Trastuzumab beyond progression in retrospective analyses: an issue of equal opportunities

Results of the Hermine study of trastuzumab beyond progression in breast cancer patients, published by Extra and colleagues in The Oncologist, are re-examined and an alternative explanation for the dismal postprogression survival time of patients stopping therapy is presented.We read with great interest the retrospective study published by Extra et al. [1] in The Oncologist and the accompanying editorial [2]. In particular, the analysis of patients continuing trastuzumab beyond disease progression was intriguing because of the inclusion of a control group of patients stopping trastuzumab at or just before disease progression. The authors correctly pointed out that the baseline prognostic profile of patients discontinuing trastuzumab was worse than that of patients in the continuation group. This introduced an obvious bias toward better clinical outcomes in patients continuing trastuzumab. However, we believe that the striking difference in the median survival times from the date of first progression (21.3 months versus 4.6 months) favoring patients continuing trastuzumab must have a more severe underlying bias. In a similar analysis that we published in The Oncologist in 2006, we could not find significant differences in clinical outcomes according to whether trastuzumab was continued or stopped in patients progressing during an initial trastuzumab-based regimen [3]. In particular, we observed that the median survival time from the date of first progression (henceforth, postprogression survival) for 40 patients continuing trastuzumab was 21.0 months, which is similar to that reported by Extra et al. [1]. However, 71 patients stopping trastuzumab and receiving additional anticancer therapy experienced a median postprogression survival interval of 18.7 months (Fig. 1). Notably, we identified two further groups of patients who did not continue trastuzumab beyond progression. Fourteen patients had experienced unacceptable trastuzumab-related toxicity leading to treatment discontinuation before progression. When disease progression occurred, they were not retreated with this monoclonal antibody. Another 21 patients experienced rapid progression during first-line trastuzumab-based therapy and were unable to receive additional anticancer therapy, but just supportive care. The median postprogression survival durations in the former and latter groups of patients were 7.8 months and 2.4 months, respectively (Fig. 1).Open in a separate windowFigure 1.Kaplan–Meier estimates of survival from the date of first progression in patients continuing trastuzumab beyond disease progression (black solid line), stopping trastuzumab and receiving additional anticancer therapy (black dashed line), stopping trastuzumab because of toxicity (grey solid line), and receiving only supportive care because of progression (grey dashed line).We excluded from our analysis these two groups of patients. In fact, a fair comparison of clinical outcomes to evaluate the hypothesis that continuing trastuzumab beyond progression is beneficial over no continuation requires that patients in the “control” group have “equal therapeutic opportunities” to patients in the “experimental” group. For patients experiencing prohibitive toxicity with trastuzumab or eligible for supportive care only, continuing trastuzumab beyond progression and, probably, receiving optimal anticancer treatment were not suitable therapeutic opportunities. Indeed, the clinical outcome of these patients was dismal, as described above.We noted that “stopping trastuzumab” was the only requirement described in patients in the control group of the Hermine study. We, therefore, went back to our original dataset and reanalyzed data using this same definition. All 106 patients stopping trastuzumab were compared with patients continuing trastuzumab beyond disease progression (Fig. 2). Survival from the date of first progression for patients continuing trastuzumab beyond disease progression was about 10 months longer than for those stopping trastuzumab (21.0 months versus 10.6 months; p = .03).Open in a separate windowFigure 2.Kaplan–Meier estimates of survival from the date of first progression in patients continuing trastuzumab beyond disease progression (solid line) or stopping trastuzumab (dashed line) (see text for details for the comparison group).We subsequently analyzed a comparison population including only those patients who could not receive trastuzumab because of prior toxicity or rapid disease progression (35 patients) (Fig. 3). In this case, patients stopping trastuzumab had a median postprogression survival duration of 3.7 months (p < .01), a finding that is remarkably similar to what was reported by Extra et al. [1]. We, therefore, argue that the dismal median postprogression survival time reported for the Hermine study (4.6 months) may not be a result of stopping trastuzumab. A more likely explanation is that a proportion of patients stopping trastuzumab could not go on to receive optimal anticancer therapy.Open in a separate windowFigure 3.Kaplan–Meier estimates of survival from the date of first progression in patients continuing trastuzumab beyond disease progression (solid line) or stopping trastuzumab (dashed line) (see text for details of the comparison group).Based on these considerations, it would be interesting if Extra and colleagues could reanalyze their data by distinguishing patients stopping trastuzumab according to whether or not they had “equal opportunities” to patients continuing trastuzumab beyond progression.Editor''s note: Dr. Extra was invited to reply but declined comment.     

