PD-L1 expression can be regarded as prognostic factor for survival of non-small cell lung cancer patients after chemoradiotherapy.

Inoperable locally advanced non-small cell lung cancer (LA NSCLC) is treated with concurrent or sequential chemotherapy (ChT) and radiation therapy (RT). Survival rates with this treatment remains poor, reported 5-year survival is about 15%. New treatment strategies, including immunotherapy with programmed death ligand-1 (PD-L1) check point inhibitors are being investigated. The clinical significance of PD-L1 expression in tumor samples from patients with inoperable LA NSCLC who underwent concurrent chemoradiotherapy (CRT) in our institution between 2005 and 2010 was evaluated. The expression of PD-L1 was correlated with clinical and pathological parameters and outcome of treatment. We analysed 107 patients treated with concurrent CRT. Only 43 patients (36 males and 7 females) had sufficient tissue for immunohistochemical (IHC) staining. PD-L1 expression was demonstrated in 7 tumors. No statistical significant differences in patient characteristics, including age, smoking status and gender, were found according to the PD-L1 expression. After a median follow up of 103.6 months, median progression free survival (PFS) was 19.9 months in patients without and 10.1 months in patients with PD-L1 expression (p=0.006). Median overall survival (OS) was 28.4 and 12.1 months for PD-L1 negative and PD-L1 positive patients, respectively (p=0.012).In conclusions, PD-L1 expression was negative prognostic factor for PFS and OS after concurrent CRT in LA NSCLC. As only small number of patients had enough tissue for the IHC testing, no firm conclusions could be made and further investigation is warranted.

Phase I-II trial of low-dose gemcitabine in prolonged infusion and cisplatin for advanced non-small cell lung cancer.

After monotherapy with gemcitabine in low dose in long infusion, promising results in a variety of advanced chemoresistant tumors have been reported. In a previous phase I trial on heavily pre-treated patients, maximum tolerated dose (MTD) of gemcitabine in a 6 h infusion was 250 mg/m. The objective of our phase I-II trial was to test the combination of gemcitabine in a 6-h infusion and cisplatin in the treatment of advanced non-small cell lung cancer (NSCLC). Eligible patients were chemonaive, had locally advanced or metastatic NSCLC, Eastern Oncology Cooperative Oncology Group performance status 0-2 and normal organ function. Treatment consisted of gemcitabine in a 6-h infusion on days 1 and 8, and cisplatin at 75 mg/m on day 2 of a 3-week cycle. During phase I of the trial, the dose of gemcitabine was escalated from 130 to 170, 210 and 250 mg/m. After establishing dose-limiting toxicity (DLT) and MTD of the combination, the trial continued as phase II. Altogether, 61 patients were enrolled, of whom 54 had stage IV disease. In phase I of the trial, groups of six, seven, eight and eight patients were treated at the four dose levels of gemcitabine. In phase II, the remaining 32 patients all received gemcitabine at 250 mg/m. Serious toxicity included a patient with grade 5 ventricular arrhythmia and another with grade 4 cerebrovascular ischemia; four patients had grade 3 anemia. Reversible thrombocytosis with platelets over 500 was recorded in 32 patients; 42 patients had grade 2 alopecia. In general, tolerance to this treatment was good. One patient had complete response and 27 had partial responses, for a 28 of 61 (46%) response rate. Median progression-free survival, median survival and 1-year survival were 6 months, 9.5 months and 40%, respectively. We conclude that this treatment has an acceptable, yet distinct, toxicity profile; routine thromboprophylaxis is recommended. In our population of chemonaive patients, no DLT has been encountered. Due to the remarkable response rate, further research is warranted.

The significance of adrenal metastases from lung carcinoma.

AIM: The aim of our study was to correlate spread of the lung cancer into the adrenal glands with the progression of the primary disease. METHODS: We diagnosed and confirmed adrenal metastases in 50 patients with non-small cell lung cancer (NSCLC). We correlated the site of the primary lung carcinoma with the site of the adrenal metastasis, and the adrenal metastasis pattern, ipsi-, contra-, and bilateral adrenal metastases, with the operability and number of other sites of metastatic disease. RESULTS: Adrenal metastases were ipsilateral in 20 patients, contralateral in 15 patients and bilateral in 15 patients. An inverse incidence of contra- and bilateral metastasis was observed in 37% of operated patients, and in 71% of patients with inoperable carcinoma. The difference between both groups was statistically significant (P=0.034). CONCLUSIONS: We suggest that an isolated ipsilateral adrenal metastasis in a patient with resectable primary NSCLC could be considered (and treated) as a localized disease rather than a symptom of systemic spread.

A personal critique: evidence-based medicine, methodology, and ethics of randomised clinical trials.

