Tobacco Smoking and Increased Risk of Death and Progression for Patients With p16-Positive and p16-Negative Oropharyngeal Cancer

Purpose Tobacco smoking is associated with oropharynx cancer survival, but to what extent cancer progression or death increases with increasing tobacco exposure is unknown. Patients and Methods Patients with oropharynx cancer enrolled onto a phase III trial of radiotherapy from 1991 to 1997 (Radiation Therapy Oncology Group [RTOG] 9003) or of chemoradiotherapy from 2002 to 2005 (RTOG 0129) were evaluated for tumor human papillomavirus status by a surrogate, p16 immunohistochemistry, and for tobacco exposure by a standardized questionnaire. Associations between tobacco exposure and overall survival (OS) and progression-free survival (PFS) were estimated by Cox proportional hazards models. Results Prevalence of p16-positive cancer was 39.5% among patients in RTOG 9003 and 68.0% in RTOG 0129. Median pack-years of tobacco smoking were lower among p16-positive than p16-negative patients in both trials (RTOG 9003: 29 v 45.9 pack-years; P = .02; RTOG 0129: 10 v 40 pack-years; P < .001). After adjustment for p16 and other factors, risk of progression (PFS) or death (OS) increased by 1% per pack-year (for both, hazard ratio [HR], 1.01; 95% CI, 1.00 to 1.01; P = .002) or 2% per year of smoking (for both, HR, 1.02; 95% CI, 1.01 to 1.03; P < .001) in both trials. In RTOG 9003, risk of death doubled (HR, 2.19; 95% CI, 1.46 to 3.28) among those who smoked during radiotherapy after accounting for pack-years and other factors, and risk of second primary tumors increased by 1.5% per pack-year (HR, 1.015; 95% CI, 1.005 to 1.026). Conclusion Risk of oropharyngeal cancer progression and death increases directly as a function of tobacco exposure at diagnosis and during therapy and is independent of tumor p16 status and treatment.

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Phase III Trial Adding Vincristine-Topotecan-Cyclophosphamide to the Initial Treatment of Patients With Nonmetastatic Ewing Sarcoma: A Children's Oncology Group Report

Journal of Clinical Oncology ◽

10.1200/jco.21.00358 ◽

2021 ◽

Author(s):

Patrick J. Leavey ◽

Nadia N. Laack ◽

Mark D. Krailo ◽

Allen Buxton ◽

R. Lor Randall ◽

...

Keyword(s):

Ewing Sarcoma ◽

Tumor Volume ◽

Phase Iii ◽

Pelvic Bone ◽

Experimental Therapy ◽

Survival Outcomes ◽

Primary Tumors ◽

Risk Of Death ◽

Increased Risk ◽

To Receive

PURPOSE The primary aim of this phase III randomized trial was to test whether the addition of vincristine, topotecan, and cyclophosphamide (VTC) to interval compressed chemotherapy improved survival outcomes for patients with previously untreated nonmetastatic Ewing sarcoma. METHODS Patients were randomly assigned to receive standard five-drug interval compressed chemotherapy (regimen A) for 17 cycles or experimental therapy with five cycles of VTC within the 17 cycles (regimen B). Patients were stratified by age at diagnosis (< 18 years and ≥18 years) and tumor site (pelvic bone, nonpelvic bone, and extraosseous). Tumor volume at diagnosis was categorized as < 200 mL or ≥ 200 mL. Local control occurred following six cycles. Histologic response was categorized as no viable or any viable tumor. Event-free survival (EFS) and overall survival (OS) were compared between randomized groups with stratified log-rank tests. RESULTS Of 642 enrolled patients, 309 eligible patients received standard and 320 received experimental therapy. The 5-year EFS and OS were 78% and 87%, respectively. There was no difference in survival outcomes between randomized groups (5-year EFS regimen A v regimen B, 78% v 79%; P = .192; 5-year OS 86% v 88%; P = .159). Age and primary site did not affect the risk of an EFS event. However, age ≥ 18 years was associated with an increased risk of death at 5 years (hazard ratio 1.84; 95% CI, 1.15 to 2.96; P = .009). The 5-year EFS rates for patients with pelvic, nonpelvic bone, and extraosseous primary tumors were 75%, 78%, and 85%, respectively. Tumor volume ≥ 200 mL was significantly associated with lower EFS. CONCLUSION While VTC added to five-drug interval compressed chemotherapy did not improve survival, these outcomes represent the best survival estimates to date for patients with previously untreated nonmetastatic Ewing sarcoma.

