Factors Affecting Attitudes towards COVID-19 Vaccination: An Online Survey in Slovenia.

While the problem of vaccine hesitancy is not new, it has become more pronounced with the new COVID-19 vaccines and represents an obstacle to resolving the crisis. Even people who would usually trust vaccines and experts now prefer to wait for more information. A cross-sectional online survey was conducted in Slovenia in December 2020 to find out the attitudes of the population regarding COVID-19 vaccination and the factors that affect these attitudes. Based on 12,042 fully completed questionnaires, we find that higher intention to get vaccinated is associated with men, older respondents, physicians and medical students, respondents who got the influenza vaccination, those who knew someone who had gotten hospitalised or died from COVID-19 and those who have more trust in experts, institutions and vaccines. Nurses and technicians were less likely to get vaccinated. In answers to an open question, sceptics were split into those doubting the quality due to the rapid development of the vaccine and those that reported personal experiences with side effects of prior vaccinations. Although the Slovenian population is diverse in its attitudes towards vaccination, the results are comparable to those found in other countries. However, there are potential limitations to the generalizability of the findings that should be addressed in future studies.

Compliance and Outcome of Elderly Patients Treated in the Concurrent Once-Daily Versus Twice-Daily Radiotherapy (CONVERT) Trial.

INTRODUCTION: There is a lack of data on the efficacy and safety of concurrent chemoradiotherapy in elderly, limited-stage, patients with SCLC. METHODS: We compared outcomes of patients 70 years of age or older versus younger patients within the Concurrent Once-daily Versus twice-daily RadioTherapy (CONVERT) trial. Patients were randomized to receive 45 Gy/30 twice-daily fractions/19 days or 66 Gy/33 once-daily fractions/45 days concurrently with platinum-based chemotherapy. Overall survival and progression-free survival were evaluated using Kaplan-Meier methodology and Cox proportional hazards regression. RESULTS: Of 547 patients randomized between April 2008 and November 2013, 57 did not receive protocol treatment and were excluded. Of the 490 patients included, 67 (14%) were 70 years of age or older (median age: 73 years; range: 70-82). Fewer older patients received the optimal number of radiotherapy fractions (73% versus 85%; p = 0.03); however, chemotherapy compliance was similar in both groups (p = 0.24). Neutropenia grade 3/4 occurred more frequently in the elderly (84% versus 70%; p = 0.02) but rates of neutropenic sepsis (4% versus 7%; p = 0.07) and death (3% versus 1.4%; p = 0.67) were similar in both groups. With a median follow-up of 46 months; median survival in the elderly versus younger groups was 29 (95% confidence interval [CI]: 21-39) versus 30 months (95% CI: 26-35), respectively; (hazard ratio: 1.15, 95% CI: 0.84-1.59; p = 0.38). Median time to progression in the elderly versus younger groups was 18 months (95% CI: 13-31) versus 16 months (95% CI: 14-19), respectively (hazard ratio: 1.04, 95% CI: 0.76-1.41; p = 0.81). CONCLUSIONS: Concurrent chemoradiotherapy with modern radiotherapy techniques should be a treatment option for fit, older patients.

Toxicity and quality of life in published clinical trials for advanced lung cancer.

BACKGROUND: In every report on incurable disease, clear presentation of toxicity and of quality of life (QoL) is of essential importance. This postulate was assessed on a series of publications on systemic treatment for advanced lung cancer. MATERIALS AND METHODS: The analysis covered papers on original phase II-IV clinical trials published between 2013 and 2015 and included in the PubMed database. RESULTS: Selected for analysis were 349 publications on 333 trials with a total of 78.977 patients. Only 33 trials (10%) dealt with small cell lung cancer. Most trials (56.5%) included only information on frequency and grade of specific toxic phenomena and did not provide data on the frequency of any serious toxicity. The ratio between the frequency of any grade ≥ 3 toxicity and response rate was often unfavorable, especially for second-line treatment of non-small cell lung cancer (3.0) and second-line treatment of small cell lung cancer (5.3). Assessment of QoL was mentioned in 68 (20.4%) trials, of which only 46 publications provided adequate data. CONCLUSIONS: A substantial proportion of publications on trials for advanced lung cancer do not offer adequate information for decisions in clinical practice. Presentation of toxicity should include information on the frequency of any serious toxicity. Quality of life should be monitored and reported in every trial of an incurable disease. Simple instruments for the assessment of QoL are strongly recommended, so as to alleviate burden to patients and to staff, avoid bias due to poor compliance and enable clear analysis and presentation.

