Jacobus A. Burgers

Multicentre phase II study of gemcitabine and cisplatin in malignant pleural mesothelioma

Malignant pleural mesothelioma is a notoriously chemoresistant tumour. However, a recent single institution study showed an impressive activity of gemcitabine and cisplatin. Our aim is to investigate the efficacy and toxicity of a gemcitabine and cisplatin combination in selected and chemo-naive patients with histologically proven malignant pleural mesothelioma. Method: Gemcitabine 1250 mg m−2 was administered on day 1 and day 8 and cisplatin 80 mg m−2 was administered on day 1 in a 3-week cycle with a maximum of six cycles. Response and toxicity evaluations were performed according to WHO and NCIC-CTC criteria. Pathology and radiology were centrally reviewed. Results show that in 25 evaluable patients, four PR were observed (ORR 16%, 95% CI 1–31%). Responses of seven patients were unevaluable. No unexpected toxicity occurred. Time to progression was 6 months (5–7 months) with a median survival from registration of 9.6 months (95% CI 8–12 months). In conclusion this trial excludes with 90% power a response rate of greater than 30% in patients with malignant pleural mesothelioma using a combination of gemcitabine and cisplatin at the proposed dose and schedule.

Concurrent chemotherapy (carboplatin, paclitaxel, etoposide) and involved-field radiotherapy in limited stage small cell lung cancer: a Dutch multicenter phase II study

To improve the prognosis of limited stage small cell lung cancer (LS-SCLC) the addition of concurrent thoracic radiotherapy to a platinum-containing regimen is important. In the Netherlands, we initiated a multicenter, phase II study, of the combination of four cycles of carboplatin (AUC 5), paclitaxel (200 mg m−2) and etoposide (2 × 50 mg orally for 5 days) combined with 45 Gy (daily fractions of 1.8 Gy). The radiation was given to the involved field and concurrently with the second and third chemotherapy cycle. Patients with a partial or complete response received prophylactic cranial irradiation to a dose of 30 Gy. From January 1999 to December 2001, 37 of the 38 patients with LS-SCLC entered were eligible for toxicity analysis and response. Grade 3 and 4 haematological toxicity occurred in 57% (21/37) with febrile neutropenia in 24% (9/37). There were no treatment-related deaths or other grade 4 toxicity. Grade 3 toxicities were oesophagitis (27%), radiation pneumonitis (6%), anorexia (14%), nausea (16%), dyspnea (19%) and lethargy (22%). The objective response rate was 92% (95% confidence interval (CI) 80–98%) with a median survival time of 19.5 months (95% CI 12.8–29.2). The 1-, 2- and 5-year survival rate was 70, 47 and 27%, respectively. In field local recurrences occurred in six patients. Distant metastases were observed in 19 patients of which 13 in the brain. This study indicates that combination chemotherapy with concurrent involved-field radiation therapy is an effective treatment for LS-SCLC. Despite PCI, the brain remained the most important site of recurrence.

Association of Polymorphisms in AKT1 and EGFR with Clinical Outcome and Toxicity in Non–Small Cell Lung Cancer Patients Treated with Gefitinib

