Summary Background Vorinostat is a histone deacetylase inhibitor that changes gene expression and protein activity. On the basis of the clinical benefit reported in patients with malignant pleural ...mesothelioma treated in a phase 1 study of vorinostat, we designed this phase 3 trial to investigate whether vorinostat given as a second-line or third-line therapy improved patients' overall survival. Methods This double-blind, randomised, placebo-controlled trial was done in 90 international centres. Patients with measurable advanced malignant pleural mesothelioma and disease progression after one or two previous systemic regimens were eligible. After stratification for Karnofsky performance status, histology, and number of previous chemotherapy regimens, patients were randomly assigned (1:1) by use of an interactive voice response system with a block size of four to either treatment with vorinostat or placebo. Patients received oral vorinostat 300 mg (or matching placebo) twice daily on days 1, 2, 3, 8, 9, 10, 15, 16, and 17 of a 21-day cycle. The primary endpoints were overall survival and safety and tolerability of vorinostat. The primary efficacy comparison was done in the intention-to-treat population, and safety and tolerability was assessed in the treated population. This trial is registered with ClinicalTrials.gov , number NCT00128102. Findings From July 12, 2005, to Feb 14, 2011, 661 patients were enrolled and randomly assigned to receive either vorinostat (n=329) or placebo (n=332) and included in the intention-to-treat analysis. Median overall survival for vorinostat was 30·7 weeks (95% CI 26·7–36·1) versus 27·1 weeks (23·1–31·9) for placebo (hazard ratio 0·98, 95% CI 0·83–1·17, p=0·86). The most common grade 3 or worse adverse events for patients treated with vorinostat were fatigue or malaise (51 16% patients in the vorinostat group vs 25 8% in the placebo group) and dyspnoea (35 11% vs 45 14%). Interpretation In this randomised trial, vorinostat given as a second-line or third-line therapy did not improve overall survival and cannot be recommended as a therapy for patients with advanced malignant pleural mesothelioma. Funding Merck & Co, Inc.
Malignant pleural mesothelioma is an aggressive cancer with highly vascularised tumours. It has poor prognosis and few treatment options after failure of first-line chemotherapy. NGR-hTNF is a ...vascular-targeting drug that increases penetration of intratumoral chemotherapy and T-cell infiltration by modifying the tumour microenvironment. In this trial, we aimed to investigate the efficacy and safety of NGR-hTNF in patients with malignant pleural mesothelioma who had progressed during or after a first-line treatment.
NGR015 was a randomised, double-blind, placebo-controlled phase 3 trial done in 41 centres in 12 countries. Eligible participants had malignant pleural mesothelioma of any histological subtype (epithelial, sarcomatoid, or mixed), were aged 18 years or older, and had an Eastern Cooperative Oncology Group performance status of 0–2 and radiologically documented progressive disease after one pemetrexed-based chemotherapy regimen. Participants were randomly assigned to receive weekly NGR-hTNF 0·8 μg/m2 intravenously plus best investigator choice (n=200), or placebo plus best investigator choice (n=200). Best investigator choice was decided before random assignment and could be single-agent gemcitabine (1000–1250 mg/m2 intravenously), vinorelbine (25 mg/m2 intravenously or 60 mg/m2 orally), doxorubicin (60–75 mg/m2 intravenously), or best supportive care only. Patients were randomised (1:1) with a block size of four after stratification for performance status and best investigator choice. The primary study endpoint was overall survival in the intention-to-treat population. The trial is closed to new participants and is registered with ClinicalTrials.gov (NCT01098266).
