Use of archival versus newly collected tumor samples for assessing PD-L1 expression and overall survival: an updated analysis of KEYNOTE-010 trial.

BACKGROUND: In KEYNOTE-010, pembrolizumab versus docetaxel improved overall survival (OS) in patients with programmed death-1 protein (PD)-L1-positive advanced non-small-cell lung cancer (NSCLC). A prespecified exploratory analysis compared outcomes in patients based on PD-L1 expression in archival versus newly collected tumor samples using recently updated survival data. PATIENTS AND METHODS: PD-L1 was assessed centrally by immunohistochemistry (22C3 antibody) in archival or newly collected tumor samples. Patients received pembrolizumab 2 or 10 mg/kg Q3W or docetaxel 75 mg/m2 Q3W for 24 months or until progression/intolerable toxicity/other reason. Response was assessed by RECIST v1.1 every 9 weeks, survival every 2 months. Primary end points were OS and progression-free survival (PFS) in tumor proportion score (TPS) ≥50% and ≥1%; pembrolizumab doses were pooled in this analysis. RESULTS: At date cut-off of 24 March 2017, median follow-up was 31 months (range 23-41) representing 18 additional months of follow-up from the primary analysis. Pembrolizumab versus docetaxel continued to improve OS in patients with previously treated, PD-L1-expressing advanced NSCLC; hazard ratio (HR) was 0.66 [95% confidence interval (CI): 0.57, 0.77]. Of 1033 patients analyzed, 455(44%) were enrolled based on archival samples and 578 (56%) on newly collected tumor samples. Approximately 40% of archival samples and 45% of newly collected tumor samples were PD-L1 TPS ≥50%. For TPS ≥50%, the OS HRs were 0.64 (95% CI: 0.45, 0.91) and 0.40 (95% CI: 0.28, 0.56) for archival and newly collected samples, respectively. In patients with TPS ≥1%, OS HRs were 0.74 (95% CI: 0.59, 0.93) and 0.59 (95% CI: 0.48, 0.73) for archival and newly collected samples, respectively. In TPS ≥50%, PFS HRs were similar across archival [0.63 (95% CI: 0.45, 0.89)] and newly collected samples [0.53 (95% CI: 0.38, 0.72)]. In patients with TPS ≥1%, PFS HRs were similar across archival [0.82 (95% CI: 0.66, 1.02)] and newly collected samples [0.83 (95% CI: 0.68, 1.02)]. CONCLUSION: Pembrolizumab continued to improve OS over docetaxel in intention to treat population and in subsets of patients with newly collected and archival samples. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01905657.

Palliative care needs at different phases in the illness trajectory: a survey study in patients with cancer.

Despite the growing consensus on the benefits of initiating palliative care early in the disease trajectory, it remains unclear at what point palliative care needs emerge. This study investigates quality of life and unmet palliative care needs at three phases in the cancer trajectory, curative, life-prolonging and most advanced (prognosis <6 months/no further disease-modifying treatment). We collected self-reported data from 620 patients with cancer in the University Hospital of Ghent, Belgium. They completed a questionnaire on quality of life (using the EORTC QLQ-C30) and unmet care needs within the domains of palliative care. We used European reference values of the EORTC QLQ-C30 to compare the mean scores with a norm group. The groups further on in the cancer trajectory reported statistically and clinically poorer functioning compared with earlier phases, also when controlled for the effects of sex, age or type of cancer. Higher symptom burdens for fatigue, pain, dyspnoea and appetite loss were found in groups further into the trajectory, p < .001. Patients in the curative phase experienced physical symptoms and had clinically worse functioning than a European reference group. This paper demonstrates the ongoing need for oncologists to address the broader palliative care needs of patients from diagnosis onwards.

A randomized phase II study comparing two schedules of the 21-day regimen of gemcitabine and carboplatin in advanced non-small cell lung cancer.