EGFR mutations are strongly predictive of epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor activity in non–small cell lung cancer (NSCLC), but resistance mechanisms are not completely understood. The interindividual variability in toxicity also points out to the need of novel pharmacogenetic markers to select patients before therapy. Therefore, we evaluated the associations between EGFR and AKT1 polymorphisms and outcome/toxicity in gefitinib-treated NSCLC patients. Polymorphic loci in EGFR, and AKT1, and EGFR and K-Ras mutations were assessed in DNA isolated from blood samples and/or paraffin-embedded tumor from 96 gefitinib-treated NSCLC patients. Univariate and multivariate analyses compared genetic variants with clinical efficacy and toxicity using Fishers, log-rank test, and Coxs proportional hazards model. AKT1-SNP4 association with survival was also evaluated in 127 chemotherapy-treated/gefitinib-naive patients, whereas its relationship with AKT1 expression and gefitinib cytotoxicity was studied in 15 NSCLC cell lines. AKT1-SNP4 A/A genotype was associated with shorter time-to-progression (P = 0.04) and overall survival (P = 0.007). Multivariate analyses and comparison with the gefitinib-nontreated population underlined its predictive significance, whereas the in vitro studies showed the association of lower AKT1 mRNA levels with gefitinib resistance. In contrast, EGFR-activating mutations were significantly correlated with response, longer time-to-progression, and overall survival, whereas EGFR −191C/A (P < 0.001), −216 G/T (P < 0.01), and R497K (P = 0.02) polymorphisms were strongly associated with grade >1 diarrhea. AKT1-SNP4 A/A genotype seems to be a candidate biomarker of primary resistance, whereas EGFR −191C/A, −216G/T, and R497K polymorphisms are associated with diarrhea when using gefitinib in NSCLC patients, thus offering potential new tools for treatment optimization. Mol Cancer Ther; 9(3); 581–93

Malignant mesothelioma after radiation treatment for Hodgkin lymphoma

Malignant mesothelioma is a relatively uncommon malignancy. Although the pathogenesis is primarily related to asbestos, the disease may be associated with radiation exposure. Recently, increased risks for second primary mesothelioma after radiation for lymphoma have been reported. Because these findings are based on small numbers of patients, they need to be confirmed. We examined mesothelioma risk in 2567 5-year survivors of Hodgkin lymphoma. The risk was almost 30-fold increased in Hodgkin lymphoma patients treated with irradiation compared with the general population. Although histology and survival of the mesothelioma cases were comparable with cases from the general population, asbestos exposure and the proportion of males were lower than expected. The evidence for radiotherapy as cause for mesothelioma independent of exposure to asbestos is expanding, and the diagnosis of mesothelioma should be kept in mind whenever related symptoms arise in patients who had previous irradiation.

Tumor Response and Toxicity of Neoadjuvant Erlotinib in Patients With Early-Stage Non–Small-Cell Lung Cancer

PURPOSE The development of targeted therapy has introduced new options to improve treatment outcome in selected patients. The objective of this prospective study was to investigate the safety of preoperative erlotinib treatment and the (in vivo) response in patients with early-stage resectable non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS This study was designed as an open-label phase II trial, performed in four hospitals in the Netherlands, according to a Simons minimax two-stage procedure. Initially, operable patients with early-stage NSCLC (n = 15) were entered from an enriched population (never-smoker, female sex, nonsquamous histology, or Asian ethnicity); thereafter, unselected patients were included to a total of N = 60. Patients received preoperative erlotinib 150 mg once daily for 3 weeks. Response to treatment was evaluated using [18F] fluorodeoxyglucose positron emission tomography (PET) and computed tomography (CT) scans during treatment and histologic examination of the resection specimen. Primary end points were toxicity and pathologic response. RESULTS Sixty patients were included. Seven patients stopped treatment prematurely (12%). Skin toxicity was present in 37 patients (62%), and diarrhea was present in 21 patients (35%). PET evaluation revealed metabolic response (> 25% standardized uptake value decrease) in 16 patients (27%); CT evaluation using Response Evaluation Criteria in Solid Tumors (RECIST) showed response in three patients (5%). At surgery, no unexpected complications occurred. Pathologic examination showed more than 50% necrosis in 14 patients (23%), of whom three (5%) had more than 95% tumor necrosis. The response rate in the enriched population was 34% (10 of 29 patients). CONCLUSION According to predefined criteria, neoadjuvant erlotinib has low toxicity and sufficient activity to deserve further testing in future studies in an enriched population.

