Fadlo R. Khuri

A phase 1 Bayesian dose selection study of bortezomib and sunitinib in patients with refractory solid tumor malignancies

Background:This phase 1 trial utilising a Bayesian continual reassessment method evaluated bortezomib and sunitinib to determine the maximum tolerated dose (MTD), dose-limiting toxicities (DLT), and recommended doses of the combination.Methods:Patients with advanced solid organ malignancies were enrolled and received bortezomib weekly with sunitinib daily for 4 weeks, every 6 weeks. Initial doses were sunitinib 25u2009mg and bortezomib 1u2009mgu2009m−2. Cohort size and dose level estimation was performed utilising the Escalation with Overdose Control (EWOC) adaptive method. Seven dose levels were evaluated; initially, sunitinib was increased to a goal dose of 50u2009mg with fixed bortezomib, then bortezomib was increased. Efficacy assessment occurred after each cycle using RECIST criteria.Results:Thirty patients were evaluable. During sunitinib escalation, DLTs of grade 4 thrombocytopenia (14%) and neutropenia (6%) at sunitinib 50u2009mg and bortezomib 1.3u2009mgu2009m−2 were seen. Subsequent experience showed tolerability and activity for sunitinib 37.5u2009mg and bortezomib 1.9u2009mgu2009m−2. Common grade 3/4 toxicities were neutropenia, thrombocytopenia, hypertension, and diarrhoea. The recommended doses for further study are bortezomib 1.9u2009mgu2009m−2 and sunitinib 37.5u2009mg. Four partial responses were seen. Stable disease >6 months was noted in an additional six patients.Conclusion:Bortezomib and sunitinib are well tolerated and have anticancer activity, particularly in thyroid cancer. A phase 2 study of this combination in thyroid cancer patients is planned.

Comparison of Concurrent Use of Thoracic Radiation With Either Carboplatin-Paclitaxel or Cisplatin-Etoposide for Patients With Stage III Non-Small-Cell Lung Cancer: A Systematic Review

Importance The 2 most common chemotherapy regimens used concurrently with thoracic radiation for patients with unresectable IIIA and IIIB non–small-cell lung cancer (NSCLC) are carboplatin-paclitaxel and cisplatin-etoposide. There are no prospective comparisons of these 2 regimens in this setting. Objective To conduct a systematic review of published trials to compare outcomes and toxic effects between cisplatin-etoposide and carboplatin-paclitaxel in patients with non–small-cell lung cancer receiving thoracic radiation. Evidence Review Studies that enrolled patients with stage III disease receiving radiotherapy (RT) with carboplatin-paclitaxel or cisplatin-etoposide were identified using electronic databases (MEDLINE, EMBASE, and Cochrane library) and meeting abstracts. Trials were excluded if they were phase 1, enrolled less than 10 patients, or included surgical resection. A systematic analysis of extracted data was performed with software using random and fixed effect models. Clinical outcomes were compared using point estimates for weighted values of median overall survival, progression-free survival, response rate, and toxic effects. A 2-tailed t test with a significance level of .05 was used for all comparisons. Findings Overall, 3090 patients were included from 31 studies in the cisplatin-etoposide groups (median age, 61 years; 65% male; 40% squamous histology; median radiation dose, 63.0 Gy), and 3728 patients from 48 studies in carboplatin-paclitaxel groups (median age, 63 years; 65% male; 40% squamous histology; median radiation dose, 64.6 Gy). There was no significant difference in response rates between cisplatin-etoposide and carboplatin-paclitaxel (58% vs 56%; Pu2009=u2009.26), respectively. For cisplatin-etoposide vs carboplatin-paclitaxel, there was no significant difference in median progression free survival (12 months vs 9.3 months; Pu2009=u2009.20), overall survival (19.6 months vs 18.4 months; Pu2009=u2009.40), or 3-year survival rate (31% vs 25%; Pu2009=u2009.50). Cisplatin-etoposide was associated with higher grade 3 to 4 hematological toxic effects compared with carboplatin-paclitaxel (eg, neutropenia [54% vs 23%; Pu2009<u2009.001] and grade 3/4 nausea/vomiting [20% vs 11%; Pu2009=u2009.03]), while rates of grade 3 to 4 pneumonitis (12% vs 9%; Pu2009=u2009.12) and esophagitis (23% vs 21%; Pu2009=u2009.27) were similar. Conclusions and Relevance Cisplatin-etoposide and carboplatin-paclitaxel regimens were associated with comparable efficacy when used with concurrent definitive radiotherapy for patients with stage III unresectable NSCLC. The toxic effect profiles favored the carboplatin-paclitaxel regimen.

