Bishal Gyawali

Low skeletal muscle density is associated with poor survival in patients who receive chemotherapy for metastatic gastric cancer

Low skeletal muscle density (SMD) and low skeletal muscle index (SMI) are associated with poor overall survival (OS) in patients with various types of cancer. We retrospectively studied SMD and SMI using computed tomographic (CT) scans in patients with gastric cancer receiving chemotherapy to evaluate its prognostic significance. SMD and SMI were obtained from CT-based analysis using Slice-O-Matic® medical imaging software in patients who received S-1 plus cisplatin chemotherapy for metastatic gastric cancer. The CT images taken within 1 month before starting chemotherapy were used. The cut-off values for determining low SMD [<33 Hounsfield units (HU) in obese and <41 HU in non-obese patients] and low SMI (<41 cm2/m2 in females, <43 cm2/m2 in non-obese males and <53 cm2/m2 in obese males) were referenced from a large population based study. The CT images of 53 patients were reviewed. The median SMD was 36.8 HU (range, 19.5-59.3 HU), and the median SMI was 39.8 cm2/m2 (range, 23.7-60.0 cm2/m2). Patients with low SMD had significantly shorter OS compared with patients having normal SMD (8.9 vs. 12.8 months, P=0.03). However, OS did not differ significantly between patients with low and normal SMI (11.1 and 14.3 months, P=0.18). Multivariate analyses confirmed that low SMD was an independent predictor of poor outcomes (P<0.01). SMD is an important prognosticator of survival in patients with metastatic gastric cancer receiving chemotherapy.

Autologous Transplantation for Newly Diagnosed Multiple Myeloma in the Era of Novel Agent Induction: A Systematic Review and Meta-analysis

Importance The role of high-dose therapy with melphalan followed by autologous stem cell transplant (HDT/ASCT) in patients with multiple myeloma continues to be debated in the context of novel agent induction. Objective To perform a systematic review, conventional meta-analysis, and network meta-analysis of all phase 3 randomized clinical trials (RCTs) evaluating the role of HDT/ASCT. Data Sources We performed a systematic literature search of Cochrane Central, MEDLINE, and Scopus from January 2000 through April 2017 and relevant annual meeting abstracts from January 2014 to December 2016. The following search terms were used: “myeloma” combined with “autologous,” “transplant,” “myeloablative,” or “stem cell.” Study Selection Phase 3 RCTs comparing HDT/ASCT with standard-dose therapy (SDT) using novel agents were assessed. Studies comparing single HDT/ASCT with bortezomib, lenalidomide, and dexamethasone consolidation and tandem transplantation were included for network meta-analysis. Data Extraction And Synthesis For the random effects meta-analysis, we used hazard ratios (HRs) and corresponding 95% CIs. Main Outcomes and Measures The primary outcome was progression-free survival (PFS). Overall survival (OS), complete response, and treatment-related mortality were secondary outcomes. Results A total of 4 RCTs (2421 patients) for conventional meta-analysis and 5 RCTs (3171 patients) for network meta-analysis were selected. The combined odds for complete response were 1.27 (95% CI, 0.97-1.65; P = .07) with HDT/ASCT when compared with SDT. The combined HR for PFS was 0.55 (95% CI, 0.41-0.74; P < .001) and 0.76 for OS (95% CI, 0.42-1.36; P = .20) in favor of HDT. Meta-regression showed that longer follow-up was associated with superior PFS (HR/mo, 0.98; 95% CI, 0.96-0.99; P = .03) and OS (HR/mo, 0.90; 95% CI, 0.84-0.96; P = .002). For PFS, tandem HDT/ASCT had the most favorable HR (0.49; 95% CI, 0.37-0.65) followed by single HDT/ASCT with bortezomib, lenalidomide, and dexamethasone (HR, 0.53; 95% CI, 0.37-0.76) and single HDT/ASCT alone (HR, 0.68; 95% CI, 0.53-0.87) compared with SDT. For OS, none of the HDT/ASCT-based approaches had a significant effect on survival. Treatment-related mortality with HDT/ASCT was minimal (<1%). Conclusions and Relevance The results of the conventional meta-analysis and network meta-analysis of all the phase 3 RCTs showed that HDT/ASCT was associated with superior PFS with minimal toxic effects compared with SDT. Both tandem HDT/ASCT and single HDT/ASCT with bortezomib, lenalidomide, and dexamethasone were superior to single HDT/ASCT alone and SDT for PFS, but OS was similar across the 4 approaches. Longer follow-up may better delineate any OS benefit; however, is likely to be affected by effective postrelapse therapy.

Opioid-induced constipation.

