Showing papers by "Bishal Gyawali published in 2017"

Economics of Cancer Medicines: For Whose Benefit?

Abstract: Although new cancer drugs are continually getting approved and used, the value that these drugs add is very debatable Because of the skyrocketing cost of the new drugs, each new approval represents a multibillion market However, unlike other branches of economics, cancer drugs are intricately associated with socio-political issues, emotional overlay, public pressure, industry manipulation and propaganda In this article, we review the value added by new cancer drugs and examine the socio-political agenda around them with highlights on the increasing gulf between high-income and low-middle income countries regarding the affordability to these drugs Finally, we also suggest a way forward to address this highly complex issue

Ischemic Stroke and Impact of Thyroid Profile at Presentation: A Systematic Review and Meta-analysis of Observational Studies.

Abstract: Background Stroke is the fifth leading cause of mortality in the United States and a leading cause of disability. A complex relationship between thyroid hormone levels and severity of, and outcome after, stroke has been described. Aim Our objective is to identify the association between baseline thyroid function profile and outcome after acute ischemic stroke. Methods Studies looking at the association between thyroid function and functional stroke outcomes were identified from available electronic databases from inception to December 16, 2016. Study-specific risk ratios were extracted and combined with a random effects model meta-analysis. Results In the analysis of 12 studies with 5218 patients, we found that subclinical hypothyroidism was associated with better modified Rankin scale scores at 1 and 3 months (odds ratio [OR] 2.58, 95% confidence interval [CI] 1.13-5.91, P = .03 and OR 2.28, 95% CI 1.13-3.91, P = .003, respectively) compared with the euthyroid cases. Likewise, patients with higher initial thyrotropin-releasing hormone (TSH) and fT3 or T3 levels had favorable outcomes at discharge (mean differences of TSH .12 [95% CI .03-.22, P = .009] and of fT3 .36 (CI .20-.53, P P = .03] and of T3 8.60 [CI 4.58-12.61, P Conclusions Elevated initial TSH (clinical or subclinical hypothyroidism) may correspond to better functional outcomes, whereas low initial T3/fT3 might correlate with worse outcomes in acute ischemic stroke among clinically euthyroid patients. This complex relation merits further well-designed investigations. Whether correcting thyroid profile with hormone supplementation or antagonism may lead to improved outcomes will require large, prospective, interventional studies.

Drugs that lack single-agent activity: are they worth pursuing in combination?

Abstract: Over the past decade, many anticancer drugs have been approved for use only in combination regimens and only in palliative settings, despite having negligible single-agent activity in the same disease. We examine whether these agents provide any tangible clinical benefits and are worthy of continued development, or whether R&D efforts would be better focused elsewhere.

Low-value practices in oncology contributing to financial toxicity.

Abstract: Financial toxicity of cancer treatment is now a well-recognised problem in cancer medicine leading to patient bankruptcy and even poor survival, including in high-income countries and countries with public health care systems. Many oncologists, despite acknowledging the severity of financial toxicity as a problem, resign the responsibility of reducing the costs of cancer treatment to the government, industry, and oncology societies. However, an oncologist can play an important role in reducing the costs of cancer treatment because all cancer treatment decisions are made between the oncologist and the patient. In this article, I point out a few examples of low value practices from various oncology disciplines that we oncologists can easily replace or abandon in our practice and contribute to lessening the financial toxicities to patients and society. As these examples suggest, reducing cost does not necessarily mean compromising efficacy. We should continuously keep looking for other similar cost-saving strategies in our practice.

Bevacizumab in Advanced Cervical Cancer: Issues and Challenges for Low- and Middle-Income Countries

Abstract: Bevacizumab became the first molecular antibody to show survival benefit in advanced cervical cancer. In the GOG-0240 (Paclitaxel and Cisplatin or Topotecan With or Without Bevacizumab in Treating Patients With Stage IVB, Recurrent, or Persistent Cervical Cancer) trial, it improved overall survival by a significant 3.7 months over platinum doublet chemotherapy alone. However, this discovery is not likely to improve the status of global cervical cancer because more than 85% of patients with cervical cancer live in low- and middle-income countries and cannot afford bevacizumab. This commentary looks at the options by which this drug can be made more affordable and cost-effective for patients in low- and middle-income countries. We also discuss other important questions related to its affordability and cost issues such as the optimal number of cycles and personalizing the treatment. Finally, we emphasize that although the unaffordability of bevacizumab in cervical cancer seems to be a very important issue, the best cost-effective strategy against cervical cancer is prevention with screening and vaccination.

