Patients with locally advanced gastric cancer benefit from combined pre- and postoperative chemotherapy, although fewer than 50% could receive postoperative chemotherapy. We examined the value of ...purely preoperative chemotherapy in a phase III trial with strict preoperative staging and surgical resection guidelines.
Patients with locally advanced adenocarcinoma of the stomach or esophagogastric junction (AEG II and III) were randomly assigned to preoperative chemotherapy followed by surgery or to surgery alone. To detect with 80% power an improvement in median survival from 17 months with surgery alone to 24 months with neoadjuvant, 282 events were required.
This trial was stopped for poor accrual after 144 patients were randomly assigned (72:72); 52.8% patients had tumors located in the proximal third of the stomach, including AEG type II and III. The International Union Against Cancer R0 resection rate was 81.9% after neoadjuvant chemotherapy as compared with 66.7% with surgery alone (P = .036). The surgery-only group had more lymph node metastases than the neoadjuvant group (76.5% v 61.4%; P = .018). Postoperative complications were more frequent in the neoadjuvant arm (27.1% v 16.2%; P = .09). After a median follow-up of 4.4 years and 67 deaths, a survival benefit could not be shown (hazard ratio, 0.84; 95% CI, 0.52 to 1.35; P = .466).
This trial showed a significantly increased R0 resection rate but failed to demonstrate a survival benefit. Possible explanations are low statistical power, a high rate of proximal gastric cancer including AEG and/or a better outcome than expected after radical surgery alone due to the high quality of surgery with resections of regional lymph nodes outside the perigastic area (celiac trunc, hepatic ligament, lymph node at a. lienalis; D2).
Abstract APPLE is a randomized, open-label, multicenter, three-arm, phase II study in advanced, EGFR -mutant and EGFR TKI naïve NSCLC patients, to evaluate the best strategy for sequencing gefitinib ...and osimertinib. Advanced EGFR -mutant NSCLC patients, WHO Performance Status 0-2 who are EGFR tyrosine kinase inhibitors treatment-naïve and eligible to receive first-line treatment with EGFR TKI will be randomized to: • arm A : osimertinib until RECIST 1.1 progression • arm B : gefitinib until emergence of circulating tumour DNA (ctDNA) T790M positive status and then switch to osimertinib until RECIST 1.1 progression • arm C : gefitinib until RECIST 1.1 progression and then switch to osimertinib until second radiologic progression In all arms, plasmatic ctDNA T790M test will be performed by central laboratory at the Medical University of Gdansk (Poland) but will be applied as a predictive marker for making treatment decision only in arm B. The primary objective is to evaluate the best strategy for sequencing of treatment with gefitinib and osimertinib in advanced NSCLC patients with common EGFR mutation, and to understand the value of liquid biopsy for decision-making process. Progression Free Survival rate at 18 months (PFSR-18) is the primary endpoint of the trial. The activity of osimertinib versus gefitinib to prevent brain metastases will be evaluated.
Synchronous oligometastatic disease (sOM) has been described as a distinct disease entity; however, there is no consensus on OM definition (OM-d) in non–small-cell lung cancer (NSCLC). A consensus ...group was formed aiming to agree on a common OM-d that could be used in future clinical trials. A European survey was circulated to generate questions and input for the consensus group meeting.
A European Organisation for Research and Treatment of Cancer Lung Cancer Group (LCG)/sOM-d consensus group survey was distributed to LCG, sOM-d consensus group, and several European thoracic oncology societies’ members.
444 responses were analysed (radiation oncologist: 55% n = 242, pulmonologist: 15% n = 66, medical oncologist: 14% n = 64). 361 physicians (81%) aimed to cure sOM NSCLC patients and 82% (n = 362) included the possibility of radical intent treatment in their sOM-d. The maximum number of metastases considered in sOM-d varied: 12% replied 1 metastasis, 42% ≤ 3, and 17% ≥ 5 metastases. 79% (n = 353) stated that number of organs involved was important for sOM-d, and most (80%, n = 355) considered that only ≤3 involved organs (excluding primary) should be included. 317 (72%) included mediastinal lymph node involvement in the sOM-d and 22% (n = 70/317) counted mediastinal lymph node as a metastatic site. Most physicians completed sOM staging with brain magnetic resonance imaging (91%, n = 403) and positron emission tomography/computed tomography (98%, n = 437). Pathology proof of metastatic disease was a requirement to define sOM for 315 (71%) physicians. The preferred primary outcome for sOM clinical trials was overall survival (73%, n = 325).
Although consensual answers were obtained, several issues remain unresolved and will require further research to agree on a sOM-d.
•The majority aimed to cure sOM NSCLC patients.•The maximum number of metastases considered in sOM-d was 42% ≤ 3 and 17% ≥ 5.•Most considered only ≤3 involved organs (excluding primary).•Few counted mediastinal lymph node as a metastatic site.•The preferred primary outcome for sOM clinical trials was overall survival.
