Cause-specific Survival Curves Research Articles

Survival Outcomes in Oral Tongue Cancer: A Mono-Institutional Experience Focusing on Age.

ObjectiveThe prognostic role of age among patients affected by Oral Tongue Squamous Cell Carcinoma (OTSCC) is a topic of debate. Recent cohort studies have found that patients diagnosed at 40 years of age or younger have a better prognosis. The aim of this cohort study was to clarify whether age is an independent prognostic factor and discuss heterogeneity of outcomes by stage and treatments in different age groups.MethodsWe performed a study on 577 consecutive patients affected by primary tongue cancer and treated with surgery and adjuvant therapy according to stage, at European Institute of Oncology, IRCCS. Patients with age at diagnosis below 40 years totaled 109 (19%). Overall survival (OS), disease-free survival (DFS), tongue specific free survival (TSFS) and cause-specific survival (CSS) were compared by age groups. Multivariate Cox proportional hazards models were used to assess the independent role of age.ResultsThe median follow-up time was 5.01 years (range 0–18.68) years with follow-up recorded up to February 2020. After adjustment for all the significant confounding and prognostic factors, age remained independently associated with OS and DSF (respectively, p = 0.002 and p = 0.02). In CSS and TSFS curves, the role of age seems less evident (respectively, p = 0.14 and p = 0.0.37). In the advanced stage sub-group (stages III–IV), age was significantly associated with OS and CSS with almost double increased risk of dying (OS) and dying from tongue cancer (CSS) in elderly compared to younger groups (OS: HR = 2.16 95%, CI: 1.33–3.51, p= 0.001; CSS: HR = 1.76 95%, CI: 1.03–3.01, p = 0.02, respectively). In our study, young patients were more likely to be treated with intensified therapies (glossectomies types III–V and adjuvant radio-chemotherapy). Age was found as a prognostic factor, independently of other significant factors and treatment. Also the T–N tract involved by disease and neutrophil-to-lymphocyte ratio ≥3 were independent prognostic factors.ConclusionsYoung age at diagnosis is associated with a better overall survival. Fewer younger people than older people died from tongue cancer in advanced stages.

The effect of competing risks on astronaut and cosmonaut mortality

Astronauts and cosmonauts have been reported to be at substantially lower age-specific risk of death from chronic disease (primarily heart disease and cancers) in comparison to the general populations of the United States and Russia, respectively. Yet, both groups have been at greater age-specific risk of death from external causes, mainly due to plane crashes and spacecraft accidents. In this study we tested the hypothesis that the reported reductions in mortality from natural causes result, to some degree, from survival bias created by early deaths from external causes.Statistical comparisons of baseline characteristics between cause-of-death groups showed no significant differences. Cause-specific survival curves showed no difference in long-term mortality from external causes among either astronauts or cosmonauts compared to Kaplan-Meier curves with censoring for competing causes. Cause-specific survival curves for natural causes suggested a possible upward bias in mortality estimates published thus far for both groups of space explorers. Differences in survival between Kaplan-Meier curves and the cause-specific survival curves were 7% and 5% for astronauts and cosmonauts respectively after 55 years.The data do not support the hypothesis that observed reductions in mortality from natural causes are due in whole or in part to bias created by deaths from external causes at young ages. The data imply that reports of cause-specific mortality for astronauts and cosmonauts may in fact systematically overestimate mortality rates, though these findings should be interpreted with caution as the data are thin at the extremes of follow-up time.

Brachytherapy vs. external beam radiotherapy for choroidal melanoma: Survival and patterns-of-care analyses

PurposeNo modern randomized trials exist comparing external beam radiotherapy (EBRT) and plaque brachytherapy (BT) for choroidal melanoma, and the optimal treatment modality is currently unknown. This study compares the patterns of care and efficacy of EBRT vs. BT based on data in the Surveillance, Epidemiology, and End Results database. Methods and MaterialsThe Surveillance, Epidemiology, and End Results database was queried for patients aged 20–79 diagnosed with choroidal melanoma from 2004 to 2011, treated with EBRT or BT; included patients were clinically T1–T4, N0, and M0. Overall survival and cause-specific survival curves were calculated by the Kaplan–Meier method. Univariate and multivariate analyses were performed in the survival and patterns-of-care analyses. ResultsA total of 1004 cases (380 EBRT and 624 BT) were included in the survival analysis. There was no difference in the 5-year overall survival (83.3% EBRT vs. 82.5% BT, p = 0.69) and 5-year cause-specific survival (88.3% EBRT vs. 88.3% BT, p = 0.92). In the survival analysis, older age and advanced tumor stage were predictors of increased risk of death. In the patterns-of-care analysis, later year of diagnosis and smaller tumor stage were predictors of BT use. ConclusionsAdvanced tumor stage and older age seem to be independent predictors for risk of death from choroidal melanoma. The use of BT favors smaller tumors and later year of diagnosis. There is no difference in survival between those treated with EBRT or BT, and the utilization of BT is increasing.