Health policy: Me-too drugs with limited benefits — the tale of regorafenib for HCC

Abstract: Regorafenib is only the second agent approved by the FDA for the treatment of patients with advanced-stage hepatocellular carcinoma. Herein, we discuss the evidence that led to the approval of this agent. Examination of this process reveals important challenges associated with drug regulation, relating to trial design, treatment toxicity, and real-world clinical benefit.

Combining drugs and extending treatment - a PFS end point is not sufficient.

Abstract: In studies investigating the combination of two or more anticancer drugs that are already approved for independent use, or 'maintenance' regimens, the use of progression-free survival as the end point for approval is inadequate; sequential treatment with the same agents or existing salvage therapies, respectively, might provide an equivalent survival benefit, with lower toxicity, cost, and treatment burden, therefore, the use of an overall survival end point is essential to justify such interventions

Me-too drugs with limited benefits — the tale of regorafenib for HCC

Abstract: Regorafenib is only the second agent approved by the FDA for the treatment of patients with advanced-stage hepatocellular carcinoma. Herein, we discuss the evidence that led to the approval of this agent. Examination of this process reveals important challenges associated with drug regulation, relating to trial design, treatment toxicity, and real-world clinical benefit.

Point: The Imprecise Pursuit of Precision Medicine: Are Biomarkers to Blame?

Abstract: Precision medicine is the concept of tailoring treatment to individual patients based on the presence or absence of certain objectively measurable parameters known as biomarkers. These biological markers can be predictive (ie, tell whether a given drug will work) or prognostic (ie, tell how better or worse the cancer outcomes will be regardless of treatment) or both. Precision medicine (ie, personalized therapy or tailored treatment) has gained enormous popularity because it aims to improve the benefit/risk profile of cancer treatment. Providing the drug only to patients who are likely to benefit and avoiding the drug in those who are not is certainly an attractive concept. In reality, however, we don’t seem to be achieving as much tangible result from this approach as promised. Experts have openly questioned the value of precision medicine—and rightly so, because the only randomized controlled trial (RCT) of precision medicine to date has provided negative results.1,2 Why has such an attractive approach failed to improve outcomes? This is a logical question to ask. Although it may well be that the concept of precision medicine is fallacious, it would be prudent to first look at biomarkers, because if there are errors in measurement of a biomarker or questions about its validity, the whole framework of precision medicine crumbles. Precision medicine is impossible without precision in the measurement and validation of biomarkers. However, accurate measurement of biomarkers is not easy. There are many potential avenues for errors. The case history of excision repair cross-complement group 1 protein (ERCC1) as a biomarker for platinum therapy in non–small cell lung cancer (NSCLC) illustrates these problems very well. ERCC1 has been touted as a predictive biomarker for platinum therapy in NSCLC for many years, and is now even available commercially, but no evidence supports or refutes this claim. A recent study mapped all the research activities concerning ERCC1 over the past 12 years.3 During this period, 28 studies of ERCC1 as a predictive biomarker for platinum therapy in NSCLC were reported. Of these, only 2 were prospective studies. Putting all the studies over 12 years together using what the authors called the “Accumulating Evidence and Research Organization” (AERO) model helped recognize major flaws in the ERCC1 research: most studies were poorly designed, the studies used different methods to measure ERCC1 levels, the cutoff points used were different across studies, the chemotherapy regimens were not uniform, and there has been little replication or validation of techniques. Thus, despite considerable investment in terms of time, money, human power, and logistics for this research over 12 years, we are unable to derive any conclusions. In this context, the ERCC1 Trial was an important study; it was the first prospective phase III study assessing both the predictive and prognostic utility of ERCC1 for squamous and nonsquamous NSCLC.4 This study found no utility of ERCC1 as a predictive or prognostic marker for platinum therapy in NSCLC. Although at first look the results suggest that this properly conducted phase III RCT settled the question of whether ERCC1 is a predictive marker of benefit from platinum therapy in NSCLC, a problem remains: this study measured ERCC1 levels using 8F1 assay. However, the accuracy of 8F1 assay in measuring ERCC1 levels has been questioned. Experiments have shown that ERCC1 is not the principal antigen recognized by the 8F1 antibody and that 8F1 does not discriminate between ERCC1-positive and Bishal Gyawali, MD

Human Trafficking in Nepal: Post-Earthquake Risk and Response.

