ABSTRACT
Small cell carcinoma of the urinary bladder is a rare subtype (incidence of 1-9/1,000,000), characterized by an aggressive behavior with early metastasis and poor prognosis. Chemotherapy, radiation, and surgery are the usual treatment options, but to date, no accepted standard treatment exists. Since small cell bladder cancer shares similar clinicopathological features with small cell lung cancer, the same type of chemotherapy has been used. Recently, immune checkpoint inhibitors have shown effect in small cell lung cancer, but data regarding small cell bladder cancer is insufficient. Here we present a case where a 73-year-old male with chemorefractory metastatic small cell bladder cancer received a successful treatment with immune checkpoint inhibitor pembrolizumab resulting in a major durable response and no side effects. To our knowledge, this is the second case report on successful treatment of the rare subtype of small cell bladder cancer with an immune checkpoint inhibitor, supporting the use of pembrolizumab as a therapeutic option for small cell bladder cancer. Serum neuron-specific enolase was a useful biomarker both for chemo- and immunotherapy response.
ABSTRACT
BACKGROUND/AIM: There are several definitions of limited disease (LD) in small cell lung cancer (SCLC), differing with respect to N3 disease accepted. We analyzed patients from a randomized trial comparing two schedules of thoracic radiotherapy (TRT) in LD SCLC to investigate whether there were survival differences between N3 subcategories (n=144). PATIENTS AND METHODS: Patients with a baseline CT scan available were analysed. Patients received four courses of cisplatin/etoposide and TRT of 45 Gy/30 fractions (twice daily) or 42 Gy/15 fractions (once daily). RESULTS: Median overall survival (OS) was 23.3 months in the whole cohort. N3-patients (n=37) had shorter survival than those with N0-2 (16.7 vs. 33.0 months; p<0.001). There were no significant OS-differences between the N3 subcategories, but patients with metastases to two or more N3 regions had shorter survival than other N3 patients (13.4 vs. 19.9 months; p=0.011). CONCLUSION: There were no survival differences between the N3 subcategories, suggesting that all N3 disease should be considered as LD.
Subject(s)
Lymph Nodes/pathology , Small Cell Lung Carcinoma/pathology , Small Cell Lung Carcinoma/therapy , Adult , Aged , Aged, 80 and over , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Chemoradiotherapy , Cisplatin/administration & dosage , Etoposide/administration & dosage , Female , Humans , Lymphatic Metastasis , Male , Middle Aged , Neoplasm Staging , Small Cell Lung Carcinoma/drug therapy , Small Cell Lung Carcinoma/radiotherapy , Survival Rate , Tomography, X-Ray ComputedABSTRACT
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 (45Gy/30 fractions) with once-daily (42Gy/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 ÷16mm (÷84 to +10mm), 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.
Subject(s)
Chemoradiotherapy/methods , Drug Therapy/standards , Small Cell Lung Carcinoma/drug therapy , Small Cell Lung Carcinoma/radiotherapy , Symptom Assessment/methods , Tumor Burden/drug effects , Adult , Aged , Aged, 80 and over , Combined Modality Therapy , Disease-Free Survival , Female , Humans , Lung Neoplasms/pathology , Lung Neoplasms/therapy , Male , Middle Aged , Neoplasm Staging , Norway/epidemiology , Radiotherapy Dosage , Randomized Controlled Trials as Topic , Remission Induction , Small Cell Lung Carcinoma/diagnostic imaging , Small Cell Lung Carcinoma/pathology , Survival Analysis , Tomography, X-Ray Computed , Treatment OutcomeABSTRACT
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.