Markers for the non-invasive diagnosis of mesothelioma: a systematic review

Background:Numerous markers have been evaluated to facilitate the non-invasive diagnostic work-up of mesothelioma. The purpose of this study was to conduct a structured review of the diagnostic performance of non-invasive marker tests for the detection of mesothelioma in patients with suspected mesothelioma.Methods:Studies on the diagnostic accuracy of serum and cytological markers published till 31 December 2009, available in either PUBMED or Embase, to detect or exclude the presence of mesothelioma were extracted. Study quality was assessed with use of the Quadas criteria.Results:In total, 82 articles were included in this systemic review. Overall, quality of the incorporated studies to address our objective was poor. The most frequently studied immunohistochemical markers for cytological analysis were EMA, Ber-Ep4, CEA, and calretinin. The most frequently investigated serum marker was soluble mesothelin-related protein (SMRP). The markers CEA, Ber-EP4, and calretinin were most valuable in discriminating mesothelioma from other malignant diseases. Markers EMA and SMRP were most valuable in discriminating mesothelioma from non-malignant diseases. No marker performed well in discriminating between mesothelioma and all other diseases.Conclusion:Currently, there is only limited evidence to properly assess the value of non-invasive marker tests in the diagnosis of mesothelioma. Studies were of limited value to address our objective and results showed considerable unexplained study heterogeneity.

Thalidomide versus active supportive care for maintenance in patients with malignant mesothelioma after first-line chemotherapy (NVALT 5): an open-label, multicentre, randomised phase 3 study.

BACKGROUND Standard chemotherapy does not lead to long-term survival in patients with malignant pleural mesothelioma. Malignant pleural mesothelioma is strongly dependent on vasculature with high vessel counts and high concentrations of serum vascular growth factors. Thalidomide has shown antiangiogenic activity, and we hypothesised that its use in the maintenance setting could improve outcomes. METHODS In this open-label, multicentre, randomised phase 3 study, eligible patients had proven malignant pleural or peritoneal mesothelioma and had received a minimum of four cycles of first-line treatment containing at least pemetrexed, with or without cisplatin or carboplatin, and had not progressed on this treatment. Patients were randomly assigned (in a 1:1 ratio, stratified by previous first-line chemotherapy, histological subtype, and recruiting hospital) to receive thalidomide 200 mg per day (including a 2 week run in of 100 mg per day) plus active supportive care or active supportive care alone until disease progression. Patients were required to be registered and to start treatment with thalidomide within 10 weeks after the end of the first-line chemotherapy. Thalidomide was given for a maximum of 1 year or until unacceptable toxicity. The primary endpoint was time to progression. The primary analyses were by intention to treat. The study is registered, ISRCTN13632914. FINDINGS Between May 11, 2004, and Dec 23, 2009, we randomly assigned 222 patients, 111 in each group (one patient on active supportive care later withdrew consent and was excluded from analyses). At the time of this final analysis, median follow-up was 33.1 months (IQR 22.3-66.8), and physician-reported disease progression had occurred in 104 patients in the thalidomide group and 107 in the active supportive care group; 92 patients in the thalidomide group and 93 in the active supportive care group had died. Median time to progression in the thalidomide group was 3·6 months (95% CI 3.2-4.1) compared with 3.5 months (2.3-4.8) in the active supportive care group (hazard ratio 0.95, 95% CI 0.73-1.20, p=0.72). 43 (39%) grade 3 or 4 adverse events were reported in the thalidomide group and 31 (28%) in the active supportive care group; neurosensory events were reported by two (2%) patients on thalidomide and none on active supportive care, cardiac events by two (2%) patients on thalidomide and three (3%) on active supportive care, and thromboembolic events by three (3%) patients on thalidomide and none on active supportive care. INTERPRETATION No benefit was noted in time to progression with the addition of thalidomide maintenance to first-line chemotherapy. Different treatment strategies are needed to improve outcomes in patients with malignant mesothelioma. FUNDING Dutch Cancer Society (KWF), Eli Lilly, NSW Dust Disease Compensation Board, University of Sydney, and Cancer Australia.