La salute del cavo orale nel bambino in sovrappeso

Objectives

To evaluate food habits and oral care level of eleven and twelve years old students with the purpose of preventing obesity and oral diseases. The role of Dental Hygienists in the prevention of such problems was examined as well.

Materials and methods

A questionnaire was distributed to a sample of 90 secondary school students (41 males and 49 females).

Results

The answers point out that some improper food habits are particularly common, such as the excessive consumption of sweets and fizzy drinks, and the low consumption of fruit and vegetables.

Conclusions

Since not all children have a good oral care and follow a correct diet, the role of Dental Hygienists is paramount.     

Protocolli preventodontici per pazienti diabetici

Objectives

To suggest a treatment protocol for diabetic patients with periodontal disease, and to assess the effectiveness of probiotic bacteria in controlling periodontal pathogens.

Material and methods

Ten patients affected by diabetes and periodontal disease were selected. PCR real time was used for bacterial count in samples collected from periodontal pockets before and after the maintenance therapy, including the administration of probiotic bacteria.

Results

A greater reduction of the bacterial count was observed in patient taking probiotic bacteria comparing the bacterial count before and after the experimental protocol.

Conclusions

The administration of probiotic bacteria, together with the use of toothbrush, dental floss, and specific oral care products, may help to balance bacterial flora. At the end of an active therapy, an appropriate maintenance protocol allows excellent results in diabetic patients as well.     

Leptin therapy improves insulin-deficient type 1 diabetes by CNS-dependent mechanisms in mice

Leptin monotherapy reverses the deadly consequences and improves several of the metabolic imbalances caused by insulin-deficient type 1 diabetes (T1D) in rodents. However, the mechanism(s) underlying these effects is totally unknown. Here, we report that intracerebroventricular (icv) infusion of leptin reverses lethality and greatly improves hyperglycemia, hyperglucagonemia, hyperketonemia, and polyuria caused by insulin deficiency in mice. Notably, icv leptin administration leads to increased body weight while suppressing food intake, thus correcting the catabolic consequences of T1D. Also, icv leptin delivery improves expression of the metabolically relevant hypothalamic neuropeptides proopiomelanocortin, neuropeptide Y, and agouti-related peptide in T1D mice. Furthermore, this treatment normalizes phosphoenolpyruvate carboxykinase 1 contents without affecting glycogen levels in the liver. Pancreatic β-cell regeneration does not underlie these beneficial effects of leptin, because circulating insulin levels were undetectable at basal levels and following a glucose overload. Also, pancreatic preproinsulin mRNA was completely absent in these icv leptin-treated T1D mice. Furthermore, the antidiabetic effects of icv leptin administration rapidly vanished (i.e., within 48 h) after leptin treatment was interrupted. Collectively, these results unveil a key role for the brain in mediating the antidiabetic actions of leptin in the context of T1D.     