Subject(s)
Lung Neoplasms/drug therapy , Lung Neoplasms/radiotherapy , Small Cell Lung Carcinoma/drug therapy , Small Cell Lung Carcinoma/radiotherapy , Adult , Aged , Aged, 80 and over , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Chemoradiotherapy/adverse effects , Chemoradiotherapy/methods , Cisplatin/adverse effects , Cisplatin/therapeutic use , Comorbidity , Cranial Irradiation , Disease-Free Survival , Etoposide/adverse effects , Etoposide/therapeutic use , Female , Humans , Lung Neoplasms/epidemiology , Lung Neoplasms/mortality , Male , Middle Aged , Small Cell Lung Carcinoma/epidemiology , Small Cell Lung Carcinoma/mortality , Survival Analysis , Treatment OutcomeABSTRACT
BACKGROUND: Concurrent chemotherapy and thoracic radiotherapy (TRT) is recommended for limited disease small cell lung cancer (LD SCLC). Twice daily TRT is well documented, but not universally implemented - probably mainly due to inconvenience and concerns about toxicity. A schedule of three-week hypofractionated TRT is a commonly used alternative. This is the first randomized trial comparing twice daily and hypofractionated TRT in LD SCLC. MATERIAL AND METHODS: Patients received four courses of cisplatin/etoposide (PE) and were randomized to TRT of 42 Gy in 15 fractions (once daily, OD) or 45 Gy in 30 fractions (twice daily, BID) between the second and third PE course. Good responders received prophylactic cranial irradiation of 30 Gy in 15 fractions. RESULTS: 157 patients were enrolled between May 2005 and January 2011 (OD: n = 84, BID: n = 73). Median age was 63 years, 52% were men, 84% had performance status 0-1, 72% had stage III disease and 11% non-malignant pleural effusion. The treatment arms were well balanced. The response rates were similar (OD: 92%, BID: 88%; p = 0.41), but more BID patients achieved a complete response (OD: 13%, BID: 33%; p = 0.003). There was no difference in one-year progression-free survival (PFS) (OD: 45%, BID: 49%; p = 0.61) or median PFS (OD: 10.2 months, BID: 11.4 months; p = 0.93). The median overall survival in the BID arm was 6.3 months longer (OD: 18.8 months, BID: 25.1 months; p = 0.61). There were no differences in grade 3-4 esophagitis (OD: 31%, BID: 33%, p = 0.80) or pneumonitis (OD: 2%, BID: 3%, p = 1.0). Patients on the BID arm reported slightly more dysphagia at the end of the TRT. CONCLUSION: There was no difference in severe toxicity between the two TRT schedules. The twice daily schedule resulted in significantly more complete responses and a numerically longer median overall survival, but no firm conclusions about efficacy could be drawn from this phase II trial.
Subject(s)
Dose Fractionation, Radiation , Lung Neoplasms/radiotherapy , Small Cell Lung Carcinoma/radiotherapy , Adult , Aged , Aged, 80 and over , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Brachytherapy/adverse effects , Cisplatin/administration & dosage , Cisplatin/therapeutic use , Combined Modality Therapy , Cranial Irradiation , Disease-Free Survival , Etoposide/administration & dosage , Etoposide/therapeutic use , Female , Follow-Up Studies , Humans , Lung Neoplasms/drug therapy , Male , Middle Aged , Norway/epidemiology , Radiotherapy Planning, Computer-Assisted , Radiotherapy, Conformal/adverse effects , Small Cell Lung Carcinoma/drug therapy , Survival Analysis , Tomography, X-Ray Computed , Treatment OutcomeABSTRACT
BACKGROUND: In a phase III trial of patients with unresectable, locally advanced, stage III non-small-cell lung cancer (NSCLC) with a poor prognosis, palliative concurrent chemoradiotherapy (CRT) provided a significantly better outcome than chemotherapy alone, except among performance status (PS) 2 patients. In the present subgroup analysis, we evaluated the effect on patients aged ≥ 70 years (42% of all included) compared with patients aged < 70 years enrolled in the trial. PATIENTS AND METHODS: All patients received 4 courses of intravenous carboplatin and oral vinorelbine. The experimental arm also received radiotherapy (42 Gy in 15 fractions). The included patients were required to have large tumors (> 8 cm), weight loss (> 10% within the previous 6 months) and/or PS 2. RESULTS: The overall survival was increased among the CRT patients in both age groups, but the difference was significant only in patients aged < 70 years (median survival, 14.8 vs. 9.7 months; P = .001; age ≥ 70 years, median survival, 10.2 vs. 9.1 months; P = .09). Patients aged ≥ 70 years experienced better preserved health-related quality of life (QOL) and significantly less hematologic toxicity. The 2- and 3-year survival was significantly increased in both age groups receiving CRT. CONCLUSION: Elderly patients aged ≥ 70 years with unresectable, stage III, locally advanced, NSLCL and a poor prognosis can tolerate CRT with the doses adjusted to age and palliative intent. These results indicate that CRT can provide both survival and QOL benefits in elderly patients, except for those with PS 2 or worse. The male predominance in the ≥ 70-year-age group and the reduced chemotherapy intensity for the patients aged > 75 years might explain the lack of significant survival improvement among those patients aged ≥ 70 years.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Carcinoma, Non-Small-Cell Lung/therapy , Chemoradiotherapy/methods , Lung Neoplasms/therapy , Aged , Aged, 80 and over , Carboplatin/administration & dosage , Carcinoma, Non-Small-Cell Lung/pathology , Chemoradiotherapy/adverse effects , Female , Humans , Lung Neoplasms/pathology , Male , Middle Aged , Neoplasm Staging , Palliative Care , Prognosis , Quality of Life , Survival Analysis , Vinblastine/administration & dosage , Vinblastine/analogs & derivatives , VinorelbineABSTRACT
