Combination therapy

Combination therapy proves effective in resected pancreatic cancer

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Results from one of the largest pancreatic cancer trials ever conducted may change the standard of care for patients with pancreatic cancer who have undergone surgery.

In the ESPAC-4 (European Study Group on Pancreatic Cancer-4) phase III randomized controlled trial, patients with resected pancreatic ductal adenocarcinoma achieved significant survival benefits with the addition of capecitabine to standard gemcitabine chemotherapy. Patients who received the combination regimen had an estimated 5-year survival rate of 28.8 percent vs 16.3 percent with gemcitabine alone. [ASCO 2016, abstract LBA4006]

The median overall survival was 28.0 months in the combination arm vs 25.5 months in the monotherapy arm (hazard ratio [HR], 0.82; p=0.032).

“The difference in median survival may seem modest, but the improvement in long-term survival is substantial for this cancer,” said Dr. John Neoptolemos of the University of Liverpool, UK, lead author of the trial. “We’ve gone from a 5-year survival rate of 8 percent with surgery alone to nearly 30 percent with adjuvant therapy.”

In the study, 732 patients with pancreatic cancer who had undergone surgery within 12 weeks were randomized to receive either six 4-week cycles of intravenous gemcitabine alone or gemcitabine with oral capecitabine. Patients had a median maximum tumour size of 30 mm, while 42 and 55 percent had a WHO performance status of 0 or 1, respectively. Sixty percent of patients had R1 resections, with 80 percent having node-positive disease and 40 percent having poorly-differentiated tumours.

The patient characteristics were representative of a real-world pancreatic cancer population, with a large proportion of patients having unfavorable prognostic factors. The presence of these factors, however, did not affect the survival benefit seen with the combination regimen.

Patients in the two study arms had similar rates and types of treatment-related serious adverse events (SAEs). In the combination therapy group, 154 SAEs were reported among 24 percent of patients compared with 151 SAEs among 26 percent in the monotherapy group. Rates of severe diarrhea (14 vs 5 patients) and fatigue (16 vs 14 patients) were higher with combination therapy, but patients’ quality of life remained comparable between the two arms.

These findings establish the safety and efficacy of the gemcitabine/capecitabine combination regimen and suggest a potential change in the standard of care for resected pancreatic patients. Currently, gemcitabine is the standard adjuvant treatment for patients with surgically resected pancreatic cancer based on positive results from the ESPAC-1 and ESPAC-3 trials.

Given the improvement in survival with no increased toxicity, the results of ESPAC-4 also suggest an opportunity to add additional treatments to the combination regimen to further improve outcomes.

“Unfortunately, most patients are not candidates for surgery when they are diagnosed with pancreatic cancer,” noted Neoptolemos. “These findings are significant because they show that patients who can undergo surgery have a fighting chance of surviving with the combination of two commonly used chemotherapies.”

Combination Lyxumia, insulin therapy reduces HbA1c in adults with diabetes after pancreatectomy

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Adults who underwent partial pancreatectomy and went on to develop type 2 diabetes experienced improved blood glucose and weight loss with combination therapy of insulin and Lyxumia, according to research in the Journal of Diabetes Investigation.

Toru Kitazawa, MD, of the Tokyo Metropolitan Cancer and Infectious Diseases Center at Komagome Hospital, Japan, and colleagues analyzed data from 10 adults with type 2 diabetes who had undergone a partial pancreatectomy (eight men; mean age, 70.2 years; mean BMI, 20.53 kg/m²). Within the cohort, eight patients had pancreatic cancer; two patients had a duodenal tumor. The average time from pancreatectomy to starting lixisenatide/insulin therapy was 470.3 days.

All patients were monitored at the hospital, where insulin doses were adjusted at baseline to achieve target fasting plasma glucose levels between 100 mg/dL and 130 mg/dL; Lyxumia (lixisenatide, Sanofi) was added once target levels were achieved and continued for 12 weeks. Insulin was administered at bedtime.

Researchers measured plasma glucose levels and C-peptide immunoreactivity before breakfast, 1 hour after breakfast and 2 hours after breakfast; HbA1c and body weight were measured at baseline and 12 weeks. Patients also underwent a CT scan to measure visceral and subcutaneous fat.