Abstract Opioid-induced constipation (OIC) is a very troublesome, difficult to manage and a nearly universal complication of chronic opioid use to control pain associated with advanced illness. Some studies have reported that OIC is so intolerable in some patients that they skip their opioid medications and bear pain instead of OIC. Laxatives have commonly been used as a prophylaxis and treatment of OIC but they are frequently ineffective because the commonly available laxatives do not target the underlying mechanism of OIC, which is the blockade of peripheral mu-receptors. Recently, there have been a number of advances in the treatment of OIC, which any physician involved with opioid-prescribing discipline should be aware of. This review will update the new options and strategies available for treating OIC along with the relevant clinical trials. Finally, this review also provides a recommendation on the preferred way to approach a patient with OIC in the modern era as well as highlight on the importance of doctor–patient communication in this setting.

Chemotherapy in locally advanced head and neck squamous cell carcinoma

Chemotherapy, in combination with a local treatment, has a role in nearly all the settings of locally advanced head and neck squamous cell carcinoma (LAHNSCC) treatment: as definitive, adjuvant or induction therapy. However, despite many years of trials, controversies still exist regarding the best approach to using chemotherapy in the multi-modal treatment of LAHNSCC. Opinions are divided on sequential versus concurrent use of chemotherapy and radiotherapy for unresectable LAHNSCC. More debate exists on whether the addition of induction chemotherapy to concomitant chemoradiotherapy is clinically meaningful. After the approval of cetuximab in combination with radiotherapy for this disease, making treatment choices have become further complicated. Although new data from trials are arriving every year, the results have been inconclusive. In this review, we provide the readers with the latest information on various strategies of using chemotherapy and cetuximab that will help to make an evidence-based decision in the treatment of LAHNSCC, including the approach to larynx preservation. We conclude that with the available information, concurrent chemoradiotherapy should be preferred over induction chemotherapy, except in the setting of larynx preservation. Furthermore, given the paucity of positive data and severe financial toxicity associated with cetuximab, concurrent chemoradiotherapy should be the preferred choice over cetuximab-radiotherapy. Future trials in head and neck cancer should be properly planned to address these controversies and provide clear solutions.

Duration of adjuvant trastuzumab in HER2 positive breast cancer: Overall and disease free survival results from meta-analyses of randomized controlled trials

BACKGROUND One year of trastuzumab, chosen empirically, improves survival of women with early-stage, HER2-positive breast cancer but also adds substantially to cost, toxicity, and inconvenience. Longer treatment does not improve outcomes, but potentiates toxicities. METHODS Medline, Embase, and major conference proceedings were searched systematically in June 2017 to identify Randomized Controlled Trials (RCTs) comparing one year versus shorter durations of trastuzumab in adjuvant treatment of breast cancer. Reported Hazard-Ratios (HR) for Overall Survival (OS) and Disease-Free Survival (DFS), and Odds-Ratio for cardiac events, with respective 95% Confidence Intervals (CI) from each study was weighted using generic inverse-variance, and pooled in a meta-analysis. Inter-study heterogeneity and sub-group difference (based on hormone-receptors and node-positivity) were assessed using I2, and chi2 statistics, respectively. RESULTS Four studies (n=7614) satisfied inclusion criteria. Individual RCTs had diverse pre-specified upper-limits of 95% CI for declaring non-inferiority (range: <1.15 to <1.53). Pooled results demonstrated significant improvements in OS (HR 1.28, p=0.04), and DFS (HR 1.24, p=0.005) with 1year of trastuzumab compared to shorter durations. Absence of multiplicity argument allowed for declaring superiority of 1year of trastuzumab based on our results despite non-inferiority designs of individual trials. No influence on overall effect by duration of trastuzumab in experimental arm (9weeks versus 6months) was noted. No statistical interaction by hormone-receptor status and node-positivity on overall results was noticed [p(sub-group difference) 0.73, and 0.52, respectively]. Odds-Ratio for cardiac events was 2.65 (p<0.001) favoring shorter duration. CONCLUSION One year of trastuzumab prolongs overall, and disease-free survivals in women with early-stage HER2 positive breast cancer compared to shorter durations and this should remain as the standard of care. Cardiotoxicity increased significantly with the 1-year treatment.

Economics of Cancer Medicines: For Whose Benefit?

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.

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

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.

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

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

Same Data; Different Interpretations

Interpretation of oncology clinical trial data are not always straightforward or consistent. Similar trial results with disparate interventions may be interpreted differently by the oncology community. One of the main reasons for this discrepancy is the debate regarding what is the appropriate end point for demonstration of efficacy of cancer drugs. There is no doubt that overall survival (OS) is the best parameter to judge the utility of any intervention, and it is free from bias in ascertainment and measurement; but for conditions with few treatment options and dire outcomes, the need for new agents is high and the oncology community sometimes settles on a surrogate end point that, in many cases, is progression-free survival (PFS). It is easy to understand why PFS is favored among the researchers: It occurs early and is not influenced by postprogression therapy. At the same time, it would make little sense to have an agent that reduces chances of dying of cancer but increases off-target deaths; hence, the need for verification of OS. Phase III trials that report on significant PFS benefits without OS prolongation become the apples of discord in the oncology community. In this commentary, we present three examples from lung, ovarian, and breast cancers and demonstrate how the oncology community interprets similar data differently. Finally, we take our best guess as to why this phenomenon happens.

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

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.