Selection of Non-small Cell Lung Cancer Patients for Intercalated Chemotherapy and Tyrosine Kinase Inhibitors.

BACKGROUND: When treating patients with advanced non-small cell lung cancer (NSCLC) with tyrosine kinase inhibitors and chemotherapy, intercalated schedule with time separation between the two classes of drugs should avoid their mutual antagonism. In a survey of published trials, we focus on relation between eligibility criteria and effectiveness of intercalated treatment. METHODS: Published documents were identified using major medical databases, conference proceedings and references of published trials. Median progression-free survival (PFS) was taken as the basic parameter of treatment efficacy. Correlation between characteristics of patients and median PFS was assessed through the Pearson's correlation coefficient and the coefficient of determination, separately for first-line and second-line setting. RESULTS: The series includes 11 single-arm trials and 18 randomized phase II or phase III trials with a total of 2903 patients. Treatment-naive patients or those in progression after first-line treatment were included in 16 and 13 trials, respectively. In 14 trials, only patients with non-squamous histology were eligible. Proportion of patients with non-squamous carcinoma (in first-line setting), proportion of never-smokers (both in first- and second-line setting) and proportion of epidermal growth factor receptor (EGFR) mutant patients (both in first- and second-line setting) showed a moderate or strong correlation with median PFS. In six trials of intercalated treatment applied to treatment-naive EGFR-mutant patients, objective response was confirmed in 83.1% of cases and median PFS was 18.6 months. CONCLUSIONS: Most suitable candidates for intercalated treatment are treatment-naive patients with EGFR-mutant tumors, as determined from biopsy or liquid biopsy. For these patients, experience with intercalated treatment is most promising and randomized trials with comparison to the best standard treatment are warranted.

Immunohistochemistry for EGFR Mutation Detection in Non-Small-Cell Lung Cancer.

INTRODUCTION: The sensitivity and specificity of immunohistochemistry (IHC) was compared with the standard polymerase chain reaction (PCR)-based method for detecting common activating epidermal growth factor receptor (EGFR) mutations in non-small-cell lung cancer (NSCLC). Additionally, we evaluated predictive value of IHC EGFR mutation-positive status for EGFR tyrosine kinase inhibitor (TKI) treatment outcome and estimated cost-effectiveness for the upfront IHC testing. METHODS: The trial included 79 consecutive EGFR mutation-positive and 29 EGFR mutation-negative NSCLC cases diagnosed with reflex PCR-based testing. Two mutation-specific antibodies against the most common exon 19 deletion, namely E746-A750del (clone SP111) and L858R mutation (clone SP125) were tested by using automated immunostainer. Sixty of 79 EGFR mutation-positive cases were treated with EGFR TKIs for advanced disease and included in treatment outcome analysis. A decision tree was used for the cost-effectiveness analysis. RESULTS: The overall sensitivity and specificity of the IHC-based method compared with the PCR-based method were 84.8% (95% confidence interval [CI] 74.6-91.6) and 100% (95% CI 85.4-100), respectively. The median progression-free survival (PFS) and overall survival (OS) of patients with IHC-positive EGFR mutation status were highly comparable to the total cohort (PFS: 14.3 vs. 14.0 months; OS: 34.4 vs. 34.4 months). The PCR and IHC cost ratio needs to be approximately 8-to-1 and 4-to-1 in White and Asian populations, respectively, to economically justify upfront use of IHC. CONCLUSION: The trial confirmed an excellent specificity with fairly good sensitivity of IHC with mutation-specific antibodies for common EGFR mutations and the accuracy of IHC testing for predicting response to EGFR TKIs. The use of upfront IHC depends mainly on the population EGFR mutation positivity probability.

Long-term survival in glioblastoma: methyl guanine methyl transferase (MGMT) promoter methylation as independent favourable prognostic factor.

