Concurrent palliative chemoradiation leads to survival and quality of life benefits in poor prognosis stage III non-small-cell lung cancer: a randomised trial by the Norwegian Lung Cancer Study Group

Background: The palliative role of chemoradiation in the treatment of patients with locally advanced, inoperable non-small-cell lung cancer stage III and negative prognostic factors remains unresolved. Methods: Patients not eligible for curative radiotherapy were randomised to receive either chemoradiation or chemotherapy alone. Four courses of intravenous carboplatin on day 1 and oral vinorelbin on days 1 and 8 were given with 3-week intervals. Patients in the chemoradiation arm also received radiotherapy with fractionation 42 Gy/15, starting at the second chemotherapy course. The primary end point was overall survival; secondary end points were health-related quality of life (HRQOL) and toxicity. Results: Enrolment was terminated due to slow accrual after 191 patients from 25 Norwegian hospitals were randomised. Median age was 67 years and 21% had PS 2. In the chemotherapy versus the chemoradiation arm, the median overall survival was 9.7 and 12.6 months, respectively (Po0.01). One-year survival was 34.0% and 53.2% (Po0.01). Following a minor decline during treatment, HRQOL remained unchanged in the chemoradiation arm. The patients in the chemotherapy arm reported gradual deterioration during the subsequent months. In the chemoradiation arm, there were more hospital admissions related to side effects (Po0.05). Conclusion: Chemoradiation was superior to chemotherapy alone with respect to survival and HRQoL at the expense of more hospital admissions due to toxicity

Expression and clinical significance of the proliferation marker minichromosome maintenance protein 2 (Mcm2) in diffuse astrocytomas WHO grade II

Background The WHO classification system for astrocytomas is not considered optimal, mainly because of the subjective assessment of the histopathological features. Few prognostic variables have been found that stratify the risk of clinical progression in patients with grade II astrocytoma. For that reason there is a continuous search for biomarkers that can improve the histopathological diagnosis and prognostication of these tumours. Aim This study was designed to investigate the prognostic significance of the proliferative marker Mcm2 (minichromosome maintenance protein 2) in diffuse astrocytomas WHO grade II and correlate the findings with histopathology, mitoses, and Ki67/MIB-1 immunostaining. Method 61 patients with histologically verified grade II astrocytoma (WHO 2007) were investigated. Paraffin sections were immunostained with anti-Mcm2, and the Mcm2 proliferative index (PI) was determined as the percentage of immunoreactive tumour cell nuclei. Results Mcm2 PI was not associated with any histopathological features but correlated significantly with mitotic count and Ki67/MIB-1 PI (p0.05). Conclusions In our hands Mcm2 immunostaining has no advantage over Ki67/MIB-1 in the evaluation of grade II astrocytomas. Larger studies are needed to fully clarify the prognostic role of this biomarker. Virtual slides The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/171500279194403

Poor prognosis patients with inoperable locally advanced NSCLC and large tumors benefit from palliative chemoradiotherapy: A subset analysis from a randomized clinical phase III trial

Introduction: Poor prognosis patients with bulky stage III locally advanced non–small-cell lung cancer may not be offered concurrent chemoradiotherapy (CRT). Following a phase III trial concerning the effect of palliative CRT in inoperable poor prognosis patients, this analysis was performed to explore how tumor size influenced survival and health-related quality of life (HRQOL). Methods: A total of 188 poor prognosis patients recruited in a randomized clinical trial received four courses intravenous carboplatin day 1 and oral vinorelbine day 1 and 8, at 3-week intervals. The experimental arm (N = 94) received radiotherapy with fractionation 42 Gy/15, starting at the second chemotherapy course. This subset study compares outcomes in patients with tumors larger than 7cm (N = 108) versus tumors 7 cm or smaller (N = 76). Results: Among those with tumors larger than 7cm, the median overall survival in the chemotherapy versus CRT arm was 9.7 and 13.4 months, respectively (p = 0.001). The 1-year survival was 33% and 56%, respectively (p = 0.01). Except for a temporary decline during treatment, HRQOL was maintained in the CRT arm, regardless of tumor size. Among those who did not receive CRT, patients with tumors larger than 7cm experienced a gradual decline in the HRQOL. The CRT group had significantly more esophagitis and hospitalizations because of side effects regardless of tumor size. Conclusion: In patients with poor prognosis and inoperable locally advanced non–small-cell lung cancer, large tumor size should not be considered a negative predictive factor. Except for performance status 2, patients with tumors larger than 7 cm apparently benefit from CRT

Tumour size reduction after the first chemotherapy-course and outcomes of chemoradiotherapy in limited disease small-cell lung cancer

