Modeling survival and the development of second primary tumors among Hodgkin's disease patients

Hodgkin's disease (HD) is a cancer of the lymphatic system. Survivors of HD face varieties of consequent adverse effects, in which secondary primary tumors (SPT) is one of the most serious consequences. This dissertation is aimed to model time-to-SPT in the presence of death and HD relapses during follow-up.^ The model is designed to handle a mixture phenomenon of SPT and the influence of death. Relapses of HD are adjusted as a covariate. Proportional hazards framework is used to define SPT intensity function, which includes an exponential term to estimate explanatory variables. Death as a competing risk is considered according to different scenarios, depending on which terminal event comes first. Newton-Raphson method is used to estimate the parameter estimates in the end.^ The proposed method is applied to a real data set containing a group of HD patients. Several risk factors for the development of SPT are identified and the findings are noteworthy in the development of healthcare guidelines that may lead to the early detection or prevention of SPT.^

Second Primary Tumors in Patients with Head and Neck Cancer

This is a review on second primary tumors in patients with head and neck cancer. These patients have a high risk of developing other cancers simultaneously or subsequently. The incidence of multiple primary tumors in this population can be as high as 27%. Recurrences are the most common cause of treatment failure within the first 2 years of follow-up. After the third year the diagnosis of a second primary tumor becomes the most important cause of morbimortality in head and neck cancer patients, especially in those treated for cancers early diagnosed. Most second primary tumors occur in the upper aerodigestive tract (40%-59%), lung (31%-37.5%), and esophagus (9%-44%). Patients who develop second primary tumor have a significant reduction of survival expectancy.

Risk of second primary tumors following treatment of non-small cell lung cancer

Background. The rise in survival rates along with more detailed follow-up using sophisticated imaging studies among non-small lung cancer (NSCLC) patients has led to an increased risk of second primary tumors (SPT) among these cases. Population and hospital based studies of lung cancer patients treated between 1974 and 1996 have found an increasing risk over time for the development of all cancers following treatment of non-small cell lung cancer (NSCLC). During this time the primary modalities for treatment were surgery alone, radiation alone, surgery and post-operative radiation therapy, or combinations of chemotherapy and radiation (sequentially or concurrently). There is limited information in the literature about the impact of treatment modalities on the development of second primary tumors in these patients. ^ Purpose. To investigate the impact of treatment modalities on the risk of second primary tumors in patients receiving treatment with curative intent for non-metastatic (Stage I–III) non-small cell lung cancer (NSCLC). ^ Methods. The hospital records of 1,095 NSCLC patients who were diagnosed between 1980–2001 and received treatment with curative intent at M.D. Anderson Cancer Center with surgery alone, radiation alone (with a minimum total radiation dose of at least 45Gy), surgery and post-operative radiation therapy, radiation therapy in combination with chemotherapy or surgery in combination with chemotherapy and radiation were retrospectively reviewed. A second primary malignancy was be defined as any tumor histologically different from the initial cancer, or of another anatomic location, or a tumor of the same location and histology as the initial tumor having an interval between cancers of at least five years. Only primary tumors occurring after treatment for NSCLC will qualified as second primary tumors for this study. ^ Results. The incidence of second primary tumor was 3.3%/year and the rate increased over time following treatment. The type of NSCLC treatment was not found to have a striking effect upon SPT development. Increased rates were observed in the radiation only and chemotherapy plus radiation treatment groups; but, these increases did not exceed expected random variation. Higher radiation treatment dose, patient age and weight loss prior to index NSCLC treatment were associated with higher SPT development. ^

Smad2 and Smad6 as predictors of overall survival in oral squamous cell carcinoma patients