BACKGROUND: In spite of significant improvement after multi-modality treatment, prognosis of most patients with glioblastoma remains poor. Standard clinical prognostic factors (age, gender, extent of surgery and performance status) do not clearly predict long-term survival. The aim of this case-control study was to evaluate immuno-histochemical and genetic characteristics of the tumour as additional prognostic factors in glioblastoma. PATIENTS AND METHODS: Long-term survivor group were 40 patients with glioblastoma with survival longer than 30 months. Control group were 40 patients with shorter survival and matched to the long-term survivor group according to the clinical prognostic factors. All patients underwent multimodality treatment with surgery, postoperative conformal radiotherapy and temozolomide during and after radiotherapy. Biopsy samples were tested for the methylation of MGMT promoter (with methylation specific polymerase chain reaction), IDH1 (with immunohistochemistry), IDH2, CDKN2A and CDKN2B (with multiplex ligation-dependent probe amplification), and 1p and 19q mutations (with fluorescent in situ hybridization). RESULTS: Methylation of MGMT promoter was found in 95% and in 36% in the long-term survivor and control groups, respectively (p < 0.001). IDH1 R132H mutated patients had a non-significant lower risk of dying from glioblastoma (p = 0.437), in comparison to patients without this mutation. Other mutations were rare, with no significant difference between the two groups. CONCLUSIONS: Molecular and genetic testing offers additional prognostic and predictive information for patients with glioblastoma. The most important finding of our analysis is that in the absence of MGMT promoter methylation, longterm survival is very rare. For patients without this mutation, alternative treatments should be explored.

Intercalated chemotherapy and erlotinib for non-small cell lung cancer (NSCLC) with activating epidermal growth factor receptor (EGFR) mutations.

Among attempts to delay development of resistance to tyrosine kinase inhibitors (TKIs) in patients with advanced non-small cell lung cancer (NSCLC) with activating mutations of epidermal growth factor receptor (EGFR), intercalated therapy has not been properly evaluated. In a phase II trial, 38 patients with EGFR mutated NSCLC in advanced stage were treated with 4 to 6 3-weekly cycles of intercalated schedule with gemcitabine (1250 mg/m2, days 1 and 4), cisplatin (75 mg/m2, day 2) and erlotinib (150 mg, days 5 - 15), followed by continuous erlotinib as maintenance. In addition to standard radiologic evaluation according to RECIST, PET/CT was done prior to treatment and at 6 months, using PERCIST as a method for assessment of response. The primary endpoint was progression-free survival (PFS). In general, tolerance to treatment was good, even among 8 patients with performance status 2-3 and 13 patients with brain metastases; grade 4 toxicity included 2 cases of neutropenia and 4 thrombo-embolic events. Complete response (CR) or partial response (PR) were seen in 15 (39.5%) and 17 (44.7%) cases, respectively. All cases of CR were confirmed also by PET/CT. Median PFS was 23.4 months and median overall survival (OS) was 38.3  months. After a median follow-up of 35 months, 8 patients are still in CR and on maintenance erlotinib. In conclusion, intercalated treatment for treatment-naive patients with EGFR activating mutations leads to excellent response rate and prolonged PFS and survival. Comparison of the intercalated schedule to monotherapy with TKIs in a randomized trial is warranted.

Independent Clinical Research May Alleviate Disparities in Cancer Treatment.

Disparities in cancer care are a reality of the modern world. Unfortunately, current clinical research is in the hands of for-profit pharmaceutical companies and of researchers from the developed world. Problems specific to cancer care in developing countries and among deprivileged populations are ignored. Independent clinical research can offer new valuable knowledge and identify affordable and cost-effective treatments. As such, research not depending on commercial sponsors should become one of the important avenues to alleviate the problem of cancer disparities.

Intercalated chemotherapy and erlotinib for advanced NSCLC: high proportion of complete remissions and prolonged progression-free survival among patients with EGFR activating mutations.