PURPOSE: Carboplatin area under the curve (AUC) 5 ml/min on day 1 with gemcitabine 1,250 mg/m(2) on day 1 and day 8 is a widely used regimen in advanced non-small cell lung cancer. Grade 3-4 thrombocytopenia and neutropenia are frequent. The aim of this study is to investigate whether toxicity of gemcitabine/carboplatin could be reduced by administering carboplatin on day 8 instead of day 1 without a decrease in response rate (RR). METHODS: Patients received gemcitabine 1,250 mg/m(2) on days 1 and 8, carboplatin AUC 5 on day 1 (arm A) or day 8 (arm B). Drugs were administered over a 21-day cycle. Toxicity and RR were evaluated weekly and every second cycle, respectively. RESULTS: 71 patients were enrolled into the study. We found 79% (95% CI 61-91%) grade 3-4 toxicity (neutropenia and thrombocytopenia) in arm A and 50% (95% CI 32-68%) in arm B; 66% grade 3-4 thrombocytopenia in arm A and 26% in arm B. We observed 30% grade 4 hematological toxicity in arm A and 3% in arm B. In arm A an overall RR of 20% (95% CI 7.7-38.6%) was seen, and 18.2% (95% CI 7-35.5%) in arm B. CONCLUSIONS: Although the study was prematurely closed, the current data are of interest. The schedule with carboplatin on day 8 is associated with substantially lower grade 3-4 neutropenia and thrombocytopenia with comparable dose intensity and RR.

Lessons to learn from EORTC study 08981: a feasibility study of induction chemoradiotherapy followed by surgical resection for stage IIIB non-small cell lung cancer.

The present EORTC phase II feasibility study in stage IIIB (T4-N3) NSCLC was conducted to investigate whether an induction regimen with concurrent chemoradiotherapy followed by surgery after restaging by re-mediastinoscopy and/or fluorodeoxyglucose-positron emission tomography (FDG-PET) was feasible in a multicenter setting. Unfortunately, the study closed prematurely because of poor accrual. The combination of more stringent selection criteria, the incorrect prevailing view of Ethical Boards that a tri-modality approach is too toxic, competing studies in the participating centers and the fact that patients with N3 disease could only be enrolled if a re-mediastinoscopy could be performed, underlie the low accrual. Although this study illustrates that the conduct of a tri-modality study across Europe appeared to be difficult at that time, the number of centers with highly qualified and experienced specialists involved in this kind of multi-modality approaches is rapidly increasing. Future initiatives should, therefore, certainly be encouraged. Minimally invasive procedures such as EUS and EBUS should preferably be used for up-front mediastinal staging, mediastinoscopy with or without EUS should preferably be reserved for restaging, and especially right-sided pneumonectomies should be avoided. Though evident, the feasibility to complete this kind of studies within a reasonable time period is still a condition sine qua non.

[Long-term results of the multidisciplinary surgical treatment of non-small-cell bronchial carcinoma in the superior sulcus (Pancoast tumour): a retrospective study]. / Langetermijnresultaten van de multidisciplinaire chirurgische behandeling van niet-kleincellig bronchuscarcinoom in de thoraxkoepel (pancoasttumor); retrospectief onderzoek.

OBJECTIVE: To establish the long-term results of a combination of radiotherapy or chemoradiotherapy and surgery for the treatment of patients with a Pancoast tumour in the Erasmus MC-Daniel den Hoed, Rotterdam, the Netherlands, with special attention for the prognostic factors. DESIGN: Retrospective. METHODS: During the period from 1 January 1991 to 31 December 2004, 36 patients underwent surgical treatment combined with radiotherapy or chemoradiotherapy for a non-small-cell bronchial carcinoma with invasion of the superior sulcus. The study was terminated on 31 January 2006. The data were analysed according to the intention-to-treat principle, with overall survival and disease-free survival as the outcome variables. Cox regression analysis revealed differences between the subgroups on the basis of which prognostic factors could be studied. RESULTS: 36 patients with a non-small-cell bronchial carcinoma invading the superior sulcus (Pancoast tumour) underwent multidisciplinary treatment consisting of pre-operative radiotherapy (since 2002 concomitant chemoradiotherapy), superior-sulcus resection and (partial) lung resection with intra-operative brachytherapy. 2 patients died postoperatively. In 80% of the patients there was a positive histological effect of the preoperative treatment. The median follow-up was 26 months. The 2-year overall and disease-free survival was 45 and 31%, respectively, and at 5 years this was 28 and 19%. These results were comparable with those for stage IIB lung cancer without invasion. Favourable prognostic factors were: at least 75% necrosis of the tumour after pre-treatment, lack of positive mediastinal lymph nodes, and younger age.