Assessing treatment benefit with competing risks not affected by the randomized treatment.

The comparison of overall survival curves between treatment arms will always be of interest in a randomized clinical trial involving a life-shortening disease. In some settings, the experimental treatment is only expected to affect the deaths caused by the disease, and the proportion of deaths caused by the disease is relatively low. In these settings, the ability to assess treatment-effect differences between Kaplan-Meier survival curves can be hampered by the large proportion of deaths in both arms that are unrelated to the disease. To address this problem, frequently displayed are cause-specific survival curves or cumulative incidence curves, which respectively censor and immortalize events (deaths) not caused by the disease. However, the differences between the experimental and control treatment arms for these curves overestimate the difference between the overall survival curves for the treatment arms and thus could result in overestimation of the benefit of the experimental treatment for the patients. To address this issue, we propose new estimators of overall survival for the treatment arms that are appropriate when the treatment does not affect the non-disease-related deaths. These new estimators give a more precise estimate of the treatment benefit, potentially enabling future patients to make a more informed decision concerning treatment choice. We also consider the case where an exponential assumption allows the simple presentation of mortality rates as the outcome measures. Applications are given for estimating overall survival in a prostate-cancer treatment randomized clinical trial, and for estimating the overall mortality rates in a prostate-cancer screening trial.

Disease-specific survival for patients with multiple myeloma: significant improvements over time in all age groups

This study analyzed the survival of patients with multiple myeloma. Surveillance, Epidemiology, and End Results (SEER) and Centers for Disease Control and Prevention (CDC) databases were queried to calculate myeloma cause-specific survival curves by the Kaplan and Meier product-limit method. The Cox proportional hazards model was used to assess univariate and multivariate predictors of myeloma cause-specific survival. The outcome of interest was death due to myeloma. Results from a Cox proportional hazards model restricted to age and time period at diagnosis demonstrated that the magnitude of improvement in survival by time period varied by age at diagnosis. Among patients under 60 years at diagnosis, hazard ratios for myeloma cause-specific death decreased by more 50% from the first interval of observation to the last. Hazard ratios decreased during the study period by 39% among patients 60–69 years of age and by 27% among patients who were 70 years of age and older. Survival is improving in patients with myeloma of all ages.

Comparison of the clinical outcome after hormonal therapy for prostate cancer between Japanese and Caucasian men

To investigate the impact of race on the effectiveness of hormonal therapy in patients with prostate cancer, by comparing the outcomes of Caucasian men (CM) and Japanese-American men (JAM) treated with hormonal therapy at one institution. Fifty-nine CM and 105 JAM with prostate cancer were treated with hormonal therapy at The Queen's Medical Center in Honolulu. Age, stage, Gleason score, race, and pretreatment PSA levels were abstracted. The Kaplan-Meier method was used to construct overall and cause-specific survival curves, which were compared using log-rank statistics. These factors were assessed as to their interdependence and correlation with the clinical course using a Cox proportional hazards regression model. Although there were no statistical differences in patient background, JAM who had received hormonal treatment had a better outcome than CM for overall and cause-specific survival rate (P = 0.001 and 0.036, respectively). Race was one of the significant prognostic factors in the multivariate analysis (P = 0.03). The findings suggest a difference in the effectiveness of hormonal therapy for prostate cancer in JAM living in Hawaii compared to CM. There were marked racial differences in clinical outcome after hormonal therapy between JAM and CM. A prospective study with more patients might be necessary to elucidate the differential effectiveness of hormonal therapy for prostate cancer in different races, especially between Japanese and Caucasians.