BACKGROUND: Pharmaco-dynamic separation of cytotoxic and targeted drugs might avoid their mutual antagonistic effect in the treatment of advanced non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: Eligible patients were treatment-naive with stage IIIB or IV NSCLC. In addition, inclusion was limited to never-smokers or light smokers or, after 2010, to patients with activating epidermal growth-factor receptor (EGFR) mutations. Treatment started with 3-weekly cycles of gemcitabine and cisplatin on days 1, 2 and 4 and erlotinib on days 5 to 15. After 4 to 6 cycles, patients continued with erlotinib maintenance. RESULTS: Fifty-three patients were recruited into the trial: 24 prior to 2010 (of whom 9 were later found to be positive for EGFR mutations), and 29 EGFR mutation-positive patients recruited later. Unfavourable prognostic factors included stage IV disease (51 patients - 96%), performance status 2-3 (11 patients - 21%) and brain metastases (15 patients -28%). Grade 4 toxicity included 2 cases of neutropenia and 4 thrombo-embolic events. The 15 EGFR negative patients had 33% objective response rate, median progression-free survival (PFS) 6.0 months and median survival 7.6 months. Among 38 EGFR positive patients, complete response (CR) or partial response (PR) were seen in 16 (42.1%) and 17 (44.7%) cases, respectively. PET-CT scanning was performed in 30 patients and confirmed CR and PR in 16 (53.3%) and 9 (30.0%) cases, respectively. Median PFS for EGFR mutated patients was 21.2 months and median survival was 32.5 months. CONCLUSIONS: While patients with EGFR negative tumors do not benefit from addition of erlotinib, the intercalated schedule appears most promising for those with EGFR activating mutations.

Induction gemcitabine in standard dose or prolonged low-dose with cisplatin followed by concurrent radiochemotherapy in locally advanced non-small cell lung cancer: a randomized phase II clinical trial.

BACKGROUND: The optimal combination of chemotherapy with radiation therapy for treatment locally advanced non-small cell lung cancer (NSCLC) remains an open issue. This randomized phase II study compared gemcitabine in two different schedules and cisplatin - as induction chemotherapy, followed by radiation therapy concurrent with cisplatin and etoposid. PATIENTS AND METHODS: Eligible patients had microscopically confirmed inoperable non-metastatic non-small cell lung cancer; fulfilled the standard criteria for platin-based chemotherapy; and signed informed consent. Patients were treated with 3 cycles of induction chemotherapy with gemcitabine and cisplatin. Two different aplications of gemcitabine were compared: patients in arm A received gemcitabine at 1250 mg/m(2) in a standard half hour i.v. infusion on days 1 and 8; patients in arm B received gemcitabine at 250 mg/m(2) in prolonged 6-hours i.v. infusion on days 1 and 8. In both arms, cisplatin 75 mg/m(2) on day 2 was administered. All patients continued treatment with radiation therapy with 60-66 Gy concurrent with cisplatin 50 mg/m(2) on days 1, 8, 29 and 36 and etoposid 50 mg/m(2) on days 1-5 and 29-33. The primary endpoint was response rate (RR) after induction chemotherapy; secondary endpoints were toxicity, progression-free survival (PFS) and overall survival (OS). RESULTS: From September 2005 to November 2010, 106 patients were recruited to this study. No statistically signifficant differences were found in RR after induction chemotherapy between the two arms (48.1% and 57.4%, p = 0.34). Toxicity profile was comparable and mild with grade 3/4 neutropenia as primary toxicity in both arms. One patient in arm B suffered from acute peripheral ischemia grade 4 and an amputation of lower limb was needed. With a median follow-up of 69.3 months, progression-free survival and median survival in arm A were 15.7 and 24.8 months compared to 18.9 and 28.6 months in arm B. The figures for 1- and 3-year overall survival were 73.1% and 30.8% in arm A, and 81.5 % and 44.4% in arm B, respectively. CONCLUSIONS: Among the two cisplatin-based doublets of induction chemotherapy for inoperable NSCLC, both schedules of gemcitabine have a comparable toxicity profile. Figures for RR, PFS and OS are among the best reported in current literature. While there is a trend towards better efficacy of the treament with prolonged infusion of gemcitabine, the difference between the two arms did not reach statistical significance.

Brain metastases in lung adenocarcinoma: impact of EGFR mutation status on incidence and survival.

