Marinus A. Paul

Stereotactic ablative radiotherapy versus lobectomy for operable stage I non-small-cell lung cancer: a pooled analysis of two randomised trials

BACKGROUND The standard of care for operable, stage I, non-small-cell lung cancer (NSCLC) is lobectomy with mediastinal lymph node dissection or sampling. Stereotactic ablative radiotherapy (SABR) for inoperable stage I NSCLC has shown promising results, but two independent, randomised, phase 3 trials of SABR in patients with operable stage I NSCLC (STARS and ROSEL) closed early due to slow accrual. We aimed to assess overall survival for SABR versus surgery by pooling data from these trials. METHODS Eligible patients in the STARS and ROSEL studies were those with clinical T1-2a (<4 cm), N0M0, operable NSCLC. Patients were randomly assigned in a 1:1 ratio to SABR or lobectomy with mediastinal lymph node dissection or sampling. We did a pooled analysis in the intention-to-treat population using overall survival as the primary endpoint. Both trials are registered with ClinicalTrials.gov (STARS: NCT00840749; ROSEL: NCT00687986). FINDINGS 58 patients were enrolled and randomly assigned (31 to SABR and 27 to surgery). Median follow-up was 40·2 months (IQR 23·0-47·3) for the SABR group and 35·4 months (18·9-40·7) for the surgery group. Six patients in the surgery group died compared with one patient in the SABR group. Estimated overall survival at 3 years was 95% (95% CI 85-100) in the SABR group compared with 79% (64-97) in the surgery group (hazard ratio [HR] 0·14 [95% CI 0·017-1·190], log-rank p=0·037). Recurrence-free survival at 3 years was 86% (95% CI 74-100) in the SABR group and 80% (65-97) in the surgery group (HR 0·69 [95% CI 0·21-2·29], log-rank p=0·54). In the surgery group, one patient had regional nodal recurrence and two had distant metastases; in the SABR group, one patient had local recurrence, four had regional nodal recurrence, and one had distant metastases. Three (10%) patients in the SABR group had grade 3 treatment-related adverse events (three [10%] chest wall pain, two [6%] dyspnoea or cough, and one [3%] fatigue and rib fracture). No patients given SABR had grade 4 events or treatment-related death. In the surgery group, one (4%) patient died of surgical complications and 12 (44%) patients had grade 3-4 treatment-related adverse events. Grade 3 events occurring in more than one patient in the surgery group were dyspnoea (four [15%] patients), chest pain (four [15%] patients), and lung infections (two [7%]). INTERPRETATION SABR could be an option for treating operable stage I NSCLC. Because of the small patient sample size and short follow-up, additional randomised studies comparing SABR with surgery in operable patients are warranted. FUNDING Accuray Inc, Netherlands Organisation for Health Research and Development, NCI Cancer Center Support, NCI Clinical and Translational Science Award.

Survival in Early Breast Cancer Patients Is Favorably Influenced by a Natural Humoral Immune Response to Polymorphic Epithelial Mucin

PURPOSE Polymorphic epithelial mucin (PEM or MUC1) is being studied as a vaccine substrate for the immunotherapy of patients with adenocarcinoma. The present study analyzes the incidence of naturally occurring MUC1 antibodies in early breast cancer patients and relates the presence of these antibodies in pretreatment serum to outcome of disease. MATERIALS AND METHODS We measured immunoglobulin G (IgG) and immunoglobulin M (IgM) antibodies to MUC1 with an enzyme-linked immunoassay (PEM.CIg), which uses a MUC1 triple-tandem repeat peptide conjugated to bovine serum albumin, in pretreatment serum samples obtained from 154 breast cancer patients (52 with stage I disease and 102 with stage II) and 302 controls. The median disease-specific survival time of breast cancer patients was 74 months (range, 15 to 118 months). A positive test result was defined as MUC1 IgG or IgM antibody levels equal to or greater than the corresponding rounded-up median results obtained in the total breast cancer population. RESULTS A positive test result for both MUC1 IgG and IgM antibodies in pretreatment serum was associated with a significant benefit in disease-specific survival in stage I and II (P =.0116) breast cancer patients. Positive IgG and IgM MUC1 antibody levels had significant additional prognostic value to stage (P =.0437) in multivariate analysis. Disease-free survival probability did not differ significantly. However, stage II patients who tested positive for MUC1 IgG and IgM antibody and who relapsed had predominantly local recurrences or contralateral disease, as opposed to recurrences at distant sites in the patients with a negative humoral response (P =.026). CONCLUSION Early breast cancer patients with a natural humoral response to MUC1 have a higher probability of freedom from distant failure and a better disease-specific survival. MUC1 antibodies may control hematogenic tumor dissemination and outgrowth by aiding the destruction of circulating or seeded MUC1-expressing tumor cells. Vaccination of breast cancer patients with MUC1-derived (glyco)peptides in an adjuvant setting may favorably influence the outcome of disease.