Abstract Background To test if the expression of Smad1-8 mRNAs were predictive of survival in patients with oral squamous cell carcinoma (SCC). Patients and Methods We analyzed, prospectively, the expression of Smad1-8, by means of Ribonuclease Protection Assay in 48 primary, operable, oral SCC. In addition, 21 larynx, 10 oropharynx and 4 hypopharynx SCC and 65 matched adjacent mucosa, available for study, were also included. For survival analysis, patients were categorized as positive or negative for each Smad, according to median mRNA expression. We also performed real-time quantitative PCR (QRTPCR) to asses the pattern of TGFβ1, TGFβ2, TGFβ3 in oral SCC. Results Our results showed that Smad2 and Smad6 mRNA expression were both associated with survival in Oral SCC patients. Cox Multivariate analysis revealed that Smad6 positivity and Smad2 negativity were both predictive of good prognosis for oral SCC patients, independent of lymph nodal status (P = 0.003 and P = 0.029, respectively). In addition, simultaneously Smad2- and Smad6+ oral SCC group of patients did not reach median overall survival (mOS) whereas the mOS of Smad2+/Smad6- subgroup was 11.6 months (P = 0.004, univariate analysis). Regarding to TGFβ isoforms, we found that Smad2 mRNA and TGFβ1 mRNA were inversely correlated (p = 0.05, R = -0.33), and that seven of the eight TGFβ1+ patients were Smad2-. In larynx SCC, Smad7- patients did not reach mOS whereas mOS of Smad7+ patients were only 7.0 months (P = 0.04). No other correlations were found among Smad expression, clinico-pathological characteristics and survival in oral, larynx, hypopharynx, oropharynx or the entire head and neck SCC population. Conclusion Smad6 together with Smad2 may be prognostic factors, independent of nodal status in oral SCC after curative resection. The underlying mechanism which involves aberrant TGFβ signaling should be better clarified in the future.

Factors associated with HPV16 status and survival among patients with squamous cell carcinoma of the oropharynx

Background: Squamous cell carcinoma of the oropharynx (SCCOP) is characterized by local tumor aggressiveness, high recurrence rates, a high incidence of second primary tumors, and medical comorbidities. Significant trends in demographic and clinical characteristics as well as survival among SCCOP patients have been observed over time, likely owing to the changing etiology of the disease. Human papillomavirus type 16 (HPV16) infection is associated with a significant proportion of these cancers. Biomarkers that may aid in identifying patients that are at higher risk of recurrence and death are important so that these patients may be followed more closely to improve their quality of life. ^ Study population and methods: The retrospective review (Specific Aim 2) included 3891 newly diagnosed, previously untreated patients presenting to our institution between 1955 and 2004. A total of 2299 patients treated at our institution were included in survival and recursive partitioning analysis. The prospective cohort study (Specific Aim 3) included 266 patients presenting to our institution between January 2006 and September 2009. ^ Results: The results from the retrospective review showed that over time, patients presented at younger ages and were more likely to have base of tongue/tonsil tumors and to be never/former smokers and moreover survival improved significantly over time. In survival and recursive partitioning analyses, the TNM staging system was efficient in prognosticating patients prior to 1995. However, in the recent decade, the TNM staging system was completely inadequate. The factors having the greatest positive effect on overall survival since 1995 were those common to HPV-associated SCCOP. The results from the prospective cohort study indicate that patients with high nodal stage and those with late stage disease have increased levels of pretreatment serum HPV DNA. ^ Conclusions: We saw a distinct improvement in survival among SCCOP patients over the past 50 years at our institution. The main factors contributing to this were changes in clinical characteristics, in particular surrogates for HPV status. The current TNM staging system for SCCOP is inadequate and incorporation of HPV status (and perhaps smoking status) is encouraged. Furthermore, although pretreatment circulating levels of HPV DNA was associated with higher N category and overall disease stage, it has limited utility as a marker for recurrence among SCCOP patients.^

Primary tumor resection and overall survival in patients with metastatic colorectal cancer treated with palliative intent