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A phase III study of xilonix in refractory colorectal cancer patients with weight loss.

Journal of Clinical Oncology ◽

10.1200/jco.2015.33.3_suppl.685 ◽

2015 ◽

Vol 33 (3_suppl) ◽

pp. 685-685 ◽

Cited By ~ 2

Author(s):

George A. Fisher

Keyword(s):

Colorectal Cancer ◽

Cancer Progression ◽

Human Monoclonal Antibody ◽

Well Being ◽

Phase Iii ◽

Controlled Study ◽

Open Label ◽

Risk Of Death ◽

Increased Risk ◽

Median Change

685 Background: Xilonix, an anti-interleukin-1α true human monoclonal antibody is being assessed as cancer therapy to improve overall survival (OS) in advanced colorectal cancer (CRC) patients. Methods: An open label multicenter randomized comparator controlled study to evaluate efficacy and safety of Xilonix in CRC complicated with cachexia. Eligible patients had metastatic CRC, failed oxaliplatin or irinotecan based chemotherapy, and lost ≥5% total body weight in the previous 6 months (m). Patients were 1:1 randomized to Xilonix (3.75 mg/kg intravenously every two weeks) or megestrol acetate (MA, oral 800 mg daily) until progression. Primary endpoint was OS. Secondary endpoints included assessment of patient well-being using the EORTC QLQ-C30 questionnaire. Platelets support tumor growth and metastasis and platelet counts increase during cancer progression. IL-1α on platelets may be a target of Xilonix and thus platelet count was a key pharmacodynamic measure. Results: 40 patients were enrolled between March 2013 and July 2014, at which time the study was halted to revise inclusion criteria to reduce screen failures. An eligibility violation excluded 1 Xilonix patient from analysis (Xilonix n=19, MA n=20). MA treatment arm had a 39% shorter median OS (2.0 versus 2.8 months) and a trend in increased risk of death (hazard ratio 2.17, p=0.17). Physical and role function worsened in patients receiving megesterol (median change of -13.3 (p=0.02), -16.7 (p=0.02) respectively), whereas in Xilonix treated patients these functions did not decline during therapy (median change 0, p=0.88 and 0, p=0.69, respectively). Xilonix patients had treatment-related reduction in platelets compared to the MA group (median -60,000/mm3, vs 10,000/mm3, p=0.03). No infusion reactions, no discontinuations due to adverse events (AEs) and no related SAEs were reported for Xilonix. Conclusions: The trend in OS for Xilonix patients was encouraging and consistent with improved function and intended pharmacodynamic activity. An amended Phase III protocol has been developed to simplify enrollment for an ongoing study of Xilonix in an advanced CRC population. (NCT01767857) Clinical trial information: NCT01767857.

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Human Papillomavirus and Overall Survival After Progression of Oropharyngeal Squamous Cell Carcinoma

Journal of Clinical Oncology ◽

10.1200/jco.2014.55.1937 ◽

2014 ◽

Vol 32 (30) ◽

pp. 3365-3373 ◽

Cited By ~ 267

Author(s):

Carole Fakhry ◽

Qiang Zhang ◽

Phuc Felix Nguyen-Tan ◽

David Rosenthal ◽

Adel El-Naggar ◽

...

Keyword(s):