Objectives: Concurrent chemotherapy and thoracic radiotherapy (TRT) is recommended for limited disease small-cell lung cancer (LD SCLC). TRT should start as early as possible, often meaning with the second course due to patient referral time and the fact that TRT planning takes time. Early assessment of response to the first course of chemotherapy may be a useful way to individualise treatment. The aims of this study were to assess tumour size reduction after the first chemotherapy-course, and whether this reduction was associated with outcomes in LD SCLC. Material and methods: A randomised trial comparing twice-daily (45 Gy/30 fractions) with once-daily (42 Gy/15 fractions) TRT, given concurrently with four courses of cisplatin/etoposide (n = 157) was the basis for this study. Tumour size was assessed on CT scans at baseline and planning scans for TRT according to RECIST 1.0. Results: CT scans were available for 135 patients (86%). Ninety-four percent had a reduction in tumour size after the first chemotherapy-course. The median reduction in sum of diameters (SOD) of measurable lesions was ÷16 mm (÷84 to +10 mm), corresponding to ÷18% (÷51 to +12%). Eighty-two percent had stable disease, 18% partial response. Reduction in SOD was significantly associated with complete response at first follow-up (OR: 1.05, 95% CI 1.01–1.09; p=0.013), PFS (HR: 0.97, 95% CI 0.96-0.99; p=0.001), and overall survival (HR: 0.98, 95% CI 0.96–1.00; p=0.010). Conclusion: Response from the first course of chemotherapy had a significant positive association with outcomes from chemoradiotherapy, and might be used to stratify and randomise patients in future studies

Comorbidity and outcomes of concurrent chemo- and radiotherapy in limited disease small cell lung cancer

Background: Many patients with limited disease small cell lung cancer (LD SCLC) suffer from comorbidity. Not all patients with comorbidity are offered standard treatment, though there is little evidence for such a policy. The aim of this study was to investigate whether patients with comorbidity had inferior outcomes in a LD SCLC cohort. Material and methods: We analyzed patients from a randomized study comparing two three-week schedules of thoracic radiotherapy (TRT) plus standard chemotherapy in LD SCLC. Patients were to receive four courses of cisplatin/etoposide and TRT of 45 Gy/30 fractions (twice daily) or 42 Gy/15 fractions (once daily). Responders received prophylactic cranial irradiation (PCI). Comorbidity was assessed using the Charlson Comorbidity Index (CCI), which rates conditions with increased one-year mortality. Results: In total 157 patients were enrolled between May 2005 and January 2011. Median age was 63 years, 52% were men, 16% had performance status 2, and 72% stage III disease. Forty percent had no comorbidity; 34% had CCI-score 1; 15% CCI 2; and 11% CCI 3–5. There were no significant differences in completion rates of chemotherapy, TRT or PCI across CCI-scores; or any significant differences in the frequency of grade 3–5 toxicity (p ¼ 0.49), treatment-related deaths (p ¼ 0.36), response rates (p ¼ 0.20), progression-free survival (p ¼ 0.18) or overall survival (p ¼ 0.09) between the CCI categories. Conclusion: Patients with comorbidity completed and tolerated chemo-radiotherapy as well as other patients. There were no significant differences in response rates, progression-free survival or overall survival – suggesting that comorbidity alone is not a reason to withhold standard therapy in LD SCLC

Comorbidity and outcomes of concurrent chemo- and radiotherapy in limited disease small cell lung cancer

Background: Many patients with limited disease small cell lung cancer (LD SCLC) suffer from comorbidity. Not all patients with comorbidity are offered standard treatment, though there is little evidence for such a policy. The aim of this study was to investigate whether patients with comorbidity had inferior outcomes in a LD SCLC cohort. Material and methods: We analyzed patients from a randomized study comparing two three-week schedules of thoracic radiotherapy (TRT) plus standard chemotherapy in LD SCLC. Patients were to receive four courses of cisplatin/etoposide and TRT of 45 Gy/30 fractions (twice daily) or 42 Gy/15 fractions (once daily). Responders received prophylactic cranial irradiation (PCI). Comorbidity was assessed using the Charlson Comorbidity Index (CCI), which rates conditions with increased one-year mortality. Results: In total 157 patients were enrolled between May 2005 and January 2011. Median age was 63 years, 52% were men, 16% had performance status 2, and 72% stage III disease. Forty percent had no comorbidity; 34% had CCI-score 1; 15% CCI 2; and 11% CCI 3–5. There were no significant differences in completion rates of chemotherapy, TRT or PCI across CCI-scores; or any significant differences in the frequency of grade 3–5 toxicity (p = 0.49), treatment-related deaths (p = 0.36), response rates (p = 0.20), progression-free survival (p = 0.18) or overall survival (p = 0.09) between the CCI categories. Conclusion: Patients with comorbidity completed and tolerated chemo-radiotherapy as well as other patients. There were no significant differences in response rates, progression-free survival or overall survival – suggesting that comorbidity alone is not a reason to withhold standard therapy in LD SCLC

Molecular Resistance Fingerprint of Pemetrexed and Platinum in a Long-Term Survivor of Mesothelioma