Traditional Versus Up-Front [18F] Fluorodeoxyglucose–Positron Emission Tomography Staging of Non–Small-Cell Lung Cancer: A Dutch Cooperative Randomized Study

PURPOSE We investigated whether application of positron emission tomography (PET) immediately after first presentation might simplify staging while maintaining accuracy, as compared with traditional strategy in routine clinical setting. METHODS At first presentation, patients with a provisional diagnosis of lung cancer without overt dissemination were randomly assigned to traditional work-up (TWU) according to international guidelines or early PET followed by histologic/cytologic verification of lesions, or imaging and follow-up. Patients with [18F] fluorodeoxyglucose (18FDG) -avid, noncentral tumors without suspicion of mediastinal or distant metastases on PET proceeded directly to thoracotomy. Follow-up in presumed benign lesions was at least 12 months. In patients treated with surgery or neoadjuvant therapy, the quality of staging was measured by comparing the clinical stage to the final stage (combination of peroperative staging and 6 months of follow-up). To investigate test substitution, we analyzed the number of (non)invasive tests to achieve clinical TNM staging, and its associated costs. RESULTS Between 1999 and 2001, 465 patients (233 TWU, 232 PET) were enrolled at 22 hospitals. The mean (standard deviation) number of procedures to finalize staging was equal in the TWU arm and the PET arm: 7.9 (2.0) v 7.9 (1.9), P = .90, respectively. Mediastinoscopies occurred significantly less often in the PET arm. Agreement between clinical and final stage was good in both arms (kappa = .85 v .78; P = .07). Costs did not differ significantly. CONCLUSION Up-front 18FDG-PET in patients with (suspected) lung cancer does not reduce the overall number of diagnostic test, but it maintains quality of TNM staging with the use of less invasive surgery.

Oral Nutritional Supplements Containing (n-3) Polyunsaturated Fatty Acids Affect the Nutritional Status of Patients with Stage III Non-Small Cell Lung Cancer during Multimodality Treatment

Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), (n-3) fatty acids from fish oil, have immune-modulating effects and may improve nutritional status in cancer. The objective of this study was to investigate the effects of an oral nutritional supplement containing (n-3) fatty acids on nutritional status and inflammatory markers in patients with non-small cell lung cancer (NSCLC) undergoing multimodality treatment. In a double-blind experiment, 40 patients with stage III NSCLC were randomly assigned to receive 2 cans/d of a protein- and energy-dense oral nutritional supplement containing (n-3) fatty acids (2.0 g EPA + 0.9 g DHA/d) or an isocaloric control supplement. EPA in plasma phospholipids, energy intake, resting energy expenditure (REE), body weight, fat free mass (FFM), mid-upper arm circumference (MUAC), and inflammatory markers were assessed. Effects of intervention were analyzed by generalized estimating equations and expressed as regression coefficients (B). The intervention group (I) had a better weight maintenance than the control (C) group after 2 and 4 wk (B = 1.3 and 1.7 kg, respectively; P < 0.05), a better FFM maintenance after 3 and 5 wk (B = 1.5 and 1.9 kg, respectively; P < 0.05), a reduced REE (B = -16.7% of predicted; P = 0.01) after 3 wk, and a trend for a greater MUAC (B = 9.1; P = 0.06) and lower interleukin-6 production (B = -27.9; P = 0.08) after 5 wk. After 4 wk, the I group had a higher energy and protein intake than the C group (B = 2456 kJ/24 h, P = 0.03 and B = 25.0 g, P = 0.01, respectively). In conclusion, a protein- and energy-dense oral nutritional supplement containing (n-3) fatty acids beneficially affects nutritional status during multimodality treatment in patients with NSCLC.

Immunoparalysis as a cause for invasive aspergillosis

Aspergillus infections are among the most feared opportunistic infections in humans. These organisms are ubiquitous in nature; protection against infection is usually provided by anatomical barriers and by the immune system. Tissue invasion by Aspergillus is uncommon, occurring primarily in the setting of immunosuppression. The prognosis of invasive aspergillosis is very poor. Although it is widely recognised that critically ill patients in the Intensive Care Unit (ICU) are at risk for nosocomial infections, it is not generally appreciated that such patients may also be at risk for opportunistic infections usually seen only in immunocompromised patients. This might be explained by a biphasic immunological pattern during sepsis: an early hyperinflammatory phase followed by an anti-inflammatory response, leading to a hypo-inflammatory state, the so-called compensatory anti-inflammatory response syndrome (CARS or immunoparalysis). We describe four patients admitted to our ICU for various reasons, without a history of abnormal immune function, who developed invasive pulmonary aspergillosis. We hypothesise that the occurrence of these opportunistic infections in our patients may have been due to immunoparalysis, and that perhaps all ICU patients with sepsis and multiple organ dysfunction syndrome (MODS) may be at risk for opportunistic infections such as aspergillosis as a result of this syndrome. Physicians treating critically ill patients in the ICU should be aware of the CARS/immunoparalysis syndrome and its potential to cause opportunistic infections, even in patients with normal immune function prior to ICU admission.