Abstract: As Nepal mourns the 1-year commemoration of the April 2015 earthquake and its aftershocks that killed more than 8500 people and left thousands injured and displaced, other more hidden repercussions of the resultant chaotic environment need attention: the increased risk of human trafficking. Considering that natural disasters provide a milieu for this illicit trade, there is a need for a robust response from stakeholders such as donors, civil society organizations, and government organizations against human trafficking following disasters such as the Nepal earthquake. Responsibility to prevent and fight trafficking should be explicitly included in the mandate of relief and rehabilitation mechanisms set up at the national level to coordinate the disaster relief response, serving to support populations in both rural and urban areas. (Disaster Med Public Health Preparedness. 2017;11:153-154).

The OlympiAD trial: who won the gold?

Abstract: OlympiAD was a phase 3 randomized controlled trial of a PARP inhibitor olaparib for metastatic HER2 negative breast cancer patients harboring a BRCA mutation. Although the OlympiAD trial met its primary endpoint, there are concerns regarding whether olaparib truly improves meaningful outcomes for these patients. In this editorial, I examine these issues in detail. An exploration of these issues will provide important educational insights for oncologists and cancer policy makers. I conclude that although olaparib seems to have won the Gold with OlympiAD, the patients probably have not. We need to stop celebrating a gold-plated bronze as a true gold so that one day our patients can finally get the gold they deserve.

Biosimilars in oncology: everybody agrees but nobody uses?

Abstract: Reducing the cost of biologics is an important avenue for addressing financial toxicity in oncology, one of the biggest challenges for health systems. The use of biosimilars, the cheaper alternatives to biologics, is an important strategy to that end. But the enthusiasm of developing biosimilars is meaningless if they get to the market, but they’re not prescribed by the physicians, concerned by unexpected side effects or inferior efficacy. A recent study found no differences between biosimilars and erythropoietin stimulating agents originators in the composite outcome including all-cause mortality, blood transfusion and major cardiovascular events. Such studies are important to allay the concerns of physicians and patients regarding the use of biosimilars. Physician and patient education, backed by clinical guidelines and patient advocacy groups, are the keys to improving the uptake of biosimilars in clinical practice.

Outcomes of haploidentical transplant compared with matched donor allogeneic stem cell transplant.

Abstract: The risk of acute and chronic graft-versus-host disease (GVHD) with haploidentical transplant with post-transplant high-dose cyclophosphamide may be lower compared with matched unrelated donor transplant and largely similar to matched related donor transplant. The lower probability of GVHD with the haploidentical donor may result in a risk of nonrelapse mortality that is at least similar to or even lower than the matched donor. The incidence of relapse and survival are also largely similar to different donor types. Haploidentical transplant may be associated with slower engraftment. Given a lower risk of GVHD, haploidentical transplant has gained popularity. Additionally, the use of post-transplant high-dose cyclophosphamide has been extended to lower the risk of GVHD with matched donor and mismatched unrelated donor transplant.

Unconvincing Benefit of Combination Therapy With Gefitinib and Pemetrexed in Advanced Non-Small-Cell Lung Cancer.

Abstract: TO THE EDITOR: In a recent issue of Journal of Clinical Oncology, the study by Cheng et al was interesting because it showed that first-line therapy with pemetrexed plus gefitinib significantly improved progression-free survival (PFS) compared with gefitinib alone in patients with epidermal growth factor receptor (EGFR) –mutation positive advanced nonsquamous non–small-cell lung cancer. The Kaplan-Meier curves for PFS overlapped during the first 7 to 8 months and subsequently started to diverge. The coinciding curves at the beginning showed that the addition of pemetrexed did not provide any synergistic or additive benefit. The subsequent divergence at later time points implies that the beneficial effect on PFS was attributed solely to pemetrexed. The similar high response rates in both arms are comparable to those obtained in a previous study of EGFR-mutation–positive advanced-stage non–small-cell lung cancer treated with singleagent EGFR tyrosine kinase inhibitor therapy, suggesting that gefitinib in the study by Cheng et al had extremely dominant activity, irrespective of the combination with pemetrexed. Hence, we believe it is not the combination per se that provided the PFS gains. The antitumor effects seen in the combination arm after the divergence of the curves could simply reflect the effect of pemetrexed alone. Given that the combination is associated with a substantial increase in toxicity and that the development of drug resistance to EGFR tyrosine kinase inhibitors is nearly unavoidable after several months, we believe that the difference in PFS in this study suggests that sequential treatment with pemetrexed after the development of resistance to gefitinib is more effective than concurrent treatment with gefitinib plus pemetrexed. It would be interesting to have access to the overall survival data from this study because most patients in the gefitinib monotherapy group who had disease progression probably received second-line chemotherapy (as most likely did those in the pemetrexed plus gefitinib group). Access to the overall survival data would allow us to determine whether there was a difference in overall survival between the treatment groups.