BACKGROUND: Lung cancer can be caused by occupational exposure. This is not always recognised or reported, and not all patients receive the benefits to which they are entitled. MATERIAL AND METHOD: We collected occupational case histories for patients from Sør-Trøndelag county with a first-time diagnosis of lung cancer. The number of reported cases of occupationally related lung cancer was collected from the Norwegian Labour Inspection Authority, and information on approval of occupational illness was collected from the Norwegian Labour and Welfare Authority (NAV). RESULTS: 105 patients with lung cancer took part in the study, 73 men and 32 women. Among the men, altogether 12 cases (16%) were assessed as likely and 16 (22%) as possibly occupationally related. Among the women, none of the cases were assessed as occupationally related. The reporting frequency from the health regions to the Norwegian Labour Inspection Authority varied from 1.7% to 5.1%. Altogether 9 out of 11 likely cases and 5 out of 12 possible cases of occupationally related lung cancer were granted injury compensation by the Norwegian Labour and Welfare Authority. INTERPRETATION: In this study, we found that approximately 20% of the cases of lung cancer in men are occupationally related, and that the underreporting of occupationally related lung cancer appears to be considerable. The obligation of doctors to report to the Norwegian Labour Inspection Authority should be made better known. Most likely, more patients would have had their lung cancer verified as an occupational illness and could have received injury compensation if they had been aware of the opportunity to apply for this.
Subject(s)
Lung Neoplasms/etiology , Occupational Diseases/etiology , Occupational Exposure/adverse effects , Air Pollutants, Occupational/adverse effects , Asbestos/adverse effects , Female , Humans , Inhalation Exposure/adverse effects , Inhalation Exposure/statistics & numerical data , Lung Neoplasms/epidemiology , Male , Mandatory Reporting , Metals, Heavy/adverse effects , Norway/epidemiology , Occupational Diseases/epidemiology , Occupational Exposure/statistics & numerical data , Oils/adverse effects , Polycyclic Aromatic Hydrocarbons/adverse effects , Smoking/adverse effects , Smoking/epidemiology , Workers' CompensationABSTRACT
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 7 cm (N = 108) versus tumors 7 cm or smaller (N = 76). RESULTS: Among those with tumors larger than 7 cm, 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 7 cm 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.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Carcinoma, Non-Small-Cell Lung/therapy , Chemoradiotherapy , Lung Neoplasms/therapy , Palliative Care , Aged , Carboplatin/administration & dosage , Carcinoma, Non-Small-Cell Lung/pathology , Chemoradiotherapy/adverse effects , Dose Fractionation, Radiation , Esophagitis/etiology , Female , Hospitalization , Humans , Lung Neoplasms/pathology , Male , Prognosis , Quality of Life , Survival Rate , Tumor Burden , Vinblastine/administration & dosage , Vinblastine/analogs & derivatives , VinorelbineABSTRACT
Histopathological grading of human meningiomas is based on criteria adopted by the World Health Organization (WHO). However, interpretation of the defined histopathological criteria is often subjective. The aim of this study was to investigate the clinical and histopathological features in these tumours associated with patient survival. This enables evaluation of current grading guidelines and practice. In this study, 196 primary, intracranial, and consecutively treated patients from one institution were included. All histological sections were reviewed. Survival data were controlled with the Norwegian Cause of Death Registry. Falcine location, sheet-like growth, frequent mitoses, subtotal resection grade, and absence of psammoma bodies were strong prognostic factors. Of these factors, the latter two were statistically significantly associated with decreased time to recurrence in multivariate analyses. The WHO 2000 and 2007 classifications were associated with decreased time to recurrence. However, the grading criteria suggested by Ho et al. (2002) and in this study achieved stronger prognostic values. Easily recognizable histopathological criteria are essential in tumour grading. We suggest that any two of the following three variables can be used to recognize atypical (grade II) meningiomas: absence of psammoma bodies, presence of necrosis, and/or ≥4 mitoses per 10 high power fields.