In the genomics era, our main goal should be to identify large and meaningful differences in small, molecularly selected groups of patients. Classical phase I, II and III models for drug development ...require large resources, limiting the number of experimental agents that can be tested and making the evaluation of targeted agents inefficient. There is an urgent need to streamline the development of new compounds, with the aim of identifying "trials designed to learn", which could lead to subsequent "trials designed to conclude". Basket trials are often viewed as parallel phase II trials within the same entity, designed on the basis of a common denominator, which can be a molecular alteration(s). Most basket trials are histology-independent and aberration-specific clinical trials. Umbrella trials are built on a centrally performed molecular portrait and molecularly selected cohorts with matched drugs, and can include patients' randomisation and strategy validation. Beyond new designs, new end-points and new evaluation techniques are also warranted to finally achieve methodology and clinical improvements, in particular within immunotherapy trials.
Mycosis fungoides (MF) is the most common primary cutaneous T-cell lymphoma. There is a need for multicenter trials involving defined patient populations using rigorous assessment criteria. We have ...investigated pegylated liposomal doxorubicin (PLD) in a clearly defined patient population with advanced MF.
Eligible patients had stage IIB, IVA, or IVB MF, refractory or recurrent after at least two previous systemic therapies. Patients were registered to receive a maximum of six cycles of PLD 20 mg/m2 on days 1 and 15, every 28 days (one cycle). The primary end point was response rate (RR).
Nine centers recruited 49 eligible patients. The median number of chemotherapy cycles received was five. There were no grade 3 to 4 hematologic toxicities. Grade 3 or 4 nonhematologic/nonbiochemical toxicities included cardiac symptom (2%), allergy/hypersensitivity (2%), constitutional symptom (4%), hand and foot reaction (2%), other dermatologic toxicity (6%), other GI toxicity (4%), infection (4%), pulmonary embolism (2%), and cardiac ischemia (2%). Of 49 patients, 20 (40.8%) were responders (complete clinical response CCR or partial response PR as overall response): three (6.1%) experienced CCRs, and 17 (34.7%) experienced PRs. A 50% or greater reduction of cutaneous manifestations was observed in 26 (60.5%) of 43 assessable patients. Two early deaths were reported, resulting from related cardiovascular toxicity and disease progression. The lower limit of the one-sided 90% CI for RR was 31.2%. Median time to progression and median duration of response were 7.4 and 6 months, respectively.
PLD has an acceptable safety profile in patients with advanced MF. The efficacy of PLD seems promising.
Recent trials have shown significant survival benefit from adjuvant chemotherapy for non-small-cell lung cancer (NSCLC). Whether elderly patients tolerate platinum-based adjuvant chemotherapy and ...derive the same survival advantage is unknown. This retrospective study evaluated the influence of age on survival, adjuvant chemotherapy delivery, and toxicity in National Cancer Institute of Canada (NCIC) Clinical Trials Group study JBR.10.
Pretreatment characteristics and survival were compared for 327 young (< or = 65 years) and 155 elderly (> 65 years) patients. Chemotherapy delivery and toxicity were compared for 213 treated patients (63 elderly, 150 young).
Baseline demographics by age were similar with the exception of histology (adenocarcinoma: 58% young, 43% elderly; squamous: 32% young, 49% elderly; P = .001) and performance status (PS; PS 0: 53% young, 41% elderly; P = .01). Chemotherapy significantly prolonged overall survival for elderly patients (hazard ratio, 0.61; 95% CI, 0.38 to 0.98; P = .04). This benefit is similar to the effect for all patients in JBR.10. Mean dose-intensities of vinorelbine and cisplatin were 13.2 and 18.0 mg/m2/wk in young, respectively, and 9.9 and 14.1 mg/m2/wk in elderly patients (vinorelbine, P = .0004; cisplatin, P = .001), respectively. The elderly received significantly fewer doses of vinorelbine (P = .014) and cisplatin (P = .006). Fewer elderly patients completed treatment and more refused treatment (P = .03). There were no significant differences in toxicities, hospitalization, or treatment-related death by age group. Fifteen (11.9%) of 126 deaths in the young resulted from nonmalignant causes, and 15 (21.1%) of 71 in the elderly (P = .13).
Despite elderly patients' receiving less chemotherapy, adjuvant vinorelbine and cisplatin improves survival in patients older than 65 years with acceptable toxicity. Adjuvant chemotherapy should not be withheld from elderly patients.
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.