CAG Polymorphic Repeat Length in Androgen Receptor Gene Combined with Pretreatment Serum Testosterone Level as Prognostic Factor in Patients with Metastatic Prostate Cancer

Objective: Androgen ablation has been the initial treatment of choice for men with metastatic prostate cancer, but the disease generally relapses to an androgen-independent state thereafter. To understand which groups respond well or poorly to endocrine therapy is thus important. Several studies have shown that pretreatment serum testosterone (T) levels and the length of the CAG repeat at the N-terminal region of the androgen receptor are significant. However, the relevance of a combination of these factors has not been reported. We therefore investigated the clinical significance of CAG repeat length and pretreatment serum T levels among Japanese patients with metastatic prostate cancer (TxNxM1), and analyzed their relevance to survival. Methods: Fifty-two Japanese patients with metastatic prostate cancer were enrolled in this study. We determined the length of the CAG repeat by both PCR sequencing and fragment analysis. Pretreatment serum T levels were measured using a radioimmunoassay. We examined the clinical significance of the CAG repeats and T levels individually and in combination with respect to several clinical factors. Results: The pretreatment T level in the responder group was significantly higher than that in the non-responders ( p = 0.009) and the mean was 4.33 ± 2.12 ng/ml. Kaplan–Meier analyses revealed that cause-specific survival was significantly enhanced in patients with higher levels of T ( p = 0.0489). The length of the CAG repeat was positively associated with age at diagnosis ( p = 0.032). The mean CAG repeat length was 22.5 ± 3.0 and this value was significantly shorter in patients with poorly differentiated, than with well and moderately differentiated tumors ( p = 0.019). Kaplan–Meier analyses revealed a significantly better cause-specific survival rate as well as progression-free survival rate in patients with longer CAG repeats. Cause-specific survival curves were better in patients with higher T levels and longer CAG repeats than with lower T levels and shorter CAG repeats ( p = 0.0066). A multivariate analysis showed that the most significant prognostic factor was histological grade, followed by EOD grade, marker response and the combination of T and CAG. Conclusion: Pretreatment serum T levels together with the length of the N-terminal CAG repeat of the androgen receptor gene can distinguish responders from non-responders to androgen ablation. These parameters appear to be clinically useful, in that therapies appropriate to individual patients could be selected. Further studies are necessary to confirm these results.

Significance of thrombocytosis for determining prognosis in patients with localized renal cell carcinoma

Objectives To evaluate the significance of thrombocytosis for determining survival in patients with localized renal cell carcinoma (RCC) who underwent radical nephrectomy with curative intent. Methods The study population comprised 151 patients who underwent radical nephrectomy with a diagnosis of localized RCC. The inclusion criteria were at least one preoperative platelet count and a tissue diagnosis of RCC. Thrombocytosis was defined as a platelet count greater than 400,000/mm 3. The charts of these patients were retrospectively reviewed and the relationship between the preoperative platelet counts and survival was evaluated according to the histologic variants. Results The mean follow-up was 37.1 ± 24.1 months (median 34, range 3 to 91). Of these 151 patients, 21 had a preoperative platelet count greater than 400,000/mm 3. The thrombocytosis rate was significantly greater in those with advanced T stage ( P = 0.045). Lymph node positivity also correlated with thrombocytosis ( P = 0.028). However, no statistically significant correlation was found between grade and histologic subtypes and thrombocytosis ( P = 0.053 and P = 0.354, respectively). Ten (47.6%) of 21 patients with thrombocytosis and 21 (16.2%) of the remaining 130 patients died of disease progression ( P = 0.002). The Kaplan-Meier cause-specific survival curves showed that patients who had thrombocytosis had a mean survival of 45.2 months compared with 76.6 months in patients without thrombocytosis ( P = 0.0002). Conclusions Preoperative thrombocytosis is a significant predictor for determining prognosis in patients with localized RCC. Thrombocytosis was found more frequently in patients with advanced stage RCC, and patients with preoperative thrombocytosis had a worse survival compared with those with normal platelet counts.

Per-operative frozen section examination of pelvic nodes is unnecessary for the majority of clinically localized prostate cancers in the prostate-specific antigen era.