Overall Survival ◽

Human Papillomavirus ◽

Disease Progression ◽

Cancer Progression ◽

Radiation Therapy Oncology Group ◽

Treatment Protocol ◽

Risk Of Death ◽

Hpv Status ◽

Increased Risk ◽

Risk Of Cancer

Purpose Risk of cancer progression is reduced for patients with human papillomavirus (HPV) –positive oropharynx cancer (OPC) relative to HPV-negative OPC, but it is unknown whether risk of death after progression is similarly reduced. Patients and Methods Patients with stage III-IV OPC enrolled onto Radiation Therapy Oncology Group trials 0129 or RTOG 0522 who had known tumor p16 status plus local, regional, and/or distant progression after receiving platinum-based chemoradiotherapy were eligible for a retrospective analysis of the association between tumor p16 status and overall survival (OS) after disease progression. Rates were estimated by Kaplan-Meier method and compared by log-rank; hazard ratios (HRs) were estimated by Cox models. Tests and models were stratified by treatment protocol. Results A total of 181 patients with p16-positive (n = 105) or p16-negative (n = 76) OPC were included in the analysis. Patterns of failure and median time to progression (8.2 v 7.3 months; P = .67) were similar for patients with p16-positive and p16-negative tumors. After a median follow-up period of 4.0 years after disease progression, patients with p16-positive OPC had significantly improved survival rates compared with p16-negative patients (2-year OS, 54.6% v 27.6%; median, 2.6 v 0.8 years; P < .001). p16-positive tumor status (HR, 0.48; 95% CI, 0.31 to 0.74) and receipt of salvage surgery (HR, 0.48; 95% CI; 0.27 to 0.84) reduced risk of death after disease progression whereas distant versus locoregional progression (HR, 1.99; 95% CI, 1.28 to 3.09) increased risk, after adjustment for tumor stage and cigarette pack-years at enrollment. Conclusion Tumor HPV status is a strong and independent predictor of OS after disease progression and should be a stratification factor for clinical trials for patients with recurrent or metastatic OPC.

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EFFECTS OF SMOKING ON THE DISEASE PROGNOSIS IN CANCER PATIENTS

Problems in oncology ◽

10.37469/0507-3758-2019-65-3-321-329 ◽

2019 ◽

Vol 65 (3) ◽

pp. 321-329

Author(s):

David Zaridze ◽

Anush Mukeriya

Keyword(s):

Smoking Cessation ◽

Cancer Patients ◽

Malignant Tumors ◽

Scientific Data ◽

Second Primary ◽

Primary Tumors ◽

Smoking Intensity ◽

Risk Of Death ◽

Disease Prognosis ◽

Increased Risk

Smoking not only increases the risk of the development of malignant tumors (MT), but affects the disease prognosis, mortality and survivability of cancer patients. The link between the smoking of cancer patients and increased risk of death by all diseases and oncological causes has been established. Mortality increases with the growth of the smoking intensity, i.e. the number of cigarettes, smoked per day. Smoking is associated with the worst general and oncological survivability. The statistically trend-line between the smoking intensity and survivability was observed: each additional unit of cigarette consumption (pack/year) leads to the Overall Survival Reduction by 1% (p = 0.002). The link between smoking and the risk of developing second primary tumors has been confirmed. Smoking increases the likelihood of side effects of the antitumor therapy both drug therapy and radiation therapy and reduces the treatment efficacy. The smoking cessation leads to a significant improvement in the prognosis of a cancer patient. Scientific data on the negative effect of smoking on the prognosis of cancer patients have a major clinical importance. The treatment program for cancer patients should include science-based methods for the smoking cessation. The latter is fundamentally important, taking into account that the smoking frequency among cancer patients is much higher than in the population.

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Predictive utility of serum cytokine levels in patients with metastatic renal cell carcinoma (MRCC) treated with interferon alfa (IFNa)

Journal of Clinical Oncology ◽

10.1200/jco.2006.24.18_suppl.14503 ◽

2006 ◽

Vol 24 (18_suppl) ◽

pp. 14503-14503

Author(s):

A. J. Montero ◽

C. Diaz-Montero ◽

X. Wang ◽

B. W. McIntyre ◽

N. Tannir

Keyword(s):