Abstract Background Response criteria have always been difficult to apply to malignant pleural mesothelioma (MPM), due to its unique pattern of growth. We developed some models to show that ...progression free survival rate (PFSR) could be a better predictor of overall survival (OS) than the response rate (RR) in MPM patients. The results were validated independently in the European Organisation for Research and Treatment of Cancer (EORTC) 08052, a phase II study in MPM. Methods Individual patient data from 10 EORTC-Lung Cancer Group (LCG) studies of first-line chemotherapy in MPM were pooled. Response to therapy was assessed according to World Health Organisation (WHO) criteria in all except the two most recent trials, which used Response Evaluation Criteria in Solid Tumours (RECIST). Landmark analyses (LA) at 9 weeks and 18 weeks after registration/randomisation were performed to assess the association between PFSR and OS. Independent validation of the results was conducted in EORTC 08052 study (82 patients) employing the same LA. Results All 10 studies ( N = 523 patients) were included in the LA of PFSR at 9 and 18 weeks (PFSR-9 and PFSR-18). PFSR-9 and PFSR-18 were confirmed as predictors of OS, with hazard ratio (HR) of 0.37 (95% confidence interval (CI), 0.30–0.47) and 0.50 (0.38–0.65) and C-index of 0.62 and 0.58, respectively. In the validation study, 28.4% achieved CR/PR and 77.8% had disease control (CR/PR/SD) as their best overall response. PFSR-9 and PFSR-18 weeks were both strongly correlated with OS (HR of 0.35 80% CI, 0.25–0.49 and 0.46 (0.32–0.67) and C-index of 0.66 and 0.60, respectively). Conclusion PFSR-18 was strongly correlated and discriminated patients with better OS from the poorer prognosis patients. An earlier end-point, PFSR-9 was also strongly correlated to OS with better discriminating capacity. The results were independently validated.
Abstract Purpose The EORTC 08062 phase II randomised trial investigated the activity and safety of single agent amrubicin, cisplatin combined with amrubicin, and cisplatin combined with etoposide as ...first line treatment in extensive disease (ED) small cell lung cancer (SCLC). Patients and methods Eligible patients with previously untreated ED-SCLC, WHO performance status (PS) 0–2 and measurable disease were randomised to 3 weekly cycles of either amrubicin alone 45 mg/m2 i.v. day(d) 1–3 (A), cisplatin 60 mg/m2 i.v. d1 and amrubicin 40 mg/m2 i.v. d1–3 (PA), or cisplatin 75 mg/m2 i.v. d1 and etoposide 100 mg/m2 d1, d2–3 i.v./po (PE). The primary end-point was overall response rate (ORR) as assessed by local investigators (RECIST1.0 criteria). Secondary end-points were treatment toxicity, progression-free survival and overall survival. Results The number of randomised/eligible patients who started treatment was 33/28 in A, 33/30 in PA and 33/30 in PE, respectively. Grade (G) ⩾3 haematological toxicity in A, PA and PE was neutropenia (73%, 73%, 69%); thrombocytopenia (17%, 15%, 9.4%), anaemia (10%, 15%, 3.1%) and febrile neutropenia (13%, 18%, 6%). Early deaths, including treatment related, occurred in 1, 3 and 3 patients in A, PA and PE arms, respectively. Cardiac toxicity did not differ among the 3 arms. Out of 88 eligible patients who started treatment, ORR was 61%, (90% 1-sided confidence intervals CI 47–100%), 77% (CI 64–100%) and 63%, (CI 50–100%) for A, PA and PE respectively. Conclusion All regimens were active and PA met the criteria for further investigation, despite slightly higher haematological toxicity.
National Cancer Institute of Canada Clinical Trials Group JBR.10 study is among the landmark trials that have established third generation platinum-based adjuvant chemotherapy as the standard of care ...after resection of stages IB-II NSCLC, improving absolute 5-year survival by 15% and median survival by 21 months. This cost-effectiveness analysis of adjuvant chemotherapy from the perspective of Canada's public health care system was undertaken based on the JBR.10 study population.
The primary outcome of the study was the incremental cost effectiveness ratio (ICER) expressed in dollars per life-year gained (LYG). Direct medical resource utilization data were collected retrospectively from trial data and medical records of patients enrolled in the JBR.10 study at the five largest accruing Canadian centers, from the time of random assignment until death or study closure (April 2004). Survival and available costs (2005 Canadian dollars $CAD) are presented both with and without discounting at 5% per year.
Utilization data were collected from 172 Canadian patients (36% of the trial population), 85 randomly assigned to observation and 87 randomly assigned to chemotherapy. The mean costs of treatment per patient in the observation and adjuvant chemotherapy arms were $23,878 and $31,319, respectively, with an ICER of CAD$7,175/LYG discounted (95% CI, -$3,463 to $41,565), and $10,096/LYG undiscounted (95% CI, -$819 to $55,651).
Adjuvant vinorelbine plus cisplatin is a highly cost effective treatment that compares very favorably with other standard health care interventions.
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