BACKGROUND: The brain represents a frequent progression site in lung adenocarcinoma. This study was designed to analyse the association between the epidermal growth factor receptor (EGFR) mutation status and the frequency of brain metastases (BM) and survival in routine clinical practice. PATIENTS AND METHODS: We retrospectively analysed the medical records of 629 patients with adenocarcinoma in Slovenia who were tested for EGFR mutations in order to analyse the cumulative incidence of BM, the time from the diagnosis to the development of BM (TDBM), the time from BM to death (TTD) and the median survival. RESULTS: Out of 629 patients, 168 (27%) had BM, 90 patients already at the time of diagnosis. Additional 78 patients developed BM after a median interval of 14.3 months; 25.8 months in EGFR positive and 11.8 months in EGFR negative patients, respectively (p = 0.002). EGFR mutations were present in 47 (28%) patients with BM. The curves for cumulative incidence of BM in EGFR positive and negative patients demonstrate a trend for a higher incidence of BM in EGFR mutant patients at diagnosis (19% vs. 13%, p = 0.078), but no difference later during the course of the disease. The patients with BM at diagnosis had a statistically longer TTD (7.3 months) than patients who developed BM later (3.1 months). The TTD in EGFR positive patients with BM at diagnosis was longer than in EGFR negative patients (12.6 vs. 6.8, p = 0.005), while there was no impact of EGFR status on the TTD of patients who developed BM later. CONCLUSIONS: Except for a non-significant increase of frequency of BM at diagnosis in EGFR positive patients, EGFR status had no influence upon the cumulative incidence of BM. EGFR positive patients had a longer time to CNS progression. While EGFR positive patients with BM at diagnosis had a longer survival, EGFR status had no influence on TTD in patients who developed BM later during the course of disease.

Pollution in the working place and social status: co-factors in lung cancer carcinogenesis.

INTRODUCTION: Apart from the association with tobacco consumption, other factors of importance for prevention and early diagnosis of lung cancer have received little attention. We present a case-control study focusing on professional exposure to carcinogens and social status. METHODS: A written questionnaire was completed by 551 consecutive patients with lung cancer and 494 patients with large bowel cancer. The groups were balanced regarding gender and age distribution. The questionnaire included data on place of birth, education, smoking history, diet and alcohol intake, body weight and height, occupation, housing conditions and family income. According to standard epidemiological criteria, professional exposure to carcinogens was classified as professions with exposure to confirmed lung cancer carcinogens, professions with exposure to suspected lung cancer carcinogens and other professions. RESULTS: As expected, there were significant differences between the two groups regarding smoking status. While there were no significant differences in educational levels, more immigrants were among patients with lung cancer (17.9% vs 11.6%, p=0.005). On average, lung cancer patients had a lower body mass index (BMI) at 24.77, as compared to 26.14 for large bowel cancer (p=0.000). Lung cancer patients had lower income and poorer housing conditions; the bivariate difference was significant both for income levels (p=0.046) and type of residence (p=0.009). The proportion of patients working in professions with exposures to known carcinogens was 33.5% for lung cancer, and 17.1% for large bowel cancer (p=0.000). In the multivariate analysis, smoking (p=0.000), BMI (p=0.000) and type of occupation (p=0.001) were significant factors. CONCLUSIONS: While there is no doubt about smoking in lung cancer carcinogenesis, professional exposure to carcinogens and belonging to lower socio-economic strata also play an important role.

Glioblastoma patients in Slovenia from 1997 to 2008.