Incidence of T790M mutation in (sequential) rebiopsies in EGFR-mutated NSCLC-patients

AIM Non-small cell lung cancer (NSCLC)-patients with an epidermal growth factor receptor (EGFR)-mutation have median progression-free survival (PFS) of 12 months on tyrosine kinase inhibitors (TKIs). Resistance is mediated by the EGFR T790M-mutation in the majority of patients. Longitudinal follow-up data are lacking. We retrospectively evaluated EGFR-mutated NSCLC-patients who were rebiopsied after TKI-treatment. A subgroup was sequentially rebiopsied along the course of the disease. PATIENTS AND METHODS Advanced EGFR-mutated NSCLC-patients who had both a pre-TKI biopsy and post-TKI biopsy available were included. Information on treatments and (re)biopsies was collected chronologically. Primary endpoint was the incidence of the T790M-mutation. RESULTS Sixty-six patients fulfilled the inclusion criteria. In first post-TKI biopsies, T790M-mutation was detected in 34 patients (52%) of patients. Twenty-seven patients had subsequent post-TKI rebiopsies with mutation analysis available; in 10 patients (37%) the T790M-status in subsequent post-TKI rebiopsies was not consistent with the T790M-status of the first post-TKI biopsy. Progression free survival (PFS) on TKI-treatment was 12.0 months. Objective response rate on TKI-treatment was 81%. Patients developing T790M-mutation at post-TKI biopsy had longer median PFS compared to T790M-negative patients (14.2 versus 11.1 months respectively (P=0.034)) and longer overall survival (45.9 months versus 29.8 months respectively (P=0.213)). Transformation to SCLC was detected in 1 patient (2%). CONCLUSION Incidence of T790M-mutation at first post-TKI biopsy in this cohort of EGFR-mutated NSCLC-patients was 52%. Detection of T790M-mutation was not consistent over time; some patients who were T790M-positive at first post-TKI biopsy became T790M-negative in later post-TKI rebiopsies and vice versa. T790M-positive patients showed longer PFS than T790M-negative patients. Whether the low incidence of transformation to SCLC is justifying post-TKI rebiopsy in EGFR-mutated NSCLC-patients with acquired TKI-resistance in regular clinical practice is debatable.

Oral nutritional supplements containing n-3 polyunsaturated fatty acids affect quality of life and functional status in lung cancer patients during multimodality treatment: an RCT

Background/Objectives:Our objective was to investigate effects of an oral nutritional supplement containing n-3 polyunsaturated fatty acids (FAs) on quality of life, performance status, handgrip strength and physical activity in patients with non-small cell lung cancer (NSCLC) undergoing multimodality treatment.Subjects/Methods:In a double-blind experiment, 40 patients with stage III NSCLC were randomised to receive 2 cans/day of a protein- and energy-dense oral nutritional supplement containing n-3 polyunsaturated FAs (2.02 g eicosapentaenoic acid+0.92 g docosahexaenoic acid/day) or an isocaloric control supplement, during multimodality treatment. Quality of life, Karnofsky Performance Status, handgrip strength and physical activity (by wearing an accelerometer) were assessed. Effects of intervention were analysed by generalised estimating equations. P-values <0.05 were regarded as statistically significant.Results:The intervention group reported significantly higher on the quality of life parameters, physical and cognitive function (B=11.6 and B=20.7, P<0.01), global health status (B=12.2, P=0.04) and social function (B=22.1, P=0.04) than the control group after 5 weeks. The intervention group showed a higher Karnofsky Performance Status (B=5.3, P=0.04) than the control group after 3 weeks. Handgrip strength did not significantly differ between groups over time. The intervention group tended to have a higher physical activity than the control group after 3 and 5 weeks (B=6.6, P=0.04 and B=2.5, P=0.05).Conclusion:n-3 Polyunsaturated FAs may beneficially affect quality of life, performance status and physical activity in patients with NSCLC undergoing multimodality treatment.