Pleural drainage and pleurodesis: implementation of guidelines in four hospitals

The aim of the present study was to evaluate the implementation of the 2003 Dutch guideline on the diagnosis and treatment of malignant pleural effusions, and the potential effect of the implementation on the clinical outcome of pleurodesis. All patients with malignant pleural effusion who had a pleural drain placed with the intention of performing pleurodesis were registered prospectively in four centres. Details of the procedure and fluid recurrence and survival data were noted. Patients with a proven malignancy (n = 100) were entered into the registration database. Diagnostic guideline recommendations were followed in 60–70% of the patients. Surprisingly, pleurodesis was performed in only 75% of the patients, mainly due to the presence of a trapped lung. All pleurodeses were performed using talc, according to the guideline. Follow-up revealed fluid recurrence in 27 (36%) patients after a mean follow-up of 17 days (range 2–285 days); 14 patients with successful pleurodesis died with a median survival of 61 days (range 13–174 days). Systemic treatment following pleurodesis and good apposition of the pleural surfaces during drainage were good prognostic factors. Despite reasonable-to-good adherence to the guideline, the number of successful pleurodeses was low. Better predictors of a good pleurodesis outcome are needed.

Population-based survival for malignant mesothelioma after introduction of novel chemotherapy

Malignant mesothelioma is known for its dismal prognosis and poor response to conventional treatment. Chemotherapy with cisplatin–antifolate combinations recently showed promising response rates and prolonged survival in randomised trials. To assess the impact of this development on clinical practice and survival at a population-based level, treatment patterns and survival trends were studied for patients diagnosed with mesothelioma in the period 1995–2006. 4,731 records were retrieved from the Netherlands Cancer Registry and chemotherapy use and median survival were analysed. For the periods 1995–1998 to 2005–2006, chemotherapy use increased from 8% to 36%. Median survival increased over time from 7.1 months to 9.2 months. For pleural mesothelioma, multivariable analysis demonstrated that survival was poorer for elderly patients and sarcomatoid tumours. The prognostic impact of chemotherapy increased with time. Median survival for chemotherapy treated patients improved from 10.1 months (1995–1998) to 13.1 months (2005–2006). For peritoneal mesothelioma, median survival was poor (3.9 months) but better for females and younger patients. This study demonstrates that chemotherapy use increased at a national level and coincided with an improvement in survival. The novel chemotherapy regimen appears to be more effective but, due to the observational nature of this study, alternative explanations cannot be excluded.

Pharmacogenetic study of patients with advanced non-small cell lung cancer (NSCLC) treated with second-line pemetrexed or pemetrexed–carboplatin

PURPOSE To correlate candidate polymorphisms affecting pemetrexed and carboplatin activity with clinical outcome of patients with advanced non-small cell lung cancer (NSCLC) treated in second-line with pemetrexed or pemetrexed plus carboplatin. METHODS Functional polymorphisms in thymidylate synthase (TS), reduced folate carrier (RFC), gamma-glutamyl hydrolase (GGH), methylenetetrahydrofolate reductase (MTHFR) and xeroderma pigmentosum group D (XPD) genes were evaluated in 208 patients either treated within randomized phase II trials NVALT-7 and GOIRC-02.2006, comparing second-line pemetrexed with pemetrexed plus carboplatin, or with the same regimens outside of these trials. Univariate and multivariate analyses correlated genotyping data with response, clinical benefit, toxicity, progression-free (PFS) and overall survival (OS) using Pearson-χ2 test, log-rank test and Cox proportional hazards model. RESULTS Patients harboring the MTHFR-T667T variant had significantly longer PFS (5.4 versus 3.4 months; p=0.012) and OS (16.4 versus 8.5 months; p=0.026) than patients with CC-CT genotypes. No correlation was observed for other polymorphisms, except for XPD-Gln751Gln, which was associated with shorter PFS (p=0.021) and OS (p=0.044) in the subgroup of patients treated with pemetrexed plus carboplatin. Multivariate analysis confirmed the independent prognostic significance of MTHFR-C677T both in risk of disease progression (CC-CT genotypes hazard ratio [HR] 1.94, 95%CI 1.15-3.28; p=0.012) and of death (HR 2.00, 95% CI 1.12-3.54; p=0.018). CONCLUSIONS MTHFR-C667T polymorphisms appear to predict survival differences in pemetrexed-treated NSCLC. These results should be validated in larger and adequately designed prospective studies using pemetrexed.