After 12 weeks of combination therapy, average HbA1c levels decreased from 8.46% at baseline to 6.81%, with eight of 10 patients achieving an HbA1c of less than 7% (P < .001). One-hour and 2-hour postprandial glucose also significantly decreased from 222.9 mg/dL and 247.5 mg/dL at baseline to 125.1 mg/dL and 115.1 mg/dL, respectively. Patients also lost an average of 4.1 kg after 12 weeks of combination therapy. There were no recorded incidents of hypoglycemia or other relevant adverse events, according to researchers.

“Although this was a single-arm study with a small study population, it is suggested that combination therapy with basal insulin and short-acting [glucagon-like peptide-1] receptor agonists can be a useful therapeutic option to achieve good glucose control for patients who develop diabetes after partial pancreatectomy,” the researcher wrote. “More patients need to be selected and evaluated on a long-term basis. – by Regina Schaffer

Are inhaled longacting β2 agonists detrimental to asthma?

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Possible adverse effects of adrenergic bronchodilators in asthma have been the subject of discussion for more than half a century, with recent intense debate about the safety of longacting β agonists (LABAs). In this Debate, we consider the issues of bronchodilator and bronchoprotective tolerance resulting from the frequent use of bronchodilators, which is noted particularly with shortacting drugs, but has also been shown to occur quicker and to a greater extent with LABAs. Increased allergen responsiveness and masking allowing inflammation to increase, while symptoms and lung function remain apparently controlled, have also been observed. Studies in which LABAs were used as monotherapy were associated with increased mortality. However, several studies have shown the benefits of adding LABAs to inhaled corticosteroids (ICS). Meta-analyses of asthma clinical trials involving LABAs showed that, when given with mandatory ICS, LABAs were not associated with an increased risk of death, intubations, or hospital admission for exacerbations when compared with use of the same dose of ICS only. Withdrawal of LABA therapy once symptom control is achieved is often associated with subsequent loss of symptom control. When used for appropriate indications, LABAs should be combined with ICS in one inhaler so that monotherapy is not possible.

Source: lancet

 

Combined Teriparatide and Denosumab Is More Effective Than Either Drug Alone.

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Bone-mineral density was increased significantly by combination therapy in postmenopausal women with high fracture risk.

 

Bisphosphonate therapy, the first-line treatment for patients with osteoporosis, usually doesn’t restore normal bone-mineral density (BMD) and sometimes is not well-tolerated. Teriparatide (Forteo; a parathyroid hormone analog that stimulates bone formation when injected daily) and denosumab (Prolia; a long-acting injectable agent that inhibits bone resorption) are approved for treating patients with osteoporosis and high fracture risk. Combinations of bisphosphonates with teriparatide have proven to be no more effective than either agent alone, but the combination of teriparatide and denosumab has not been studied.

In a partially industry-funded study, investigators randomized 100 postmenopausal women at high risk for fracture to receive teriparatide (20 µg subcutaneously daily), denosumab (60 mg subcutaneously every 6 months), or both for 1 year. At 12 months, BMD increased significantly more in the combination group than in the monotherapy groups at the lumbar spine (9.1% vs. 6.2% and 5.2%, respectively) and at the hip. Serious adverse events in all three groups were deemed to be unrelated to study treatments.

Comment: Although only indirect comparisons can be made, combination teriparatide and denosumab seems to increase BMD more than other approved therapies do. However, this combination would need to substantially improve clinical outcomes — not just surrogate markers — to justify its very high cost (about US$9000 annually, compared with $100 annually for alendronate). Although BMD is a reliable predictor of fractures, in future studies, researchers will need to assess directly the effects of combination teriparatide and denosumab on fractures and its long-term safety.

 

Source: Journal Watch General Medicine

 

 

Oral Antibiotics for Fever in Low-Risk Neutropenic Patients With Cancer: A Double-Blind, Randomized, Multicenter Trial Comparing Single Daily Moxifloxacin With Twice Daily Ciprofloxacin Plus Amoxicillin/Clavulanic Acid Combination Therapy—EORTC Infectious Diseases Group Trial XV.