Clinical Outcome ◽

Clinical Benefit ◽

Serum Levels ◽

Phase Iii ◽

Gm Csf ◽

Risk Of Death ◽

Ifna Therapy ◽

Increased Risk ◽

Cytokine Levels ◽

Th1 Cytokines

14503 Background: IFNa may prolong survival in MRCC patients (pts) due to stimulation of cell-mediated immunity. We hypothesized that IFNa exerts an anti-tumor effect by upregulation of Th1 cytokines and that patients (pts) with elevated serum levels of Th1 cytokines either at baseline (BL) or after treatment with IFNa would have a superior clinical outcome. Methods: Cytokine profiling was performed on 104 pts with MRCC treated in a randomized phase III trial with IFNa 0.5 million units (MU) subcutaneously (SC) twice daily or 5 MU SC daily. Serum samples were collected at BL (n = 104) and after 8 weeks of IFNa therapy (C1) (n = 89). Cytokine concentrations were determined using a 16-plex immunoassay. The linear mixed-effect model was fit to assess the change of cytokine levels from BL to C1. Cox proportional hazards model was fit to evaluate the effect of BL cytokine levels or change of cytokine levels from BL to C1 on the risk of death. Results: Of 16 cytokines evaluated (IL-1b, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12 p40, IL-13, IL-15, IL-17, IFNa, IFNg, GM-CSF, TNFa, VEGF), lower BL TNFa, IL-8 (Th1), and IL-13 (Th2) levels were associated with clinical benefit (major response or progression-free status at 6 months) (p = 0.01 and 0.03, respectively). By multivariate analysis, only extremely low or high levels of IFNa (p = 0.02) and IL-12 (p = 0.002) at BL were associated with an increased risk of death. IFNa therapy after C1 produced higher levels of several Th1 cytokines (IL-8, IL-12 p40, IL-15) (p < .001) and lower levels of Th2 cytokines (IL-4, IL-13). Unexpectedly, there were significantly lower levels of TNFa and GM-CSF (Th1) and higher levels of IL-10 (Th2) with IFNa. Only an increase of IL-2 levels from BL to C1 (RR 1.45; p = 0.05) correlated with an increased risk of death. Conclusions: Lower BL serum levels of TNFa, IL-8, and IL-13 were associated with clinical benefit to IFNa. Although IFNa therapy favored a shift towards a Th1 response, this effect alone did not correlate with clinical outcome. No significant financial relationships to disclose.

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Pattern of current tobacco use in a rural block of North India

International Journal of Community Medicine and Public Health ◽

10.18203/2394-6040.ijcmph20174254 ◽

2017 ◽

Vol 4 (10) ◽

pp. 3802 ◽

Cited By ~ 1

Author(s):

Anuj Jangra ◽

J. S. Malik ◽

Srishti Singh ◽

Nitika Sharma

Keyword(s):

Tobacco Use ◽

Tobacco Smoking ◽

Rural Areas ◽

Sampling Technique ◽

Control Programme ◽

North India ◽

Systematic Random Sampling ◽

Risk Of Death ◽

Increased Risk ◽

Current Tobacco

Background: Tobacco is the only legal drug that kills many of its users when used exactly as intended by manufacturers. WHO has estimated that tobacco use (smoking and smokeless) is currently responsible for the death of about six million people across the world each year. Although often associated with ill-health, disability and death from non-communicable chronic diseases, tobacco smoking is also associated with an increased risk of death from communicable diseases. This study was conducted with aim to observe the current pattern of tobacco use in a rural block of north India. Methods: The study was conducted in Lakhanmajra block (rural) of Haryana, India, in year 2015-2016 among 1000 study subjects aged 15-64 years selected by systematic random sampling technique. Results: The overall prevalence of current tobacco-smoking use to be 12.8% and it was higher among males (11.2%) as compared to females (3.2%). The median age for initiation of smoking tobacco was 18 years, smokeless tobacco was 20 years. Conclusions: Our study stresses is the need to have rural orientation in the National Tobacco Control Programme since the poorly educated individuals living in rural areas are at the maximum risk of using tobacco, identifying ways and means of reaching out to these communities will be critical to the success or failure of the program.

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Persistent Overall Survival Benefit and No Increased Risk of Second Malignancies With Bortezomib-Melphalan-Prednisone Versus Melphalan-Prednisone in Patients With Previously Untreated Multiple Myeloma

Journal of Clinical Oncology ◽

10.1200/jco.2012.41.6180 ◽

2013 ◽

Vol 31 (4) ◽

pp. 448-455 ◽

Cited By ~ 168

Author(s):

Jesús F. San Miguel ◽

Rudolf Schlag ◽

Nuriet K. Khuageva ◽

Meletios A. Dimopoulos ◽

Ofer Shpilberg ◽

...

