No pelvic failures were detected in 88 patients receiving doses > 72 Gy. In patients with T2 who received < or = 70 Gy, overall pelvic failure rate was 4% (12/306) in those with an elapsed treatment time of < or = 9 weeks, in contrast to 27% (12/44) for those with an elapsed treatment time > 9 weeks; at 10 years, patients with T2 tumors treated in > 9 weeks had a higher actuarial pelvic failure rate (35%), in contrast to 5% to 18% with shorter treatment times. For patients with T2 tumors who received 70-72 Gy, pelvic failure rate ranged from 0% to 32%, and there were no failures in 37 patients treated to higher doses. In patients with prostate-specific antigen values whose tumors were stage T1c, the chemical failure rate was 41% (60/147) with a tumor dose < 70 Gy, compared with 17% (4/24) in those who received higher doses. In patients with stage 2 disease who were treated with < 70 Gy, the chemical failure rate was 31%, and the rate was 12%-18% in those who received higher doses. In stage T3, the clinical pelvic failure rate ranged from 25% to 32% in the three elapsed time groups, and the chemical failure rate ranged from 48% to 69%, and there was no significant correlation with elapsed time or total irradiation dose. Cause-specific survival without chemical failure in patients with stage T1c disease at 10 years was 85%-90% in the three elapsed treatment time groups. In patients with stage T2 disease, the corresponding values were 80% and 90% for elapsed treatment times < 9 weeks, in contrast to 65% for patients treated > 9 weeks. In patients with stage T3 disease, cause-specific survival was about 60% in all elapsed treatment groups. There was no significant correlation of elapsed treatment time with urinary or rectal morbidity. Patients treated with radiation therapy for stage T2 localized prostate carcinoma showed a greater incidence of pelvic and chemical failures and a lower cause-specific survival when elapsed treatment time was > 9 weeks in comparison with the failure and survival rates occurring with shorter times. Higher doses of irradiation (> 72 Gy) eliminate the influence of prolongation of treatment time on outcome.

Lack of benefit at 5 years from a short course of neoadjuvant/concurrent androgen deprivation for unfavorable prostate cancer patients treated to a high total radiation dose

Purpose/Objective: To assess the survival impact of a course of ≤6 months of adjuvant/concurrent androgen deprivation in patients with unfavorable prostate cancer treated to a very high radiation dose with external beam (EBRT) and high dose rate (HDR) brachytherapy boosts. Materials/Methods: Between 1986 and 2002, 579 patients (pts) were treated for clinically localized prostate cancer in two prospective trials of pelvic EBRT and dose escalating HDR brachytherapy boosts. There were 201 pts treated at Kiel University and 378 pts at William Beaumont Hospital with 222 pts receiving androgen deprivation therapy (ADT) for a period of ≤6 months. For this analysis, the patient had to have a follow-up ≥18 months (3 times greater than the exposure to ADT) leaving a total sample of 475 pts. All pts had 1 of the following poor prognostic factors: Stage ≥T2b, Gleason score ≥7 and pretreatment PSA of ≥10. Pts were stratified by any one factor, 219 pts, any 2 factors 194 pts, and to improve comparability, all 3 factors in 138 pts. The ASTRO definition for biochemical failure (BF) was used. Results: The mean follow-up time for all patients was 5.1 years and for those patients with all 3 poor prognostic factors was 6.1 years (range 1.7–14.5 yrs). The 5-year actuarial analysis: a) all patients, b) ADT patients c) patients without ADT and d) patients with all 3 poor prognostic factors are listed in Table 1. We analyzed overall survival (OS), cause-specific survival (CSS), biochemical control (BC), disease free survival (DSF) and clinical local recurrence (c-LR). Of great significance is that the pts receiving a short course of ADT had a lower CSS when all 475 were analyzed p=0.015. For pts with all 3 poor risk factors giving ADT resulted not only in lower CSS p=0.009 but also in lower OS p=0.05. Multivariate analysis for biochemical control demonstrated decreasing age (p=0.039), increasing stage (p=0.008), and increasing Gleason score (<0.001) were significant for biochemical failure. While increasing PSA values, the addition of ADT, the increasing number of poor prognostic factors and the increasing length of follow-up were not predictive variables. Conclusions: EBRT with conformal HDR boosts produces excellent long term outcome in terms of OS, CSS, DFS, BC and c-LR in patients with unfavorable prostate cancer. With the high biological equivalent dose delivered with this technique, the addition of a course of <6 months of neoadjuvant/concurrent ADT to this treatment protocol does not appear to confer a therapeutic advantage. In fact, ADT, did not prevent cancer deaths, has decreased OS, resulted in lower CSS and has added side effects (sexual impotence) as well as the significant cost of hormonal treatment.