Pulmonary Sarcomatoid Carcinoma: An Analysis of the National Cancer Data Base

Micro‐Abstract Pulmonary sarcomatoid carcinoma (PSC) is a rare and aggressive form of lung cancer that has been little researched. We used the National Cancer Data Base to better understand PSC. A total of 7965 patients were identified with PSC, comprising 0.5% of all non–small‐cell lung cancer (NSCLC) cases. Patients with PSC have aggressive clinical characteristics and inferior survival outcomes relative to other subtypes of NSCLC. Introduction: Pulmonary sarcomatoid carcinoma (PSC) is a grouping of 5 rare non–small‐cell lung cancer (NSCLC) subtypes. We studied the clinical characteristics and outcomes of PSC utilizing the National Cancer Data Base (NCDB), an oncology outcomes database. Methods: The NCDB lung cancer database was queried from 1998 to 2011 for PSC using ICD‐O‐3 codes. Data were extracted for patient demographics, tumor pathology, treatment, and outcomes. Overall survival (OS) data were available for patients diagnosed from 1998 to 2006 and comorbidity data from 2003 to 2011. Univariate association with covariates between PSC and other forms of NSCLC was assessed by the chi‐square test or ANOVA, as appropriate. Results: Of the 1,547,531 NSCLC patients in the NCDB from 1998 to 2011, 7965 were identified with PSC (0.5%). PSC patients had a median age of 70 years, 59% were men, and 89% were white. At presentation, 18% had American Joint Committee on Cancer stage I disease, 10% stage II, 24% stage III, and 48% stage IV. The median OS for stage I‐II PSC was 16.9 months, 5.8 months for stage III, and 5.4 months for stage IV. There was a higher risk of death on multivariate analysis for PSC patients compared to other histologic subtypes of NSCLC in all patients (hazard ratio = 1.34 (95% confidence interval, 1.20‐1.48) P < .001) and in propensity score–matched subsets (hazard ratio = 1.34; 95% confidence interval, 1.15‐1.56; P < .001). Conclusion: PSC is a rare histologic subtype of NSCLC, accounting for 0.5% of all lung cancers. The disease of patients with PSC has aggressive clinical characteristics and an inferior survival outcome relative to other histologic subtypes of NSCLC.

On the humane side of medicine

Young physicians should slow down, enjoy the journey of discovery and wisdom that comprises a life in medicine, and never forget that the physician-patient bond is a 2-way street. The patients we care for give us their trust, and whether they are great or humble, their lives and their stories matter.