Keyword(s):

Multiple Myeloma ◽

Overall Survival ◽

Final Analysis ◽

Incidence Rates ◽

Phase Iii ◽

Second Primary ◽

Risk Of Death ◽

Increased Risk ◽

Second Primary Malignancies

Purpose This final analysis of the phase III VISTA trial (Velcade As Initial Standard Therapy in Multiple Myeloma: Assessment With Melphalan and Prednisone) was conducted to determine whether the overall survival (OS) benefit with bortezomib-melphalan-prednisone (VMP) versus melphalan-prednisone (MP) in patients with myeloma who were ineligible for transplantation was maintained after 5 years of follow-up and to explore the risk of second primary malignancies. Patients and Methods In all, 682 patients received up to nine 6-week cycles of VMP or MP and were then observed every 12 weeks or less. Data on second primary malignancies were collected by individual patient inquiries at all sites from 655 patients. Results After median follow-up of 60.1 months (range, 0 to 74 months), there was a 31% reduced risk of death with VMP versus MP (hazard ratio [HR], 0.695; P < .001; median OS 56.4 v 43.1 months). OS benefit with VMP was seen across prespecified patient subgroups (age ≥ 75 years, stage III myeloma, creatinine clearance < 60 mL/min). Sixty-three percent of VMP patients and 73% of MP patients had received subsequent therapy. Time to next therapy (median, 30.7 v 20.5 months; HR, 0.557; P < .001) was longer with VMP than with MP. Among patients who received subsequent therapies, survival from start of subsequent therapy was similar following VMP (median, 28.1 months) or MP (median, 26.8 months; HR, 0.914). Following VMP/MP, incidence proportions of hematologic malignancies (1%/1%) and solid tumors (5%/3%) and exposure-adjusted incidence rates (0.017/0.013 per patient-year) were similar and were consistent with background rates. Conclusion VMP resulted in a significant reduction in risk of death versus MP that was maintained after 5 years' follow-up and despite substantial use of novel-agent-based salvage therapies. There is no emerging safety signal for second primary malignancies following VMP.

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The impact of extrahepatic disease among patients undergoing liver-directed therapy for neuroendocrine liver metastasis: A multi-institutional analysis.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.4_suppl.277 ◽

2017 ◽

Vol 35 (4_suppl) ◽

pp. 277-277

Author(s):

Aslam Ejaz ◽

Timothy M. Pawlik ◽

Bradley Reames ◽

Shishir Kumar Maithel ◽

George A. Poultsides ◽

...

Keyword(s):

Liver Metastasis ◽

Cox Regression ◽

Wedge Resection ◽

Extrahepatic Disease ◽

Primary Tumors ◽

Entire Cohort ◽

Risk Of Death ◽

Increased Risk ◽

Neuroendocrine Liver Metastasis ◽

The Impact

277 Background: Management of neuroendocrine liver metastasis (NELM) in the presence of synchronous extrahepatic disease (EHD) is controversial. We sought to examine the outcomes of patients undergoing liver-directed therapy for NELM in the presence of EHD using a large multicenter international cohort of patients. Methods: 612 patients who underwent liver-directed therapy were identified from 8 participating institutions. Postoperative outcomes, as well as overall (OS) and progression-free survival (PFS) were compared between patients with (N = 70, 11.4%) and without (N = 542, 88.6%) EHD. Results: Median age of the cohort was 57 years (IQR: 48, 65) with a slight majority of patients being male (N = 326, 53.3%). The majority of primary tumors were located in the pancreas (N = 254, 41.8%) followed by the small bowel (N = 188, 30.9%). At the time of liver-directed surgery, patients underwent surgery alone (N = 471, 77.0%), ablation alone (N = 15, 2.5%), or a combined approach (N = 126, 20.6%). Most patients underwent a non-anatomic wedge resection (N = 404, 66.0%). Patients with EHD had more aggressive high-grade tumors (EHD: 44.4% vs. no EHD: 16.1%; P < 0.001). EHD was most commonly located in the peritoneum (N = 29, 41.4%) and lung (N = 19, 27.1%). Among the 70 patients with EHD, 20.0% (N = 14) underwent concurrent resection for the EHD. After a median follow-up of 51 months, 174 (28.4%) patients died with a median OS of 140.4 months among the entire cohort. Patients with EHD had a shorter median OS versus patients who did not have EHD (EHD: 87 months vs. no EHD: not reached; P = 0.002). Similarly, PFS was shorter among patients with EHD compared with patients without EHD (EHD: 46.8 months vs. no EHD: 68.6 months; P = 0.005). In the cox regression model, the presence of EHD was independently associated with an increased risk of death (HR: 2.56, 95%CI 1.16-5.62; P = 0.02). Conclusions: Patients with NELM and EHD had more aggressive tumors, which conferred over a 2-fold increased risk of death compared with patients who did not have EHD. Surgical treatment of NELM among patients with EHD should be individualized.