Evidence-based medicine may influence our approach to clinical trials. When preparing a systematic review, the quality of individual trials is of far greater importance than their individual results. Unbiased randomisation, attention to the treatment protocol and to the rules of good clinical practice and honest evaluation of experience are essential; less important is the power of an individual trial and the statistically significant difference between the treatment arms. The recruitment period should be short, followed by timely publication of a report. Since systematic reviews and meta-analyses include and quote all available information, clinical researchers and editors should be less influenced by publication bias. These changes in methodology open clinical trials to new innovative ideas difficult to test in large multi-institutional trials, rend clinical investigators less dependent on commercial sponsors and might bring more patients into clinical research.

Gemcitabine and vincristine: an effective outpatient regimen with low myelotoxicity for stage IV non-small cell lung cancer.

The activity and tolerability of gemcitabine and the non-overlapping toxicity of gemcitabine plus vincristine were the basis for testing this regimen patients with non-small cell lung cancer (NSCLC). Forty patients (25 male/15 female, median age 52 years) with stage IV NSCLC and a Karnofsky Performance Status score > or = 60 entered the trial. Patients received gemcitabine 1000 mg/m2 on days 1, 8 and 15 and vincristine 1.4 mg/m2 on days 1 and 15, every 4 weeks. The overall response rate was 16/40 (40%) (N = 40); with 2 complete and 14 partial responses; additional 14 patients had minor responses or stable disease. Median duration of remission was 4.5 months, and the median survival was 9 months. In two patients with grade 2 generalized vesicular rash and severe malaise, respectively, treatment-related toxicity led to early termination of treatment. Among patients treated for more than two months, vincristine doses were reduced/omitted for 55% of cycles because of grade 1-2 peripheral neuropathy. Myelotoxicity was frequent but rarely clinically significant. Mean platelet counts on day 1 of cycles 2,3 and 4 were significantly higher than the pre-treatment or post-treatment values. We conclude that vincristine plus gemcitabine is an an active and well tolerated regimen. Its interesting "platelet-saving" effect deserves further investigation.

Ethics of randomized clinical trials and the 'ALARA' approach.

A balanced discussion on the ethics of randomized clinical trials should not be based on a single ethical aspect such as respect for the patient's autonomy. Rather, the analysis should consider the four ethical principles--respect for autonomy, non-maleficence, beneficence, and justice--as applicable to all groups of persons concerned. We present the ethical benefits and costs of the present practice of randomized clinical trials for four groups: patients involved in clinical trials, patients not involved in trials, participating physicians and society. The ALARA (As Low As Reasonably Achievable) approach is then introduced and practical measures to achieve a positive balance between ethical benefits and costs of randomized trials are proposed.

A survey of the ethical considerations in randomised trials for lung cancer.

BACKGROUND: In order to promote a more productive debate on the ethics of randomised clinical trials (RCTs), we present a survey on the ethical aspects of published RCTs for lung cancer. METHODS: Data from 92 published reports of RCTs for lung cancer, as identified from the Cancerlit 1993-1995 database were supplemented by a questionnaire mailed to the authors of those publications. The analysis focused on respect of autonomy, non-maleficence, beneficence, and justice as the ethical principles applicable to society, patients in trials, patients not included in RCTs and physicians. ETHICAL ANALYSIS: The benefits to society include an objective evaluation of new treatments. The principle of autonomy was often violated for patients who were inadequately informed about the disease or about RCT. In some trials with prolonged recruitment, the principle of non-maleficence was not fully respected since patients continued to be randomised in spite of an obvious advantage of one of the treatments. When compared to those not included in a trial, patients in RCTs were reported to benefit from more precise standards, superior quality assurance of diagnostic and therapeutic procedures, more attention from the physician, easier appointments and easier access to hospitalisation. However, these benefits diminish patients' autonomy and lead to injustice towards patients not included in the trials. While benefits to physicians were usually modest and in proportion to their contribution, an influence upon their autonomy cannot be excluded. CONCLUSION: More attention to the aforementioned ethical caveats of RCTs should alleviate the ethical costs and might also bring more patients into future trials.

Total body irradiation with translation method.

Total body irradiation (TBI) using translation method has been applied in 20 patients prior to bone marrow transplantation (BMT). This paper describes the technique of irradiation as well as the results of in vivo dosimetry in patients undergoing TBI. According to our experience, the translation technique is comfortable for patient and provides homogeneous dose distribution over the whole body.

A case-control study of Hodgkin's disease and pregnancy.