Between April 12, 2010 and Jan 21, 2013, we enrolled 400 eligible participants. 381 (95%) of 400 patients were selected to receive chemotherapy before all participants were randomly assigned to receive NGF-hTNF plus best investigator choice (n=200) or placebo plus best investigator choice (n=200). At the cutoff date (April 29, 2014), the median follow-up was 18·7 months (IQR 15·1–24·4), and overall survival did not differ between the two treatment groups (median 8·5 months 95% CI 7·2–9·9 in the NGR-hTNF group vs 8·0 months 6·6–8·9 in the placebo group; hazard ratio 0·94, 95% CI 0·75–1·18; p=0·58). Grade 3 or worse study-emergent adverse events occurred in 136 (70%) of patients receiving NGR-hTNF versus 118 (61%) of patients receiving placebo, with the most common being neutropenia (35 18% of 193 patients vs 36 19% of 193 patients), pain (11 6% vs 16 8%), dyspnoea (nine 5% vs seven 4%), and chills (nine 5% vs none). 50 (26%) patients in the NGR-hTNF group had a serious adverse event, compared with 47 (24%) in the placebo group. Treatment-related serious adverse events occurred in 17 (9%) patients in the NGR-hTNF group and 20 patients (10%) in the placebo group. There were 12 deaths in the NGR-hTNF group and 13 deaths in the placebo group, but none were treatment related.
The study did not meet its primary endpoint. The hypothesis-generating findings from the subgroup analyses deserve a confirmatory randomised trial because patients who rapidly progress after first-line treatment have a poor prognosis.
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Cancer of unknown primary (CUP) is a well recognized clinical syndrome, accounting for 3–5% of all malignancies. It is characterized as a disease with an early dissemination of ...metastases without a primary detected site after extensive laboratory and clinical investigations. CUP is divided into the favorable and unfavorable groups based on histopathological and clinical manifestations. Adenocarcinoma of various differentiations is the commonest histopathological subtype. Favorable groups are treated with local or systemic treatment and some of them are enjoying long-term survival. On the contrary, unfavorable groups are treated with empirical chemotherapy having usually a dismal prognosis. Gene-profiling microarray diagnosis has a high diagnostic sensitivity, but its predictive or prognostic value remains uncertain.
Lung Cancer in the Middle East and North Africa Region Jazieh, Abdulrahman R.; Algwaiz, Ghada; Errihani, Hassan ...
Journal of thoracic oncology,
November 2019, 2019-November, 2019-11-00, Volume:
14, Issue:
11
Journal Article
We conducted a phase III trial to determine whether first-line treatment with raltitrexed, a thymidine synthase inhibitor, and cisplatin results in superior outcome compared with cisplatin alone in ...patients with malignant pleural mesothelioma (MPM).
Eligible patients with histologically proven advanced MPM, not pretreated with chemotherapy, WHO performance status (PS) 0 to 2, and adequate hematological, renal, and hepatic function were randomly assigned to receive cisplatin 80 mg/m2 IV on day 1, alone (arm A) or combined with raltitrexed 3 mg/m2 (arm B). In patients with measurable disease, response was monitored using the Response Evaluation Criteria in Solid Tumors criteria. Health related quality of life (HRQOL) was measured using the European Organisation for Research and Treatment of Cancer QLQ-C30 and Lung Module (QLQ-LC13).
Two hundred fifty patients were randomized: 80% male; median age, 58 years; and WHO PS, 0, 1, 2 in 25, 62, and 13% of cases, respectively. There were no toxic deaths. The main grade 3 or 4 toxicities observed were neutropenia and emesis, reported twice as often in the combination arm. Among 213 patients with measurable disease, response rate was 13.6% (arm A) versus 23.6% (arm B; P = .056). No difference in HRQOL was observed on any of the scales. Median overall and 1-year survival in arms A and B were 8.8 (95% CI, 7.8 to 10.8) v 11.4 months (95% CI, 10.1 to 15), respectively, and 40% v 46%, respectively (P = .048).
A combination of raltitrexed and cisplatin improves overall survival compared with cisplatin alone. This study confirms that a combination of cisplatin and an antifolate is superior to cisplatin alone in patients with MPM, without harmful effect on HRQOL.