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S100A10 in Cancer Progression and Chemotherapy Resistance: A Novel Therapeutic Target against Ovarian Cancer

10.20944/preprints201810.0318.v1 ◽

2018 ◽

Author(s):

Tannith Noye ◽

Noor Lokman ◽

Martin Oehler ◽

Carmela Ricciardelli

Keyword(s):

Ovarian Cancer ◽

Cancer Cells ◽

Cancer Progression ◽

Chemotherapy Resistance ◽

Annexin A2 ◽

Ovarian Cancer Cells ◽

Functional Studies ◽

Normal Tissues ◽

Risk Of Death ◽

Increased Risk

S100A10, which is also known as p11 is located in the plasma membrane and forms a heterotetramer with annexin A2. The heterotetramer, comprising of 2 subunits of annexin A2 and S100A10, activates the plasminogen activation pathway which is involved in cellular repair of normal tissues. Increased expression of annexin A2 and S100A10 in cancer cells leads to increased levels of plasmin which promote degradation of the extracellular matrix, increased angiogenesis and invasion of the surrounding organs. Although many studies have investigated the functional role of annexin A2 in cancer cells including ovarian cancer, S100A10 has been less studied. We recently demonstrated that high stromal annexin A2 and high cytoplasmic S100A10 expression is associated with a 3.4 fold increased risk of progression and 7.9 fold risk of death in ovarian cancer patients. Other studies have linked S100A10 with multidrug resistance in ovarian cancer, however, no functional studies to date have been performed in ovarian cancer cells. This article reviews the current understanding on S100A10 function in cancer with a particular focus on ovarian cancer.

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PRECIOUS: PREvention of Complications to Improve OUtcome in elderly patients with acute Stroke. Rationale and design of a randomised, open, phase III, clinical trial with blinded outcome assessment

European Stroke Journal ◽

10.1177/2396987318772687 ◽

2018 ◽

Vol 3 (3) ◽

pp. 291-298 ◽

Cited By ~ 7

Author(s):

Hendrik Reinink ◽

Jeroen C de Jonge ◽

Philip M Bath ◽

Diederik van de Beek ◽

Eivind Berge ◽

...

Keyword(s):

Clinical Trial ◽

Elderly Patients ◽

Acute Stroke ◽

Outcome Assessment ◽

Complete Recovery ◽

Primary Outcome Measure ◽

Phase Iii ◽

Open Label ◽

Risk Of Death ◽

Increased Risk

Background Elderly patients are at high risk of complications after stroke, such as infections and fever. The occurrence of these complications has been associated with an increased risk of death or dependency. Hypothesis: Prevention of aspiration, infections, or fever with metoclopramide, ceftriaxone, paracetamol, or any combination of these in the first four days after stroke onset will improve functional outcome at 90 days in elderly patients with acute stroke. Design International, 3 × 2-factorial, randomised-controlled, open-label clinical trial with blinded outcome assessment (PROBE) in 3800 patients aged 66 years or older with acute ischaemic stroke or intracerebral haemorrhage and an NIHSS score ≥ 6. Patients will be randomly allocated to any combination of oral, rectal, or intravenous metoclopramide (10 mg thrice daily); intravenous ceftriaxone (2000 mg once daily); oral, rectal, or intravenous paracetamol (1000 mg four times daily); or usual care, started within 24 h after symptom onset and continued for four days or until complete recovery or discharge from hospital, if earlier. Outcome: The primary outcome measure is the score on the modified Rankin Scale at 90 days (± 14 days), as analysed with multiple regression. Summary: This trial will provide evidence for a simple, safe and generally available treatment strategy that may reduce the burden of death or disability in patients with stroke at very low costs. Planning: First patient included in May 2016; final follow-up of the last patient by April 2020. Registration: ISRCTN, ISRCTN82217627, https://doi.org/10.1186/ISRCTN82217627

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