To evaluate the role of pregnancy in the pathogenesis and clinical course of Hodgkin's disease (HD), we studied a series of 192 female patients aged 17-50 years at the time of diagnosis, and 496 healthy controls matched by residence and year of birth. Cases showed a marginally significant excess for the father having a high level of education, and more families were classified as white-collar workers than as industrial workers. No significant differences between cases and controls were found in other parameters describing the family and living conditions in childhood. Before the age when cases were diagnosed, 35.4% of cases and 34.7% of their controls were nulliparous. Among the cases, the mean age at first delivery was 22.4 years, with a total of 201 children (average: 1.05 per case) born before diagnosis; for the controls, the corresponding figures were 22.2 years and 573 children (average: 1.15). Within the first 6 months after the last delivery, HD was diagnosed in 12 of 124 parous cases (9.7%); for controls, the corresponding number is 18 out of 324 (5.6%). A marginally significant negative trend (P = 0.07) in odds ratios is seen with increasing duration of this interval. We conclude that our study could not confirm previous reports of a protective effect of pregnancy for the risk of HD. On the other hand, marked physiological changes in the period of puerperium may accelerate the expression of HD.

Informed consent in European multicentre randomised clinical trials--are patients really informed?

This study was designed to examine the standard of consent used by investigators in European randomised clinical trials (RCT). The participants of 12 multicentre RCTs published in the European Journal of Cancer in the years 1990-1992 were asked to complete a short questionnaire regarding their practice of obtaining consent in the trial reported. Anonymity was assured. Replies were received from 60 of 88 clinicians contacted. Data showed that 12% of clinicians did not inform their patients about the trial prior to randomisation. Thirty-eight per cent of clinicians did not always tell patients that they had been assigned to their treatment randomly. Only 32% of clinicians used written consent, 21% used written information without obligatory signing, 42% used verbal consent, and in 5% no consent was sought. Even when information was given, only 58% of clinicians gave full information on all aspects of the trial and 42% gave information on the proposed treatment arm only (27% revealing inclusion in an RCT). When examined by geographical origin, clinicians in northern Europe were more likely to obtain full consent than those from southern Europe. Similarly, the level of consent was higher in trials of supportive care than in trials testing curative or palliative antitumour therapies.

On the potential role of cyclosporin in the treatment of lymphoproliferative diseases.

Lymphomas and leukemias, as cancers of the immune system, may still retain some susceptibility to regulatory mechanisms which govern the proliferation of their cells of origin. According to this concept, an enhanced immune suppression as induced by irradiation and chemotherapy may contribute to their cytotoxic effect in inducing and maintaining a remission of the disease. Cyclosporin selectively and reversibly inhibits activation and proliferation of both normal and neoplastic T lymphocytes. In-vitro experiments and preliminary clinical data from small uncontrolled studies indicate that cyclosporin might be a promising agent in the treatment of mycosis fungoides, Hodgkin's disease, acute leukemia, and possibly other lymphoproliferative disorders, but the experience is still limited and no definitive conclusions may be made. In addition to its direct effect on lymphocytes, cyclosporin reverses the resistance of cancer cells to several antineoplastic agents and may thus find its place in combination with chemotherapy. It is hoped that a more systematic basic and clinical research will help define the role of this new therapeutic approach.

Hodgkin's disease as a failure of immune regulation: a re-interpretation of the epidemiological findings.

A failure of immune regulation has been often suspected as the basic condition leading to the development of Hodgkin's disease (HD), but the precise nature of this immune defects has not been defined. It is shown here that most of the epidemiological features fit the hypothesis of an increased risk for HD linked to an immune disbalance between a weak immune suppressor activity (ISA), and an enhanced polyclonal B cell activation (PBA). Few infections in childhood and an "untrained" immune system would lead to a weak ISA as the main risk factor among adolescent and young adults in the developed world, while an enhanced PBA due to chronic parasitic infections and malnutrition could explain a relatively high risk for HD among small children in undeveloped countries. The different histologic types of HD may reflect a variable contribution of a weak ISA, or an enhanced PBA under different conditions.

Hodgkin's disease: five steps from autoimmunity to cancer.

A five-step hypothesis on the pathogenesis of Hodgkin's disease (HD) is presented. Weak immune suppressor activity gives a predisposition for the development of the disease, after which a non-specific immune stimulation can initiate a self-perpetuating uncontrolled stimulation between interdigitating cells (IDCs), macrophages and helper T lymphocytes (TH). The disease spreads to other lymph nodes through the secretion of humoral factors and by migration of cells. The response of the suppressor branch of the immune system is delayed, and comes from areas not yet involved in the disease, primarily from the spleen and bone marrow. Treatment will result in the predominance of the suppressor activity and allow calming of the disease. In a terminal phase, a possible neoplastic transformation of the chronically stimulated immune cells may give rise to frequent extranodal localizations and a rapid progression of the disease.