New perspective on the nutritional approach to cancer-related anorexia/cachexia: preliminary results of a randomised phase III clinical trial with five different arms of treatment

Cancer-related anorexia/cachexia syndrome (CACS) is a multifactorial syndrome characterised by tissue wasting, particularly lean body mass (LBM), metabolic alterations, fatigue, anorexia and reduced food intake. In April 2005 we started a phase III randomised study to establish the most effective and safest treatment for CACS addressing as primary endpoints: LBM, resting energy expenditure (REE), total daily physical activity, interleukin (IL)-6 and tumour necrosis factor (TNF)-α levels, and fatigue. According to the statistical design the sample size was 475 patients (95 per arm). Eligibility criteria: histologically confirmed tumours of any site; weight loss −5% in the last 3 months and/or abnormal laboratory values; life expectancy >4 months. Patients were treated with either antineoplastic therapy or supportive care. All patients received as basic oral treatment polyphenols plus alpha lipoic acid plus carbocysteine plus vitamins A, C and E. Patients were then randomised to one of the following 5 arms: (1) medroxyprogesterone acetate (MPA)/megestrol acetate (MA); (2) pharmaconutritional support containing eicosapentaenoic acid (EPA); (3) l-carnitine; (4) thalidomide; and (5) a combination of all the above agents. Treatment duration was 4 months. Interim analyses were planned after every 100 randomised patients. In September 2008, 280 patients were randomised and 240 were evaluable: M/F 167/113, mean age 62 years (range 30-84), 96% stage IV. A first interim analysis on 125 patients showed a worsening of LBM, REE and fatigue in arm 2 in comparison to the others and therefore it was withdrawn from the study. A second interim analysis after the enrolment of 204 patients showed that arm 1 was clearly significantly less effective than the others for primary efficacy endpoints, therefore it was withdrawn from the study. Statistical analysis in September 2008 showed a significant improvement of LBM (by dual X-ray energy absorptiometry), REE and fatigue in arm 5, a decrease of IL-6 in arms 3 and 5, and a decrease of TNF-α in arms 3 and 4. As for toxicity, 1 patient discontinued MPA because of deep vein thrombosis and 1 patient discontinued L-carnitine because of severe diarrhoea. In conclusion, the interim results seem to suggest that the most effective treatment for cancer patients with CACS/oxidative stress (OS) should be the combination regimen. The study is in progress.     

Mitochondria and vascular pathology

Functional and structural changes in mitochondria are caused by the opening of the mitochondrial permeability transition pore (PTP) and by the mitochondrial generation of reactive oxygen species (ROS). These two processes are linked in a vicious cycle that has been extensively documented in ischemia/reperfusion injuries of the heart, and the same processes likely contribute to vascular pathology. For instance, the opening of the PTP causes cell death in isolated endothelial and vascular smooth muscle cells. Indeed, atherosclerosis is exacerbated when mitochondrial antioxidant defenses are hampered, but a decrease in mitochondrial ROS formation reduces atherogenesis.Determining the exact location of ROS generation in mitochondria is a relevant and still unanswered question. The respiratory chain is generally believed to be a main site of ROS formation. However, several other mitochondrial components likely contribute to ROS generation. Recent reports highlight the relevance of monoamine oxidases (MAO) and p66^Shc. For example, the absence of p66^Shc in hypercholesterolemic mice has been reported to reduce the occurrence of foam cells and early atherogenic lesions. On the other hand, MAO inhibition has been shown to reduce oxidative stress in many cell types eliciting significant protection from myocardial ischemia. In conclusion, evidence will be presented to demonstrate that (i) mitochondria are major sites of ROS formation; (ii) an increase in mitochondrial ROS formation and/or a decrease in mitochondrial antioxidant defenses exacerbate atherosclerosis; and (iii) mitochondrial dysfunction is likely a relevant mechanism underlying several risk factors (i.e., diabetes, hyperlipidemia, hypertension) associated with atherosclerosis.     

Migralepsy: Is the Current Definition Too Narrow?

The relationship between epilepsy and migraine is complex and remains to be determined. We report 3 cases that address 2 questions on this topic. The first and second cases showed an association between migraine without aura and the onset of epileptic seizures. The third case report describes a patient in whom migraine with aura occurred and was followed by the development of status epilepticus, which occurred 2 or 3 hours after the attack of migraine with aura. We discuss the present definition of migralepsy and reassess its definition by suggesting possible extensions to its current definition.