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Abstract

Purpose This double-blind, multicenter trial compared the efficacy and safety of a single daily oral dose of moxifloxacin with oral combination therapy in low-risk febrile neutropenic patients with cancer.

Patients and Methods Inclusion criteria were cancer, febrile neutropenia, low risk of complications as predicted by a Multinational Association for Supportive Care in Cancer (MASCC) score > 20, ability to swallow, and ≤ one single intravenous dose of empiric antibiotic therapy before study drug treatment initiation. Early discharge was encouraged when a set of predefined criteria was met. Patients received either moxifloxacin (400 mg once daily) monotherapy or oral ciprofloxacin (750 mg twice daily) plus amoxicillin/clavulanic acid (1,000 mg twice daily). The trial was designed to show equivalence of the two drug regimens in terms of therapy success, defined as defervescence and improvement in clinical status during study drug treatment (< 10% difference).

Results Among the 333 patients evaluated in an intention-to-treat analysis, therapy success was observed in 80% of the patients administered moxifloxacin and in 82% of the patients administered combination therapy (95% CI for the difference, −10% to 8%, consistent with equivalence). Minor differences in tolerability, safety, and reasons for failure were observed. More than 50% of the patients in the two arms were discharged on protocol therapy, with 5% readmissions among those in either arm. Survival was similar (99%) in both arms.

Conclusion Monotherapy with once daily oral moxifloxacin is efficacious and safe in low-risk febrile neutropenic patients identified with the help of the MASCC scoring system, discharged early, and observed as outpatients.

 

Source: JCO

Zonisamide: A Good Option for Newly Diagnosed Epilepsy?

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A large practical monotherapy trial for the treatment of new-onset epilepsy in adults shows once-daily zonisamide to be generally as effective and safe as controlled-release, twice-daily carbamazepine.

Few new antiepileptic drugs (AEDs) are studied for efficacy as monotherapy, and most such studies involve medically intractable epilepsy. Therefore, despite numerous new-generation AEDs, little guidance is available for choice in newly diagnosed epilepsy patients. Now, researchers have designed a manufacturer-funded, randomized, double-blind, international trial to test the noninferiority of zonisamide (ZNS) to carbamazepine (CBZ) in adults with newly diagnosed epilepsy. The 583 patients enrolled had only generalized tonic–clonic seizures and no evidence of idiopathic generalized epilepsy, new-onset epilepsy (with at least two seizures in the previous year and at least one seizure in the preceding 3 months), and no prior treatment with an AED for >2 weeks. The study was powered such that it met strict noninferiority criteria. The primary endpoint was the proportion of patients achieving 6-month seizure freedom. Secondary endpoints were the proportion achieving 12-month seizure freedom and times to 6- and 12-month seizure freedom. Safety and tolerability were examined by measuring the incidence of treatment-related adverse events, withdrawal, and laboratory abnormalities.

Of the 456 patients who completed the protocol, 79% and 68% taking ZNS achieved 6-month and 12-month seizure freedom, compared with 84% and 75% taking CBZ — fulfilling the strict noninferiority criteria. Intention-to-treat results supported the results of the per-protocol analysis. The times to both 6- and 12-month endpoints were the same in both arms. Few patients in either group withdrew because of treatment-related adverse events — primarily rash, dizziness, fatigue, and memory impairment. Two cases of severe rash occurred in the CBZ arm. One case of mild purpura occurred in the ZNS arm. None of the other eight reported severe adverse events had a clear association with treatment. No clinically significant laboratory abnormalities occurred in either arm.

Comment: This remarkable clinical trial addresses an important clinical question: Whether a newer-generation AED may be used as first-line monotherapy in newly diagnosed epilepsy. Moreover, the trial was designed to reflect typical clinical practice, given the population involved and the use of flexible dosing regimens for a meaningful treatment duration. Both treatment arms were well balanced, including frequency of seizures pretreatment, a strong predictor of prognosis. Because ZNS has few drug interactions and is formulated for once-daily dosing, the finding that ZNS is generally as effective as CBZ may actually change clinical practice.

Source: Journal Watch Neurology