The survival impact of primary tumor resection in patients with metastatic colorectal cancer (mCRC) treated with palliative intent remains uncertain. In the absence of randomized data, the objectives of the present study were to examine the effect of primary tumor resection (PTR) and major prognostic variables on overall survival (OS) of patients with de novo mCRC. Patients and Methods: Consecutive patients from the Australian 'Treatment of Recurrent and Advanced Colorectal Cancer' registry were examined from June 2009 to March 2015. Univariate and multivariate Cox proportional hazards regression analyses were used to identify associations between multiple patient or clinical variables and OS. Patients with metachronous mCRC were excluded from the analyses. Results: A total of 690 patients de novo and 373 metachronous mCRC patients treated with palliative intent were identified. The median follow-up period was 30 months. The median age of de novo patients was 66 years; 57% were male; 77% had an Eastern Cooperative Oncology Group performance status of 0 to 1; and 76% had a colon primary. A total of 216 de novo mCRC patients treated with palliative intent underwent PTR at diagnosis and were more likely to have a colon primary (odds ratio [OR], 15.4), a lower carcinoembryonic antigen level (OR, 2.08), and peritoneal involvement (OR, 2.58; P < .001). On multivariate analysis, PTR at diagnosis in de novo patients was not associated with significantly improved OS (hazard ratio [HR], 0.82; 99% confidence interval [CI], 0.62-1.09; P = .068). PTR at diagnosis did not correlate with outcome in de novo patients with a colon primary (HR, 0.74; 99% CI, 0.54-1.01; P = .014) or a rectal primary (HR, 0.81; 99% CI, 0.27-2.44; P = .621). Conclusion: For de novo mCRC patients treated with palliative intent, PTR at diagnosis does not significantly improve OS when adjusting for known major prognostic factors. The outcomes of randomized trials examining the survival impact of PTR are awaited.

Complete cytogenetic response and major molecular response as surrogate outcomes for overall survival in first-line treatment of chronic myelogenous leukemia: A case study for technology appraisal on the basis of surrogate outcomes evidence

Objectives In 2012, the National Institute for Health and Care Excellence assessed dasatinib, nilotinib, and standard-dose imatinib as first-line treatment of chronic phase chronic myelogenous leukemia (CML). Licensing of these alternative treatments was based on randomized controlled trials assessing complete cytogenetic response (CCyR) and major molecular response (MMR) at 12 months as primary end points. We use this case study to illustrate the validation of CCyR and MMR as surrogate outcomes for overall survival in CML and how this evidence was used to inform National Institute for Health and Care Excellence’s recommendation on the public funding of these first-line treatments for CML. Methods We undertook a systematic review and meta-analysis to quantify the association between CCyR and MMR at 12 months and overall survival in patients with chronic phase CML. We estimated life expectancy by extrapolating long-term survival from the weighted overall survival stratified according to the achievement of CCyR and MMR. Results Five studies provided data on the observational association between CCyR or MMR and overall survival. Based on the pooled association between CCyR and MMR and overall survival, our modeling showed comparable predicted mean duration of survival (21–23 years) following first-line treatment with imatinib, dasatinib, or nilotinib. Conclusions This case study illustrates the consideration of surrogate outcome evidence in health technology assessment. Although it is often recommended that the acceptance of surrogate outcomes be based on randomized controlled trial data demonstrating an association between the treatment effect on both the surrogate outcome and the final outcome, this case study shows that policymakers may be willing to accept a lower level of evidence (i.e., observational association).

BRCA1 mRNA Expression Levels Predict for Overall Survival in Ovarian Cancer after Chemotherapy.