The effect of radical treatment and rehabilitation on muscle mass and strength: a randomized trial in stages I-III lung cancer patients.

OBJECTIVES: Little is known about the impact of an oncological treatment on muscle mass and strength in patients with lung cancer and the impact of a subsequent rehabilitation program. This study investigates the effect of radical treatment and post-treatment pulmonary rehabilitation on muscle mass and strength in patients with lung cancer and the relationship between muscle mass and strength. METHODS: Lung cancer patients, candidate for radical treatment, were randomly (2:1) allocated after radical treatment to either standard follow up (CON) or a 12-week rehabilitation training program (RT). Muscle mass was estimated by bioelectric impedance and CT-scan. Muscle strength was estimated by measuring quadriceps force (QF) with a hand held dynamometer. All variables were measured before (M1) and after radical treatment (M2), and at the earliest 12 weeks after randomization (M3). Data are presented as means with standard deviation. RESULTS: 45 lung cancer patients (age: 65 years (9)) participated in the study. At M2, both muscle cross sectional area (MCSA) and QF were significantly decreased (p<0.05). 28 patients were randomized. 13/18 RT and 9/10 CON patients ended the trial. At M3, RT-patients improved significantly their MCSA compared to CON-patients (ΔMCSA: 6 cm(2) (6) (p=0.003) vs. 1cm(2) (11) (p=0.8)). CONCLUSION: Muscle mass and strength: (1) are decreased at presentation in a substantial part of lung cancer patients; (2) are significantly negatively affected by radical treatment and (3) completely recover after a 12 week structured rehabilitation program, whereas a further decline was observed in CON-patients.

Management of malignant pleural mesothelioma: have we made any progress?

As the incidence of malignant pleural mesothelioma (MPM) is increasing in the next decades, treatment is a challenge. The past 2 years have seen a number of promising achievements in the management of patients with MPM. Treatment of a symptomatic malignant pleural effusion through indwelling pleural catheter (IPC) may allow for an individualized treatment. Advances in the systemic treatment with targeted agents will undoubtedly gain by the discovery of a driver mutation which may be selectively targeted. In the meantime, the addition of monoclonal antibodies to a standard chemotherapy backbone might result in a modest improvement in outcome in patients selected for the presence of the ligand. New techniques in radiation therapy, pleural intensity-modulated radiotherapy, helical tomography and proton-therapy are exciting advances in multimodality treatment enhancing local control and therefore improving overall survival. The role of surgery remains controversial and should be further explored. Surgical procedures consist of extrapleural pneumonectomy or lung sparing operations like debulking of the parietal and visceral pleura by (extended) pleurectomy/decortication. Where the treatment in multimodality therapy may lead to improved disease-free survival and overall survival, the type of cyto-reductive procedure should be selected on institutional and surgeon's experience. The increase in mesothelioma incidence is matched only by the increasing number of researchers and studies. It is up to the clinicians to support these efforts by stimulating their patients to participate in this clinical research.

18-Fluorodeoxyglucose positron emission tomography as a tool for response prediction in solid tumours.

Current response guidelines for the treatment of solid tumours are based on CT criteria. Over the last decades new techniques have emerged to evaluate cancer therapy. FDG-PET scanning is a more functional imaging technique, which can measure differences in metabolic activity. Although it has a low specificity, studies show that it can outperform classical CT scanning criteria. Especially in lung, breast and oesophageal cancer it can predict response earlier in the neo-adjuvant setting. This could reduce the use of ineffective cancer therapies, reducing costs and patient toxicity, and direct patients sooner towards effective therapy. The main problem with FDG-PET remains the difficulty in defining thresholds for response, as there is clearly a lack in large prospective randomized studies validating the use of FDG-PET in response guidelines.We give an overview of data on response prediction in solid tumours by the application of PET.