BACKGROUND: Glioblastoma is the most common primary brain tumour. It has a poor prognosis despite some advances in treatment that have been achieved over the last ten years. In Slovenia, 50 to 60 glioblastoma patients are diagnosed each year. In order to establish whether the current treatment options have any influence on the survival of the Slovenian glioblastoma patients, their data in the period from the beginning of the year 1997 to the end of the year 2008 have been analysed. PATIENTS AND METHODS: All patients treated at the Institute of Oncology Ljubljana from 1997 to 2008 were included in the retrospective study. Demographics, treatment details, and survival time after the diagnosis were collected and statistically analysed for the group as a whole and for subgroups. RESULTS: From 1997 to 2008, 527 adult patients were diagnosed with glioblastoma and referred to the Institute of Oncology for further treatment. Their median age was 59 years (from 20 to 85) and all but one had the diagnosis confirmed by a pathologist. Gross total resection was reported by surgeons in 261 (49.5%) patients; good functional status (WHO 0 or 1) after surgery was observed in 336 (63.7%) patients, radiotherapy was performed in 422 (80.1%) patients, in 317 (75.1%) of them with radical intent, and 198 (62.5 %) of those received some form of systemic treatment (usually temozolomide). The median survival of all patients amounted to 9.7 months. There was no difference in median survival of all patients or of all treated patients before or after the chemo-radiotherapy era. However, the overall survival of patients treated with radical intent was significantly better (11.4 months; p < 0.05). A better survival was also noticed in radically treated patients who received additional temozolomide therapy (11.4 vs. 13.1 months; p = 0.014). The longer survival was associated with a younger age and a good performance status as well as with a more extensive tumour resection. In patients treated with radical intent, having a good performance status, and receiving radiotherapy and additional temozolomide therapy, the survival was significantly longer, based on multivariate analysis. CONCLUSIONS: We observed a gradual increase in the survival of glioblastoma patients who were treated with radical intent over the last ten years. Good functional surgery, advances in radiotherapy and addition of temozolomide all contributed to this increase. Though the increased survival seems to be more pronounced in certain subgroups, we have still not been able to exactly define them. Further research, especially in tumour biology and genetics is needed.

Communication in view of limited resources: international perspective.

Low socioeconomic status is associated with several risk factors for cancer, including a higher risk of presentation with advanced and often incurable disease. Treating patients in areas with limited resources requires not only the goal of saving or prolonging life, but also to alleviate suffering, including physical, emotional, and social components. Because complete coverage of all costs for modern cancer management by local institutions or governments is not possible in most (if not all) areas, most patients with cancer have to contribute toward the costs of their treatment. However, the demand for financially sustainable health care leads to restrictions in the spectrum of available treatments and often results in the creation of waiting lists for people requiring treatment. Communication between patients and providers in such circumstances is often challenging, especially when coupled with patients who have limited or no health care insurance and/or lack any ability to pay for services. Ultimately, any treatment plan should take into account the risks, benefits, personal goals, and beliefs of the individual with cancer. In areas of limited resources, the financial burden of treatment placed on the patient and his or her family must also be a part of the conversation and decisions regarding therapy. Within these parameters, sharing information and options becomes an indispensable condition for communication and the foundation of trust in the doctor-patient relationship.

Improved survival after introduction of chemotherapy for malignant pleural mesothelioma in Slovenia: Population-based survey of 444 patients.

BACKGROUND: Malignant pleural mesothelioma is a rare tumour with increasing frequency throughout the world. Due to long latency after exposure to asbestos, restrictions in the production and use of asbestos have not yet alleviated the burden of mesothelioma. During the last decade, several trials confirmed the benefit of systemic treatment with drugs such as doublets with cisplatina and gemcitabine or pemetrexed for carefully selected patients in good performance status. The purpose of this survey was to assess the impact of systemic treatment for the whole national population of patients with mesothelioma. PATIENTS AND METHODS.: A retrospective study included all patients in Slovenia with histologically confirmed diagnosis of malignant pleural mesothelioma in the period from 1974 till 2008. Data from the Cancer Registry of Slovenia were supplemented by review of clinical records of the Institute of Oncology in Ljubljana where virtually all non-surgical treatment for mesothelioma was performed. We analysed the incidence, treatment, and survival of patients treated in the era of infrequent chemotherapy (1974-2003, the first period) and after it (2004-2008, the second period). RESULTS: The survey included 444 patients, of whom 325 and 119 were diagnosed in the first and second period, respectively. Joinpoint regression analysis showed that after 1995 the trend in crude incidence rates increased more rapidly; the annual change was 0.03 per 100,000 per year before 1995 and 0.06 per 100,000 per year after. There was clear male predominance (70%) throughout the period covered by the survey. The proportion of patients above 65 years of age increased from 41.8% to 54.6% for the first and second period, respectively (p = 0.02). With a total of 52 (11.7%) operated patients, surgical treatment was rare and used only for selected patients with early disease and without comorbidity, leading to their relatively long median survival of 13.6 months. Chemotherapy was applied to 56 (17.2%) and to 96 (80.7%) patients during the first and second period, respectively. While a variety of older drugs were used in the first period, the most common regimen in the second period (applied to 91 patients) was doublet of low-dose gemcitabine in prolonged infusion and cisplatin. For the whole population of patients regardless the mode of treatment, median survival was 7.4 and 12.6 months (p-value = 0.037) for the first and second period, respectively. CONCLUSIONS: Increasing incidence, male predominance and increased proportion of older patients confirm that the burden of mesothelioma persists in spite of a 15-years old ban in the production of asbestos. Modern chemotherapy, and in particular treatment with low-dose gemcitabine in prolonged infusion and cisplatin significantly prolonged median survival of patients with malignant pleural mesothelioma in Slovenia.