Subject(s)
Meningeal Neoplasms/mortality , Meningeal Neoplasms/pathology , Meningioma/mortality , Meningioma/pathology , Necrosis/pathology , Biomarkers, Tumor , Female , Humans , Male , Neoplasm Grading , Neoplasm Recurrence, Local/pathology , PrognosisABSTRACT
BACKGROUND: On the basis of our own experience and literature search, we hypothesised that a canine olfactory test may be useful for detecting lung cancer in an unselected population of patients suspected to have lung cancer. MATERIAL AND METHODS: We conducted a prospective study of 93 patients consecutively admitted to hospital with suspected lung cancer. Exhaled breath and urine were sampled before the patients underwent bronchoscopy. The canine olfactory test was performed in a double-blinded manner. Sensitivity and specificity were outcome measures. RESULTS: With 99% sensitivity, the olfactory test demonstrated that dogs have the ability to distinguish cancer patients from healthy individuals. With an intensified training procedure, the exhaled breath and urine tests showed sensitivity rates of 56-76% and specificity rates of 8.3-33.3%, respectively, in our heterogeneous study population. CONCLUSION: Although the olfactory test appears to be a promising tool for the detection of cancer, the main challenge is to determine whether the test can sufficiently discriminate between patients at risk, patients with benign disease, and patients with malignant disease. We need to gain a deeper understanding of this test and further refine it before applying it as a screening tool for lung cancer in clinical settings.
Subject(s)
Breath Tests/methods , Dogs , Lung Neoplasms/diagnosis , Urinalysis/methods , Adult , Aged , Aged, 80 and over , Animals , Carcinoma, Non-Small-Cell Lung/diagnosis , Case-Control Studies , Double-Blind Method , Humans , Middle Aged , Prospective Studies , Sensitivity and Specificity , Small Cell Lung Carcinoma/diagnosis , Urinary Bladder Neoplasms/urineSubject(s)
Breast Neoplasms/surgery , Mastectomy, Segmental/standards , Female , Humans , Norway , Practice Guidelines as TopicABSTRACT
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 (p<0.05). In the survival analyses Mcm2 showed trends to poorer survival, however, statistical significance was not achieved in the univariate analyses (p>0.05). 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/1715002791944037.
Subject(s)
Astrocytoma/chemistry , Biomarkers, Tumor/analysis , Brain Neoplasms/chemistry , Cell Cycle Proteins/chemistry , Cell Proliferation , Nuclear Proteins/chemistry , Adult , Aged , Astrocytoma/classification , Astrocytoma/pathology , Brain Neoplasms/mortality , Brain Neoplasms/pathology , Female , Humans , Ki-67 Antigen/metabolism , Male , Middle Aged , Minichromosome Maintenance Complex Component 2 , Neoplasm Staging , Prognosis , Survival Analysis , World Health Organization , Young AdultABSTRACT
BACKGROUND: The authors consider whether differences in stage at diagnosis could explain the variation in lung cancer survival between six developed countries in 2004-2007. METHODS: Routinely collected population-based data were obtained on all adults (15-99 years) diagnosed with lung cancer in 2004-2007 and registered in regional and national cancer registries in Australia, Canada, Denmark, Norway, Sweden and the UK. Stage data for 57 352 patients were consolidated from various classification systems. Flexible parametric hazard models on the log cumulative scale were used to estimate net survival at 1 year and the excess hazard up to 18 months after diagnosis. RESULTS: Age-standardised 1-year net survival from non-small cell lung cancer ranged from 30% (UK) to 46% (Sweden). Patients in the UK and Denmark had lower survival than elsewhere, partly because of a more adverse stage distribution. However, there were also wide international differences in stage-specific survival. Net survival from TNM stage I non-small cell lung cancer was 16% lower in the UK than in Sweden, and for TNM stage IV disease survival was 10% lower. Similar patterns were found for small cell lung cancer. CONCLUSIONS: There are comparability issues when using population-based data but, even given these constraints, this study shows that, while differences in stage at diagnosis explain some of the international variation in overall lung cancer survival, wide disparities in stage-specific survival exist, suggesting that other factors are also important such as differences in treatment. Stage should be included in international cancer survival studies and the comparability of population-based data should be improved.