Abstract Background EORTC study 08021/ILCP 01/03 evaluated the role of consolidation gefitinib, an oral tyrosine kinase inhibitor (TKI), administered in patients with advanced non-small cell lung ...cancer (NSCLC), not progressing following standard 1st-line chemotherapy. Methods Patients with advanced NSCLC, not-progressing after four cycles of platinum-based chemotherapy, were randomised to receive either gefitinib 250 mg/d or matched placebo until progression or unacceptable toxicity. The primary end-point was overall survival (OS). Secondary end-points were progression-free survival (PFS) and toxicity. The study was powered to detect a 28% increase in OS from a median of 11–14.1 months (HR = 0.78) and planned to randomise 598 patients to observe 514 deaths. Results After inclusion of 173 patients, the trial was prematurely closed due to low accrual. Baseline characteristics for gefitinib ( n = 86) and placebo ( n = 87) arms were well balanced. After a median follow up of 41 months, the difference in median OS in the gefitinib and placebo arms was not statistically significant (10.9 and 9.4 months, HR 0.83 95% confidence interval (95% CI) 0.60–1.15; p = 0.2). The difference in median PFS significantly favoured gefitinib (4.1 and 2.9 months, HR = 0.61, 95% CI 0.45, 0.83), p = 0.0015). Adverse events reported in more than 10% of patients were rash (47% with gefitinib versus 13% with placebo) and diarrhoea (34% with gefitinib versus13% with placebo). Conclusions Despite its premature closure, this trial confirms previous evidence that consolidation gefitinib is safe and improves PFS. However, no difference in OS was observed in this study ( NCT00091156 ).
Purpose
Studies of the etiology of inflammatory breast cancer (IBC), a rare but aggressive breast cancer, have been hampered by limited risk factor information. We extend previous studies by ...evaluating a broader range of risk factors.
Methods
Between 2009 and 2015, we conducted a case–control study of IBC at six centers in Egypt, Tunisia, and Morocco; enrolled were 267 IBC cases and for comparison 274 non-IBC cases and 275 controls, both matched on age and geographic area to the IBC cases. We administered questionnaires and collected anthropometric measurements for all study subjects. We used multiple imputation methods to account for missing values and calculated odds ratios (ORs) and 95% confidence intervals (CIs) using polytomous logistic regression comparing each of the two case groups to the controls, with statistical tests for the difference between the coefficients for the two case groups.
Results
After multivariable adjustment, a livebirth within the previous 2 years (OR 4.6; 95% CI 1.8 to 11.7) and diabetes (OR 1.8; 95% CI 1.1 to 3.0) were associated with increased risk of IBC, but not non-IBC (OR 0.9; 95% CI 0.3 to 2.5 and OR 0.9; 95% CI 0.5 to 1.6 for livebirth and diabetes, respectively). A family history of breast cancer, inflammatory-like breast problems, breast trauma, and low socioeconomic status were associated with increased risk of both tumor types.
Conclusions
We identified novel risk factors for IBC and non-IBC, some of which preferentially increased risk of IBC compared to non-IBC. Upon confirmation, these findings could help illuminate the etiology and aid in prevention of this aggressive cancer.