Pemetrexed, a multi-folate inhibitor combined with a platinum compound is the first-line treatment of malignant mesothelioma, but median survival is still one year. Intrinsic and acquired resistance to pemetrexed is common, but its biological basis is obscure. Here we report for the first time a genome-wide profile of acquired resistance in the tumour from an exceptional case with advanced pleural mesothelioma and almost six years survival after 39 cycles of second-line pemetrexed/carboplatin treatment. Genome-wide analysis with Illumina BeadChip Kit of 25,000 genes was performed on mRNA from pre-treatment and post-resistance biopsies from this individual as well on case and control samples from our previously published study (in total 17 samples). Cell specific expression of proteins encoded by selected genes were analysed by immunohistochemistry. Serial serum levels of CA125, CYFRA21-1 and SMRP levels were examined. TS protein, the main target of pemetrexed was overexpressed. Proteins and genes related to DNA damage response, elongation and telomere extension and repair related directly and indirectly to platinum resistance were overexpressed, as the CHK1 protein and the genes CHEK2, LIG3, POLD1, POLA2, FANCD2, PRPF19, RECQ5 respectively, the last two not previously described in mesothelioma. We observed a down-regulation of leukocyte transendothelial migration and cell adhesion molecules pathways. Silencing of NT5C in two mesothelioma cell lines did not sensitize the cells to Pemetrexed. Proposed resistance markers are TS, KRT7/ CK7, TYMP/ thymidine phosphorylase and down-regulated SPARCL1 and CDKN1B. Moreover, comparison of the primary expression of the sensitive versus a primary resistant case showed multi-fold overexpressed DNA repair, cell cycle, cytokinesis, and spindle formation in the latter. Serum CA125 and SMRP reflected the clinical and radiological course and tumour burden. Genome-wide microarray of mesothelioma pre- and post-resistance biopsies indicated a novel resistance signature to pemetrexed/carboplatin that deserve validation in a larger cohort

Vinorelbine and gemcitabine vs vinorelbine and carboplatin as first-line treatment of advanced NSCLC. A phase III randomised controlled trial by the Norwegian Lung Cancer Study Group

Background: Platinum-based doublet chemotherapy is the standard first-line treatment for advanced non-small cell lung cancer (NSCLC), but earlier studies have suggested that non-platinum combinations are equally effective and better tolerated. We conducted a national, randomised study to compare a non-platinum with a platinum combination. Methods: Eligible patients had stage IIIB/IV NSCLC and performance status (PS) 0–2. Patients received up to three cycles of vinorelbine 60 mg m−2 p.o.+gemcitabine 1000 mg m−2 i.v. day 1 and 8 (VG) or vinorelbine 60 mg m−2 p.o. day 1 and 8+carboplatin area under the curve=5 (Calvert's formula) i.v. day 1 (VC). Patients ⩾75 years received 75% of the dose. Endpoints were overall survival, health-related quality of life (HRQoL), toxicity, and the use of radiotherapy. Results: We randomised 444 patients from September 2007 to April 2009. The median age was 65 years, 58% were men and 25% had PS 2. Median survival was VG: 6.3 months; VC: 7.0 months, P=0.802. Vinorelbine plus carboplatin patients had more grade III/IV nausea/vomiting (VG: 4%, VC: 12%, P=0.008) and grade IV neutropenia (VG: 7%, VC: 19%, P<0.001). Infections, HRQoL and the use of radiotherapy did not differ significantly between the treatment groups. Conclusion: The two regimens yielded similar overall survival. The VG combination had only a slightly better toxicity profile

Vinorelbine and gemcitabine vs vinorelbine and carboplatin as first-line treatment of advanced NSCLC. A phase III randomised controlled trial by the Norwegian Lung Cancer Study Group

BACKGROUND: Platinum-based doublet chemotherapy is the standard first-line treatment for advanced non-small cell lung cancer (NSCLC), but earlier studies have suggested that non-platinum combinations are equally effective and better tolerated. We conducted a national, randomised study to compare a non-platinum with a platinum combination. METHODS: Eligible patients had stage IIIB/IV NSCLC and performance status (PS) 0-2. Patients received up to three cycles of vinorelbine 60 mg m -2 p.o. þ gemcitabine 1000 mg m -2 i.v. day 1 and 8 (VG) or vinorelbine 60 mg m-2 p.o. day 1 and 8 þ carboplatin area under the curve ¼ 5 (Calvert’s formula) i.v. day 1 (VC). Patients X75 years received 75% of the dose. Endpoints were overall survival, health-related quality of life (HRQoL), toxicity, and the use of radiotherapy. RESULTS: We randomised 444 patients from September 2007 to April 2009. The median age was 65 years, 58% were men and 25% had PS 2. Median survival was VG: 6.3 months; VC: 7.0 months, P ¼ 0.802. Vinorelbine plus carboplatin patients had more grade III/IV nausea/vomiting (VG: 4%, VC: 12%, P ¼ 0.008) and grade IV neutropenia (VG: 7%, VC: 19%, Po0.001). Infections, HRQoL and the use of radiotherapy did not differ significantly between the treatment groups. CONCLUSION: The two regimens yielded similar overall survival. The VG combination had only a slightly better toxicity profile