Subject(s)
Lung Neoplasms/mortality , Neoplasm Staging , Population Surveillance , Adolescent , Adult , Age Distribution , Aged , Aged, 80 and over , Australia/epidemiology , Canada/epidemiology , Denmark/epidemiology , Female , Humans , Lung Neoplasms/pathology , Male , Middle Aged , Norway/epidemiology , Retrospective Studies , Survival Rate/trends , Sweden/epidemiology , Young AdultABSTRACT
BACKGROUND: Glioblastoma (GBM) is the most common primary malignant human brain tumor with a poor prognosis. The diagnosis of GBM is based on histological features, however, few studies have evaluated their prognostic relevance in light of the latest WHO classification of 2007. AIM: In this study we have evaluated the prognostic value of several clinical and histological characteristics encountered in human GBMs according to the WHO 2007 criteria. MATERIAL AND METHODS: 199 patients with primary GBM consecutively operated and histologically reviewed according to the 2007 WHO scheme, were included. Several clinical and histological features were recorded and related to survival. RESULTS: Mean age of the GBM patients at diagnosis was 62 years (range 21 - 84). Male/female ratio was 1.3/1, and the median survival was 8.0 months (95% CI: 7.1 - 9.0 months). In a multivariate COX analysis age, WHO performance score, subcortical localization, extent of surgery, radiation treatment, chemotherapy, and the presence of large necrosis had individual effect on overall survival (p < 0.05). In addition, females, tumors with angiocentric growth, with pseudopalisades, or without lymphocyte infiltration were related to shorter survival in univariate analyses (p < 0.05). CONCLUSION: Our findings confirm the strong prognostic value of age, treatment, performance score, and localization for glioblastoma patients. Amongst the histopathological features only large necrosis was an independent prognostic factor.
Subject(s)
Brain Neoplasms/classification , Brain Neoplasms/mortality , Glioblastoma/classification , Glioblastoma/mortality , Adult , Age Factors , Aged , Antineoplastic Agents/therapeutic use , Brain Neoplasms/pathology , Combined Modality Therapy , Female , Glioblastoma/pathology , Humans , Kaplan-Meier Estimate , Male , Middle Aged , Neurosurgical Procedures , Prognosis , Proportional Hazards Models , Radiotherapy , Retrospective Studies , Treatment Outcome , World Health Organization , Young AdultABSTRACT
BACKGROUND: 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. METHODOLOGY AND PRINCIPAL FINDINGS: 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. CONCLUSIONS: 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.