An Enzyme-Linked Immunosorbent Assay for the Measurement of Circulating Antibodies to Polymorphic Epithelial Mucin (MUC1)

Introduction: About one-third of breast and ovarian carcinoma patients have circulating antibodies reactive with polymorphic epithelial mucin (MUC1), either free or bound to immune complexes. While the presence of these immune complexes has prognostic significance in breast cancer patients, the significance of free MUC1 antibodies is less clear. The objective of this study was to develop a reliable assay for the accurate determination of circulating free antibodies to MUC1. Material and Methods: We developed an enzyme-linked immunosorbent assay (ELISA) (PEM.CIg) employing a 60 mer peptide (a triple tandem repeat sequence of the MUC1 peptide core) conjugated to bovine serum albumin and peroxidase-labeled antihuman immunoglobulin G or M antibodies. The assay was standardized and its analytical performance evaluated. A total of 492 serum samples were obtained from 40 healthy men, from 201 healthy women (including 55 women without a history of pregnancy and 45 pregnant women), and (before primary treatment) from 62 benign breast tumor patients and 190 breast cancer patients. MUC1 serum levels were determined with commercial CA 15-3 tests. Results: Circulating antibodies to MUC1 are present both in healthy subjects and in breast cancer patients. The within- and between-assay coefficients of variation were, respectively, 2 and 12% for the IgG determinations and 1.2 and 3% for the IgM determinations. Correlation coefficients for serially diluted serum samples ranged from 0.9998 to 0.9920 for IgG and from 0.9996 to 0.9818 for IgM determinations. The reactivity of serum samples was partially blocked by the addition of various MUC1 peptides and by MUC1 mucin. The inhibiting effect of modified 60 mer peptides suggests the presence of antibodies directed to more than one epitope. Conclusions: The PEM. CIg assay is a reliable ELISA for measuring free MUC1 antibodies in serum. We are in the process of relating the results obtained in the breast cancer group to disease outcome to evaluate its prognostic significance. In addition, the assay may become a useful tool for vaccine therapy monitoring.

Diaphragm Muscle Fiber Weakness and Ubiquitin–Proteasome Activation in Critically Ill Patients

RATIONALE The clinical significance of diaphragm weakness in critically ill patients is evident: it prolongs ventilator dependency, and increases morbidity and duration of hospital stay. To date, the nature of diaphragm weakness and its underlying pathophysiologic mechanisms are poorly understood. OBJECTIVES We hypothesized that diaphragm muscle fibers of mechanically ventilated critically ill patients display atrophy and contractile weakness, and that the ubiquitin-proteasome pathway is activated in the diaphragm. METHODS We obtained diaphragm muscle biopsies from 22 critically ill patients who received mechanical ventilation before surgery and compared these with biopsies obtained from patients during thoracic surgery for resection of a suspected early lung malignancy (control subjects). In a proof-of-concept study in a muscle-specific ring finger protein-1 (MuRF-1) knockout mouse model, we evaluated the role of the ubiquitin-proteasome pathway in the development of contractile weakness during mechanical ventilation. MEASUREMENTS AND MAIN RESULTS Both slow- and fast-twitch diaphragm muscle fibers of critically ill patients had approximately 25% smaller cross-sectional area, and had contractile force reduced by half or more. Markers of the ubiquitin-proteasome pathway were significantly up-regulated in the diaphragm of critically ill patients. Finally, MuRF-1 knockout mice were protected against the development of diaphragm contractile weakness during mechanical ventilation. CONCLUSIONS These findings show that diaphragm muscle fibers of critically ill patients display atrophy and severe contractile weakness, and in the diaphragm of critically ill patients the ubiquitin-proteasome pathway is activated. This study provides rationale for the development of treatment strategies that target the contractility of diaphragm fibers to facilitate weaning.

Critical Review of Nonsurgical Treatment Options for Stage I Non-Small Cell Lung Cancer

Surgery has traditionally been regarded as the treatment of choice for patients with stage I non-small cell lung cancer. However, the morbidity and mortality associated with surgery in elderly patients with considerable comorbidity remains of concern, as are the poor 5-year survival rates. Until recently, conventional radiation therapy was the only alternative curative treatment option for patients who were unfit for surgery, but with lower local control rates that were inferior to those with surgery. However, a growing body of clinical data on outcomes with newer nonsurgical treatment options such as stereotactic radiation therapy (SRT) and radiofrequency ablation (RFA) is now available. SRT is a noninvasive method showing a 2-year local control rate in excess of 85% in both T1 and T2 tumors after three to eight fractions of high-precision radiotherapy. Despite the use of very high radiation doses, high-grade toxicity is limited to approximately 5% of patients. Percutaneous RFA is an invasive method showing 2-year local control rates of approximately 64% in smaller tumors, but results are poorer in lesions > or =3 cm. Compared with SRT, a higher procedure-related morbidity and mortality rate has been reported, mainly caused by pneumothorax and hemorrhage. Although data from randomized trials of conventional radiotherapy versus SRT or RFA are not available, the use of SRT is becoming widespread for patients who are unfit for surgery. Reported 2-year local control rates after SRT are comparable with those achieved with surgery, and prospective randomized trials comparing surgery with SRT in patients who are fit to undergo surgery are now being planned.