We investigated whether BRCA1 mRNA expression levels may represent a biomarker of survival in sporadic epithelial ovarian cancer following chemotherapy treatment. EXPERIMENTAL DESIGN: The effect of loss of BRCA1 expression on chemotherapy response in ovarian cancer was measured in vitro using dose inhibition assays and Annexin V flow cytometry. Univariate and multivariate analyses were done to evaluate the relationship between BRCA1 mRNA expression levels and survival after chemotherapy treatment in 70 fresh frozen ovarian tumors. RESULTS: We show that inhibition of endogenous BRCA1 expression in ovarian cancer cell lines results in increased sensitivity to platinum therapy and decreased sensitivity to antimicrotubule agents. In addition, we show that patients with low/intermediate levels of BRCA1 mRNA have a significantly improved overall survival following treatment with platinum-based chemotherapy in comparison with patients with high levels of BRCA1 mRNA (57.2 versus 18.2 months; P = 0.0017; hazard ratio, 2.9). Furthermore, overall median survival for higher-BRCA1-expressing patients was found to increase following taxane-containing chemotherapy (23.0 versus 18.2 months; P = 0.12; hazard ratio, 0.53). CONCLUSIONS: We provide evidence to support a role for BRCA1 mRNA expression as a predictive marker of survival in sporadic epithelial ovarian cancer.

Second, primary tumours in patients with mouth cancer

Over the last decades, technical-scientific advances of oncology have brought about an increased survival rate for cancer patients. As a result, oncologists have detected an increased number of patients presenting with other neoplasms. This research aimed to analyze factors related to demography and to the anatomic site in patients having a FPT of the mouth who developed a SPT. Medical charts of 848 patients neoplasm admitted for treatment at the Head and Neck Surgery Department of the Hospital do Cancer, Antonio Candido Camargo, Brazil, from January of 1984 to December, were analysed. of these, 12 6 developed a SPT. 49.21 % were from 51 to 65 years of age, while 83.33% were of the male gender and Caucasian. Regarding FPT site 38.89% were of the tongue, and 28.5% were of the floor of the mouth. The esophagus, excepting skin (13.49%), was more often subject to SPT (11.9%), of these 74.6% were metachronic, 15.87% simultaneous and 9.52% synchronous.

Segundo tumor em pacientes com neoplasias de cabeça e pescoço

Pós-graduação em Pesquisa e Desenvolvimento (Biotecnologia Médica) - FMB

Overall Survival Improvement in Patients with Lung Cancer and Bone Metastases Treated with Denosumab Versus Zoledronic Acid Subgroup Analysis from a Randomized Phase 3 Study

Introduction: Denosumab, a fully human anti-RANKL monoclonal antibody, reduces the incidence of skeletal-related events in patients with bone metastases from solid tumors. We present survival data for the subset of patients with lung cancer, participating in the phase 3 trial of denosumab versus zoledronic acid (ZA) in the treatment of bone metastases from solid tumors (except breast or prostate) or multiple myeloma. Methods: Patients were randomized 1:1 to receive monthly subcutaneous denosumab 120 mg or intravenous ZA 4 mg. An exploratory analysis, using Kaplan-Meier estimates and proportional hazards models, was performed for overall survival among patients with non-small-cell lung cancer (NSCLC) and SCLC. Results: Denosumab was associated with improved median overall survival versus ZA in 811 patients with any lung cancer (8.9 versus 7.7 months; hazard ratio [HR] 0.80) and in 702 patients with NSCLC (9.5 versus 8.0 months; HR 0.78) (p = 0.01, each comparison). Further analysis of NSCLC by histological type showed a median survival of 8.6 months for denosumab versus 6.4 months for ZA in patients with squamous cell carcinoma (HR 0.68; p = 0.035). Incidence of overall adverse events was balanced between treatment groups; serious adverse events occurred in 66.0% of denosumab-treated patients and 72.9% of ZA-treated patients. Cumulative incidence of osteonecrosis of the jaw was similar between groups (0.7% denosumab versus 0.8% ZA). Hypocalcemia rates were 8.6% with denosumab and 3.8% with ZA. Conclusion: In this exploratory analysis, denosumab was associated with improved overall survival compared with ZA, in patients with metastatic lung cancer.