Subject(s)
Antineoplastic Agents/pharmacology , Drug Resistance, Neoplasm , Glutamates/pharmacology , Guanine/analogs & derivatives , Mesothelioma/drug therapy , Platinum/pharmacology , 5'-Nucleotidase/metabolism , Adult , Biopsy/methods , Cell Adhesion , Cohort Studies , DNA Repair , Female , Gene Expression Regulation, Neoplastic , Gene Silencing , Genome-Wide Association Study , Guanine/pharmacology , Humans , Immunohistochemistry/methods , Oligonucleotide Array Sequence Analysis , Pemetrexed , Tomography, X-Ray Computed/methods , Treatment OutcomeABSTRACT
INTRODUCTION: Enzastaurin is a protein kinase C inhibitor with anti-tumor activity. This study was designed to determine if maintenance enzastaurin improved the outcome of whole brain radiotherapy (WBRT) in lung cancer (LC) patients with brain metastases (BMs). METHODS: Patients with LC (any histology) who had received WBRT for BMs were randomized to receive oral maintenance enzastaurin (1125 mg on Day 1 followed by 500 mg daily) or placebo. The primary endpoint was time to progression (TTP) of BMs. RESULTS: Fifty-four patients received enzastaurin and 53 patients received placebo. The median TTP of BMs was (months) enzastaurin: 6.9 (95% confidence interval [CI]: 3.4-11.9); placebo: 4.9 (95% CI: 3.6-not assessable); p=0.82. Median overall survival (OS) was (months) enzastaurin: 3.8 (95% CI: 2.6-5.6); placebo: 5.1 (95% CI: 3.7-5.7); p=0.47. Median progression-free survival (PFS) was (months) enzastaurin: 2.2 (95% CI: 1.1-2.3); placebo: 2.0 (95% CI: 1.3-2.3); p=0.75. The overall response rate (ORR) for extracranial disease was enzastaurin: 0%; placebo: 4.5% (p=0.49) and for intracranial disease was enzastaurin: 9.3%; placebo 6.8% (p=0.71). Grade 4 hematologic treatment-emergent adverse events were (enzastaurin vs. placebo) thrombocytopenia (5.6% vs. 1.9%) and neutropenia (5.6% vs. 0%). There was 1 treatment-related death in each arm (enzastaurin: unknown cause; placebo: pulmonary embolism). No significant differences in health-related quality of life (HRQoL) were observed. CONCLUSIONS: Enzastaurin was well tolerated but did not improve TTP of BMs, ORR, OS, PFS, or HRQoL after WBRT in LC patients with BMs.
Subject(s)
Antineoplastic Agents/therapeutic use , Brain Neoplasms/drug therapy , Brain Neoplasms/secondary , Indoles/therapeutic use , Lung Neoplasms/pathology , Maintenance Chemotherapy , Adult , Aged , Aged, 80 and over , Antineoplastic Agents/adverse effects , Brain Neoplasms/radiotherapy , Disease Progression , Female , Humans , Indoles/adverse effects , Male , Middle Aged , Quality of Life , Treatment OutcomeABSTRACT
The histopathological diagnosis of diffuse astrocytoma is challenging. As the WHO classification system is based on subjective assessments, the prognosis for the individual patient is somewhat uncertain. The aim of this study was therefore to investigate the prognostic value of various histological features, Ki-67/MIB-1 labeling index (LI), and clinical factors. The study was designed as a retrospective study of 109 patients consecutively operated for their primary diffuse astrocytoma WHO grade II. Clinical data was collected from patient files. All routine stained sections were revised, and 20 different histological features were recorded, including cell density, atypia, mitoses, apoptoses, secondary structures (of Scherer), microcysts, and lymphocytic infiltration. Ki-67/MIB-1 LI was determined by conventional immunohistochemistry. Using uni- and multivariate analyses, the prognostic value of these factors was assessed as well as clinical parameters. Median age at primary surgery was 40 years (range 18-75). The median overall survival was 70 months with a minimum follow-up of 3 months. Neither histopathological features nor Ki-67/ MIB-1 LI (median value of 4.5% (range 0.1-16%) indicated unfavorable prognosis. However, age > 40 years, gender (male), poor preoperative performance score, and biopsy rather than resection were significant negative prognostic factors in both uni- and multivariate analyses. Among diffuse grade II astrocytomas neither any histopathological trait nor Ki-67/MIB-1 LI achieved prognostic significance, whereas clinical parameters were shown to serve as the major prognostic factors for these patients.