A phase II trial of low-dose gemcitabine in a prolonged infusion and cisplatin for malignant pleural mesothelioma.

After a favorable experience with gemcitabine at a low dose in a prolonged infusion in combination with cisplatin for advanced non-small-cell lung cancer, here, we present the results from a phase II trial for patients with malignant pleural mesothelioma. Eligible patients had biopsy-proven malignant pleural mesothelioma, were chemo-naive, Eastern Cooperative Oncology Group performance status 0-2, had normal hematopoietic liver and renal function, and gave informed consent. Treatment consisted of gemcitabine 250 mg/m in a 6-h infusion on days 1 and 8 and cisplatin at 75 mg/m on day 2 of a 3-week cycle for four cycles, followed by two additional cycles without cisplatin. Seventy-eight patients (58 men, 20 women; age 33-82 years, median 58) were recruited into the trial. The histologic types were as follows: epitheloid 56 (71.8%); four sarcomatoid (5.1%); mixed 15 (19.2%); and mesothelioma, three not otherwise specified (3.8%). Grades 3-4 toxicity included two (2.6%) patients with anemia, 18 (23.1%) with neutropenia, and one with nausea/vomiting. Reversible thrombocytosis with platelets over 1000-10/l was recorded in 10 (12.8%) patients and grade 2 alopecia in 60 (76.9%). Four (5.1%) patients showed a complete response and 35 (44.9%) showed a partial response with a response rate of 39/78 (50%). Minimal response or stable disease was seen in 35 (44.9%), whereas only four (5.1%) patients progressed during treatment. Most patients reported symptomatic improvement with a higher or a stable quality of life score in 70 (89.7%) cases. The median progression-free survival was 8.0 months (confidence interval 6.9-9.0). The median overall survival was 17.0 months (confidence interval 14.7-19.2). One-year, two-year, and three-year survival rates were 67.3, 32.7, and 19.8%, respectively. Epitheloid histological type was the only statistically significant favorable prognostic factor for progression-free survival and overall survival. Because of the acceptable toxicity, remarkable activity, and reasonable cost, this treatment should be further explored.

Intermittent chemotherapy and erlotinib for nonsmokers or light smokers with advanced adenocarcinoma of the lung: a phase II clinical trial.

BACKGROUND: Intermittent application of chemotherapy and tyrosine kinase inhibitors may avoid antagonism between the two classes of drugs. This hypothesis was tested in a Phase II clinical trial. PATIENTS AND METHODS: Eligible patients were nonsmokers or light smokers, chemo-naïve, with metastatic adenocarcinoma of the lung. TREATMENT: 4 to 6 cycles of gemcitabine 1250 mg/m(2) on days 1 and 4, cisplatin 75 mg/m(2) on day 2, and erlotnib 150 mg daily on days 5-15, followed by erlotinib as maintenance. RESULTS: 24 patients entered the trial. Four pts had grade 3 toxicity. Complete remission (CR) and partial remission (PR) were seen in 5 pts and 9 pts, respectively (response rate 58%). Median time to progression (TTP) was 13.4 months and median overall survival (OS) was 23 months. When compared to patients with negative or unknown status of EGFR mutations, 8 patients with EGFR gene activating mutations had significantly superior experience: 4 CR and 4 PR, with median TTP 21.5 months and OS 24.2 months (P < .05). CONCLUSIONS: Intermittent schedule with gemcitabine, cisplatin and erlotinib has mild toxicity. For patients who are positive for EGFR gene activating mutations, this treatment offers excellent response rate, time to progression and survival.