The incidence of unsuspected lymph node metastasis seems to be decreasing in the prostate-specific antigen (PSA) era. It remains controversial as to whether routine pelvic lymph node dissection and per-operative frozen section examination should be performed. In addition, it is still unclear whether an aggressive approach to local disease by surgery or irradiation confers survival benefits on stage D1 patients. Eighty-eight consecutive patients with clinically localized prostate cancer who underwent pelvic lymph node dissection prior to radical prostatectomy during the period between 1985 and 1998 were analyzed. The incidence of lymph node metastases after 1992 was compared with that before 1992. Sensitivity and specificity of frozen section examination was assessed. Progression-free survival and cause-specific survival curves of node-positive patients who underwent radical prostatectomy were estimated by the Kaplan-Meier method. Six of 17 patients (35.3%) treated before 1992 and five of 71 patients (7.0%) treated after 1992 showed unsuspected lymph node metastasis (P = 0.0059). Eight of 11 node-positive patients underwent radical prostatectomy and two have so far demonstrated clinical progression and cancer death with a median follow-up period of 63 months. The 5 year progression-free rate and the cause-specific survival rate for these patients were 71.4 and 85.7%, respectively. Sensitivity of frozen section examination for micrometastasis and gross-metastasis cases, respectively, was 3/6 (50%) and 4/4 (100%), while specificity was 85/85 (100%). The incidence of unsuspected lymph node metastases has been significantly decreased in the PSA era. Frozen section examination of pelvic nodes can be omitted and radical prostatectomy is an acceptable choice of treatment in patients without macroscopically apparent nodal metastases.

Differential Expression of nm23 H-1 Protein in Conjunctival Melanoma and Potential Precursor Lesions

Loss of nm23 gene expression is believed to enhance metastatic spread in diverse human tumors, including skin melanoma. The purpose of this work was to determine the pattern and prognostic relevance of nm23 protein immunoexpression in conjunctival melanoma and potential precursor lesion. Formaldehyde-fixed, paraffin-embedded conjunctival specimens comprising 85 melanocytic lesions (nevi, primary aquired melanosis with and without atypia and primary and locally recurrent malignant melanomas) from 73 patients were used. Sections from all specimens were examined by light microscopy to assess diverse prognostic parameters. Additional sections were then immunostained for nm23 H-1 protein and the immunoreactivity was assessed semi-quantitatively. Survival data for all patients were retrieved from the National Causes of Death Registry of Sweden.Nm23 H-1 protein was differentially expressed in conjunctival melanocytic lesions, however loss of immunoexpression was not more common in melanocytic lesions asociated with a high risk of malignant transformation. Also, primary and recurrent conjunctival melanomas showed an essentially similar nm23 expression pattern and we could not associate the pattern of nm23 immunoexpression with an increased risk for malignant transformation or locally recurrent disease. While there was a tentative separation between cause-specific survival curves after excision for low and high nm23 expression conjunctival melanoma, there was no statistically significant association with metastatic death of patients. However, loss of nm23 protein immunoexpression may still be of some importance as a marker for prognosis in conjunctival melanoma because the present study could only detect large differences in survival. Our results suggest that any potential prognostic value of nm23 immunoexpression would be independent of other markers, underlining the importance of further studies.

Serum Levels of Soluble Interleukin-2 Receptor in Renal Cell Carcinoma

Objectives. To evaluate increased serum soluble interleukin-2 receptor (sIL-2R) levels in patients with renal cell carcinoma (RCC). Methods. Serum sIL-2R levels were measured in 52 patients with RCC and 10 control subjects by an enzyme-linked immunosorbent assay (ELISA) technique. The correlation between serum sIL-2R levels and clinical stage, disease prognostic value, and inflammatory marker levels was analyzed. Results. Serum sIL-2R levels in patients with RCC were significantly higher than those in normal control subjects (857.2 ± 660.0 versus 291.3 ± 76.4 U/mL, P <0.0001). High serum sIL-2R levels appeared to be related to advanced clinical stage (596.0 ± 276.5 U/mL in Stage II, 776.1 ± 398.8 U/mL in Stage III, and 1310.0 ± 926.7 U/mL in Stage IV: Stage II vs. Stage III, P = 0.0078; Stage II vs. Stage IV, P <0.0001). The overall cause-specific survival curves showed that patients with high sIL-2R levels (more than 1000 U/mL) had a significantly lower survival rate than those with low (less than 500 U/mL, P = 0.0003) or intermediate levels (500 to 1000 U/mL, P = 0.0007). C-reactive protein levels apparently increased in patients with high sIL-2R concentrations. Conclusions. Measurement of serum sIL-2R concentrations in patients with RCC provides useful information for predicting the extent of disease and length of survival.