Abstract Background This was a prospective phase II study of cisplatin and bortezomib (CB) in the first line treatment of malignant pleural mesothelioma (MPM) with validation of progression free ...survival rate at 18 weeks (PFSR-18) as primary end-point. Methods Chemotherapy-naïve patients with histologically proven MPM and performance status (PS) 0/1, were treated with cisplatin 75 mg/m2 on day 1 and bortezomib 1.3 mg/m2 on days 1, 4, 8, 11 every 3 weeks. The primary end-point validation utilised the landmark method. Results Between 2007 and 2010 82 patients were entered. PFSR-18 was 53% (80% confidence intervals, CIs, 42–64%). The overall survival (OS) was 13.5 months (95% CI 10.5–15) with 56% (95% CI 44–66%) alive at 1 year. The median PFS was 5.1 months (95% CI 3.3–6.5) and the response rate was 28.4% (95% CI 18.9–39.5%). The most frequent grade 3–4 toxicities were hyponatremia (46%), hypokalaemia (17%), fatigue (12.2%), thrombocytopenia (11%), neutropenia (9.7%) and neurotoxicity (motor, sensory, other: 1.2%, 8.5%, 2.4%). There were two toxic deaths (32 and 74 days) due to acute pneumonitis and cardiac arrest. End-point validation showed that patients with no progression/progression at 18 weeks had median OS of 16.9/11.9 months, respectively. Hazard ratio was 0.46 (CI 0.32–0.67), logrank test and C-index were 0.007 and 0.60. Conclusion The 50% PFSR-18 for CB was contained within the 80% CI for (42–64%). Therefore the null hypothesis could not be rejected. Accordingly this combination does not warrant further investigation. PFSR-18 was confirmed as a strong predictor of survival.
Purpose
The theme of the St. Gallen International Breast Cancer Conference 2021 held virtually for the first time, due to the COVID-19 pandemic, was on tailoring therapies for patients with early ...breast cancer. A monkey survey that included an Egyptian Panel voted on most of the questions of the original St. Gallen consensus, and some added new questions most relevant to oncology practice in the country, to be able to compare voting results that reflect differences in breast cancer management and decision making.
Methods
The panel included 74 Egyptian scientists from different oncology specialties. Management issues including controversial diagnostic and therapeutic interventions were prepared by a small committee and then projected using the online monkey survey website:
https://www.surveymonkey.com
. The survey included 130 questions. Results were then analyzed, tabulated, and compared to the voting results of the original St. Gallen consensus.
Results and conclusions
Voting questions and resulting percentages of answers from the Egyptian panel were summarized. There was no consensus between the Egyptian and the original St. Gallen panels on 28/130 statements. They mostly included genetic and pathologic aspects, specifically the routine use of gene signature assays and a few queries involving surgical, radiotherapeutic, and systemic interventions. Probably, available resources and healthcare system differences in Egypt compared to European and the USA were the cause of these differences. This would also be applicable to other low- and low-middle-income healthcare scenarios present in many countries, especially with the present constraints of the COVID-19 pandemic.
To compare the therapeutic efficacy of paclitaxel plus cisplatin (arm A) versus gemcitabine plus cisplatin (arm B) and arm A versus paclitaxel plus gemcitabine (arm C) in chemotherapy-naive patients ...with advanced non-small-cell lung cancer (NSCLC).
Patients were randomly assigned to receive either paclitaxel 175 mg/m2 (3-hour infusion, day 1) or gemcitabine 1,250 mg/m2 (days 1 and 8) both combined with cisplatin 80 mg/m2 (day 1) or paclitaxel 175 mg/m2 (3-hour infusion, day 1) combined with gemcitabine 1,250 mg/m2 (days 1 and 8). Primary end point was comparison of overall survival for B versus A and C versus A. Secondary end points included response rate and duration, progression-free survival, toxicities, quality of life QoL, and cost of treatment.
Four hundred eighty patients (arm A, 159; arm B, 160; arm C, 161 patients) were enrolled; all baseline characteristics were balanced. Median survival times were as follows: arm A, 8.1 months; arm B, 8.9 months; arm C, 6.7 months. Response rates were 31.8% for arm A, 36.6% for arm B, and 27.7% for arm C. Other than myelosuppression (B v A, P <.005), no statistically or clinically significant differences were observed for secondary end points. The average treatment costs were 25% higher in arm C as compared with arms A and B.
Gemcitabine plus cisplatin and paclitaxel plus gemcitabine do not increase overall survival in patients with advanced NSCLC as compared with paclitaxel plus cisplatin. Treatment was well tolerated, and most QoL parameters were similar, but costs associated with the nonplatinum arm were highest.
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