Endurance and Resistance Training in Radically Treated Respiratory Cancer patients: A Pilot Study.

Introduction. Respiratory cancer and its treatment are known to contribute to muscle weakness and functional impairment. Aim. To assess the effects of rehabilitation in patients with respiratory cancer. Methods. Radically treated respiratory cancer patients were included in a 12-week multidisciplinary rehabilitation program. Results. 16 patients (age: 61 ± 7 years; FEV(1): 57 ± 16% pred.) showed a reduced exercise tolerance (VO(2)max: 56 ± 15% pred.; 6 MWD: 67 ± 11% pred.), muscle force (PImax: 54 ± 22% pred.; QF: 67 ± 16% pred.), and quality of life (CRDQd: 17 ± 5 points; CRDQf: 16 ± 5 points). Exercise tolerance, muscle force, and quality of life improved significantly after rehabilitation. Conclusion. Radically treated patients with respiratory cancer have a decreased exercise capacity, muscle force, and quality of life. 12 weeks of rehabilitation leads to a significant improvement in exercise capacity, respiratory muscle force, and quality of life.

Pemetrexed and cisplatin with concurrent radiotherapy for locally advanced non-small cell and limited disease small cell lung cancer: results from 2 phase I studies.

BACKGROUND: The objectives were to determine the maximum tolerated dose (MTD) of pemetrexed and cisplatin with concurrent radiotherapy. Secondary objectives include incidence and nature of acute and late toxicities, tumor response and overall survival. PATIENTS AND METHODS: Treatment naïve patients received 1 cycle of cisplatin 80 mg/m(2) in study I (stage III NSCLC), 75 mg/m(2) in study II (LD-SCLC) and pemetrexed 500 mg/m(2) before the phase I part. In study I, patients were treated in cohorts with escalating cisplatin doses (60-80 mg/m(2)), pemetrexed doses (400-500 mg/m(2)) and concurrent escalating radiotherapy doses (66 Gy in 33-27 fractions). In study II, patients were treated with cisplatin 75 mg/m(2) and escalating pemetrexed doses (400-500 mg/m(2)) with concurrent escalating radiotherapy doses (50-62 Gy). RESULTS: The trials closed prematurely: study I because of poor accrual, study II because of sponsor decision. Thirteen patients were treated: 4 with NSCLC, 9 with LD-SCLC. No dose-limiting toxicity was observed. There was no grade 4 toxicity, grade 3 hematological toxicity was mild. One patient developed grade 3 acute esophagitis, but was able to complete radiotherapy without delay. Two patients experienced grade 2 late pulmonary toxicity, 1 complete response, 6 partial responses and 1 progressive disease were observed. CONCLUSIONS: Although the studies stopped too early to assess MTD, we have demonstrated that the combination of cisplatin and pemetrexed with concurrent radiotherapy up to 66 Gy (33 x 2 Gy) is well tolerated and this new combination shows activity in NSCLC. Pemetrexed is the first 3rd generation cytotoxic found to be tolerable at full dose with concurrent radiotherapy.

Non-Cross Resistant Sequential Single Agent Chemotherapy in First-Line Advanced Non-Small Cell Lung Cancer Patients: Results of a Phase II Study.