FDA Approval Summary: Sonidegib-Letter.

Abstract: We read with interest the FDA approval summary for sonidegib, an inhibitor of the Hedgehog signaling pathway and smoothened receptors, for patients with locally advanced basal cell carcinoma ([1][1]). On the basis of the results from the randomized BOLT trial ([2][2]), sonidegib was approved by the

Rushing will not help to choose the best combination

Abstract: We read with great interest and welcome the publication of the CheckMate 012 trial in The Lancet Oncology, in which the authors assessed the safety and efficacy of nivolumab plus ipilimumab as firstline therapy for metastatic non-smallcell lung cancer (NSCLC). Initial cohorts that assessed the combination of nivolumab (1 or 3 mg/kg) plus ipilimumab (1 or 3 mg/kg) given every 3 weeks followed by nivolumab 3 mg/kg every 2 weeks were characterised by poor tolerability with 51% (25/49) patients having grade 3–4 treatment-related adverse events. Four additional regimens evaluated lower doses of both agents or less frequent dosing. Only two of them were fully presented in the paper because they were the two cohorts considered for clinical development: nivolumab 3 mg/kg every 2 weeks plus ipilimumab 1 mg/kg given either every 12 weeks or every 6 weeks. Grade 3–4 treatment-related toxicity occurred in 37% patients in the every-12-weeks cohort and in 33% in the every 6-weeks-cohort. Confirmed objective responses (all partial responses) were achieved by 47% patients in the every 12-weeks cohort and 38% in the every-6-weeks cohort (all partial responses). These two schedules seem to be active even in patients with low expression of programmed death ligand 1 (PD-L1) and in patients carrying an EGFR activating mutation. Notably, the results of the other two regimens (nivolumab 1 mg/kg plus ipilimumab 1 mg/kg every 3 weeks, followed by nivolumab 3 mg/kg every 2 weeks vs nivolumab 1 mg/kg every 2 weeks plus ipilimumab 1 mg/ kg every 6 weeks) were presented in the appendix (grade 3–4 treatmentrelated toxicities 29% vs 40%; objective response rate 19% vs 33%). Overall, the trial results certainly confirm the fact that increasing the dose or frequency of ipilimumab negatively affects the safety of the combination without necessarily increasing the response rate. However, we find it difficult to under stand why the combination of nivolumab 3 mg/kg every 2 weeks plus ipilimumab 1 mg/kg every 6 weeks was chosen as the regimen for further development in the ongoing phase 3 Checkmate 012 trial. Use of a 12-week ipilimumab dosing schedule, in view of the results, would have seemed more logical to us. The primary issue for us with the study design of the CheckMate 012 trial is the potential for confounding because it is a cohort study. Because patients are not randomly assigned to treatment groups, some patient characteristics might not be evenly distributed between the two groups. For example, the number of patients who were EGFR mutation positive and amount of PD-L1 expressed was not balanced across groups. Confounding occurs when these characteristics are linked to the outcomes of interest. In our opinion, it is strongly debatable to move from a phase 1 cohort straight into a phase 3 randomised trial, especially since the method of selecting the better regimen in this trial seems rather controversial. We are fully convinced that the combination of anti-PDL1 plus antiCTLA4 inhibition could represent an advance in the treatment of NSCLC, but we are concerned that not fit for purpose trial designs and the lack of phase 2 trial could jeopardise the possibilities to show clinical benefit in phase 3 trials.