Subject(s)
Astrocytoma/pathology , Brain Neoplasms/pathology , Adolescent , Adult , Aged , Astrocytoma/metabolism , Biomarkers, Tumor/metabolism , Brain Neoplasms/metabolism , Female , Humans , Ki-67 Antigen/metabolism , Male , Middle Aged , Neoplasm Recurrence, Local , Prognosis , Retrospective Studies , Ubiquitin-Protein Ligases/metabolism , Young AdultABSTRACT
PURPOSE: We report two clinical trials in non-small cell lung cancer (NSCLC) patients evaluating immune response, toxicity, and clinical outcome after vaccination with the telomerase peptide GV1001: a phase II trial (CTN-2006) in patients vaccinated after chemoradiotherapy and an 8-year update on a previously reported phase I/II trial (CTN-2000). EXPERIMENTAL DESIGN: CTN-2006: 23 inoperable stage III patients received radiotherapy (2 Gy × 30) and weekly docetaxel (20 mg/m(2)), followed by GV1001 vaccination. CTN-2000: 26 patients were vaccinated with two telomerase peptides (GV1001 and I540). The immune responses were evaluated by T-cell proliferation and cytokine assays. RESULTS: CTN-2006 trial: a GV1001-specific immune response developed in 16/20 evaluable patients. Long-term immunomonitoring showed persisting responses in 13 subjects. Serious adverse events were not observed. Immune responders recorded a median PFS of 371 days, compared with 182 days for nonresponders (P = 0.20). CTN-2000 trial update: 13/24 evaluable subjects developed a GV1001 response. The immune responders achieved increased survival compared with nonresponders (median 19 months vs. 3.5 months; P < 0.001). Follow-up of four long-time survivors showed that they all harbored durable GV1001-specific T-cell memory responses and IFNγ(high)/IL-10(low)/IL-4(low) cytokine profiles. Two patients are free of disease after 108 and 93 months, respectively. CONCLUSIONS: Vaccination with GV1001 is well tolerated, immunizes the majority of NSCLC patients and establishes durable T-cell memory. The considerable immune response rate and low toxicity in the phase II trial support the concept of combining chemoradiotherapy with vaccination. The survival advantage observed for immune responders warrants a randomized trial.
Subject(s)
Cancer Vaccines/administration & dosage , Carcinoma, Non-Small-Cell Lung/therapy , Lung Neoplasms/therapy , Peptide Fragments/administration & dosage , Taxoids/administration & dosage , Telomerase/administration & dosage , Amino Acid Sequence , Antineoplastic Agents/administration & dosage , Cancer Vaccines/adverse effects , Cancer Vaccines/immunology , Carcinoma, Non-Small-Cell Lung/immunology , Carcinoma, Non-Small-Cell Lung/pathology , Chemoradiotherapy/adverse effects , Docetaxel , Drug Administration Schedule , Female , Humans , Lung Neoplasms/immunology , Lung Neoplasms/pathology , Male , Molecular Sequence Data , Neoplasm Staging , Patient Compliance , Peptide Fragments/adverse effects , Peptide Fragments/immunology , T-Lymphocytes/immunology , Taxoids/adverse effects , Telomerase/adverse effects , Telomerase/immunologyABSTRACT
PURPOSE: The efficacy of curative irradiation in the treatment of non-small-cell lung cancer patients is considered limited. The purpose of this study was to evaluate long-term survival in a population-based approach. METHODS AND MATERIALS: Cases of non-small-cell lung cancer diagnosed from 1993 to 2001 were identified in the Cancer Registry of Norway. Electronic linkage with national data from the hospitals' radiotherapy verification systems identified those who received potentially curative doses (≥ 50 Gy). Hospital records were reviewed for all patients. RESULTS: A total of 497 patients (336 men) were identified with a radiation dose of ≥ 50 Gy delivered to the lung region. Of these, 41% received 60 Gy or more. The majority (70%) of patients included had advanced stage disease: 24% Stage IIIA and 46% Stage IIIB. The overall 1-, 3-, and 5-year observed survival rates were 53%, 16%, and 9%, respectively. Multivariable analyses identified stage and chemotherapy, but not radiation dose, as significant independent prognostic variables for survival. However, 68% of patients treated with chemotherapy participated in prospective studies with inclusion criteria that excluded patients with less favorable prognostic factors, leading to a selection bias. The number of fractions and the radiation doses varied widely among different hospitals. CONCLUSION: The long-term prognosis after radiation therapy is poor. More sophisticated, targeted, and uniform delivery of radiation therapy is needed. The apparent benefit of chemotherapy may in part be due to selection of patients with more favorable prognostic factors for this therapy.