Background. sequential chemotherapy can maintain dose intensity and preclude cumulative toxicity by increasing drug diversity. Purpose. to investigate the toxicity and efficacy of the sequential regimen of gemcitabine followed by paclitaxel in first line advanced stage non-small cell lung cancer (NSCLC) patients with good performance status (PS). Patients and methods. gemcitabine 1250 mg/m(2) was administered on day 1 and 8 of course 1 and 2; Paclitaxel 150 mg/m(2) on day 1 and 8 of course 3 and 4. Primary endpoint was response rate (RR), secondary endpoints toxicity and time to progression (TTP). Results. Of the 21 patients (median age 56, range 38-80 years; 62% males, 38% females) 10% (2/21) had stage IIIB, 90% (19/21) stage IV, 15% PS 0, 85% PS 1. 20% of patients had a partial response, 30% stable disease, 50% progressive disease. Median TTP was 12 weeks (range 6-52 weeks), median overall survival (OS) 8 months (range 1-27 months), 1-year survival was 33%. One patient had grade 3 hematological toxicity, 2 patients a grade 3 peripheral neuropathy. Conclusions. sequential administration of gemcitabine followed by paclitaxel in first line treatment of advanced NSCLC had a favourable toxicity profile, a median TTP and OS comparable with other sequential trials and might, therefore, be a treatment option for NSCLC patients with high ERCC1 expression.

Oral UFT, etoposide and leucovorin in recurrent non-small cell lung cancer: a non-randomized phase II study.

BACKGROUND: Oral treatment regimens with few side effects are appealing in the 2nd or 3rd line treatment of non-small cell lung cancer (NSCLC) patients. PURPOSE: The aim was to investigate the efficacy and toxicity of the oral combination etoposide, Uracil-Tegafur (UFT) and leucovorin in 2nd or 3rd line in Caucasian patients with advanced NSCLC. METHODS: Etoposide 50 mg/m(2), UFT 250 mg/m(2) and leucovorin 90 mg (fixed dose) were dosed in 3 gifts approximately 8h apart for 14 days followed by 1 week rest every 3 weeks until progressive disease (PD). Primary endpoint was response rate (RR), secondary endpoints toxicity and time to progression (TTP). RESULTS: The median number of cycles was 3.5 (95% CI 2-5); 9 patients received > or =6 cycles, 4>10 cycles. The median dose intensities for etoposide and UFT were 223 mg/m(2)/week (95% CI 213-232) and 1092 mg/m(2)/week (95% CI 1032-1167), the relative dose intensities 92% and 90%, respectively. Grade 3/4 neutropenia was observed in 12% (4/32), grade 3/4 thrombocytopenia in 15% (5/32), without febrile neutropenia. Non-hematological toxicity grade 3 included hepatic toxicity (6%), lethargy (15%), diarrhea (3%) and nausea (3%). One patient developed grade 4 arterial ischemia. Fourteen percent (95% CI 4-33%) (4/28) had a confirmed partial response, 57% (95% CI 44-81%) (16/28) stable disease and 28% (95% CI 19-56%) (8/28) progressive disease. The median TTP was 3 months (95% CI 1.3-4.4), the median overall survival 6.7 months (95% CI 4.0-9.3). CONCLUSION: The combination of UFT, etoposide and leucovorin is active in 2nd or 3rd line therapy of Caucasian NSCLC patients and because of its favourable toxicity profile this treatment warrants further investigation.

A phase II study of induction therapy with carboplatin and gemcitabine among patients with locally advanced non-small cell lung cancer.

INTRODUCTION: The objectives of this trial were to evaluate the activity and safety of gemcitabine carboplatin as induction therapy in patients with locally advanced non-small cell lung cancer METHODS: Patients received two cycles of gemcitabine (1250 mg/m on day 1 and 8), plus carboplatin (area under the curve = 5 on day 1), after which response was established. Patients received a third course only in the case of an objective response (OR). Non-responding patients were directly irradiated. Toxicity was assessed according to the NCI-CTC version 2, radiation toxicity was assessed according to RTOG criteria. Response evaluation was performed according to RECIST criteria. RESULTS: We identified 42 patients, of whom 37 were eligible. Of these, 51% (95% CI, 34%-68%) achieved an OR, all partial responses. No disease progression on therapy was established. Toxicity was mostly hematological: 35% trombocytopenia grade 3 and 4, and 40% neutropenia grade 3 and 4. No severe bleeding or hospitalization because of febrile neutropenia occurred. CONCLUSIONS: Gemcitabine and carboplatin administered according to a 3-week schedule is an active and safe induction regimen. Pending the results of a phase III study, we believe that it is a reasonable alternative among patients for whom cisplatin-based chemotherapy is contraindicated.