Five more years! Not everything changes

The year 2016 was certainly extraordinary. Amidst all the turmoil of US and international elections, global wars, and heart-rending refugee crises, some constancy is necessary. Donald Trump is now the president of the United States, and Fidel Castro is gone, but some things are not yet ready for change! As many of you have known for some time, I left Emory University’s Winship Cancer Institute in the summer of 2015 and have served as the president of the American University of Beirut for the last year and a half. However, although I felt that my work at Emory was largely finished, as I mentioned in my last editorial, there is much work still to do to realize our shared goals for Cancer. This is the major reason that I have decided to continue as editor-in-chief of the journal for 5 more years through the summer of 2021. By virtually all measures, we have witnessed substantial progress for our field’s flagship journal during the last 5 years. Some of this progress is easy to quantify. Our ranking in the field of oncology, as measured by the Journal Citation Reports, has now improved to 26th out of more than 210 journals, our impact factor has risen from approximately 4.7 to 5.7 during the last 5 years despite increased competition (Fig. 1), and our full-text downloads have increased dramatically over the last few years (Fig. 2). We have also adopted a more effective social media presence, which has yielded quick and impressive results, with online mentions of our articles more than doubling in the last 3 years alone (Fig. 3). Our times to first editorial decision and to online publication have declined dramatically, and this reflects that our journal is one of the most efficient, user-friendly journals in our field (Figs. 4 and 5). My first editorial of 11 so far was entitled “Why Cancer Matters.” I would argue that with our broad mission, engaged readership, and ever-improving content, Cancer matters now more than ever before as a journal even as cancer matters more than ever as a global public health menace. As we showed last year in our special issue on lung cancer in China, the scourge of tobacco-related diseases is likely to increase in the world’s most populous nations, with analogous increases highly likely in many other parts of the globe. With increased environmental carcinogens and with much of the world adopting a rapid, high-calorie, far-from-healthy diet, it is unlikely that, despite the ambitious agendas of presidents and cancer center directors, the moon shots will cure all that ails our ever-increasing population of cancer survivors.

A better angel of our nature: Hanna Michel “Jean” Khoury, MD (April 24, 1967–May 22, 2017)

Jean Khoury was a man full of passion, full of life, and resplendent with the courage to take life on in all its complexity. He was the physician’s physician, the mentor’s mentor, a wonderful father and husband, a man in full in the best sense of the phrase. He was an incredibly close friend, and always seemed to be the epitome of cool. Try explaining to yourself when you’re trying to simply color coordinate your jacket, tie, pants, and shirt, or getting through a day when you have 25 patients in a clinic, how a man with such infinite grace could glide through life and seem to never ever break a sweat, and see 50 patients in just over half the time. Except that Hanna never glided through life, and that impression frustrated him. He was smart, thoughtful, kind, athletic, patient, analytic, loving, precise, and absolutely possessed of a remarkable judgment, especially with regard to people. Here was a tremendous difference with Hanna that so few people can contemplate, much less achieve. Hanna took his time with people, and sought to extract from them their greatest qualities. He used his generosity of spirit and analytic will to turn their weaknesses into strengths, their hopes into dreams. He even sought to turn their nightmares, such as those we face with the dreaded disease that we treat and that he ultimately succumbed to after a ferocious battle, into meaningful moments of rare grace. Hanna attended the Jesuit Facult es Universitaires Notre-Dame de la Paix in Namur, Belgium, for his undergraduate degree, and the Universit e catholique de Louvain in Brussels, where he received his medical degree. He completed his residency in internal medicine at Memorial University Medical Center in Savannah, Georgia, and his fellowship in hematology-oncology as well as a bone marrow transplantation fellowship at the Washington University School of Medicine in St. Louis, Missouri. I first met Hanna in December of 2003 when he was serving on the faculty at Washington University. Ned Waller, the head of Emory University’s Section of Blood and Bone Marrow Transplantation, had come back from a visit to St. Louis absolutely convinced we had found our future Chief of Hematology. So I attended the annual American Society of Hematology meeting for the first time since my fellowship, and was quite impressed with the person I met. His track record on paper and clinical references were impressive by themselves, but what was even more startling was the quiet demeanor, the courageous but humble mien, the nuanced but decisive responses to the real challenges academic medicine faced with mentoring high-quality individuals in the physician-scientist mold without sacrificing the quality of the patient Figure 1. Hanna Michel “Jean” Khoury (April 24, 1967–May 22, 2017).

Abstract LB-348: Developing a personalized anti-metastatic therapy to treat KRAS, LKB1-mutant lung adenocarcinoma

LKB1 is the 2rd most commonly mutated tumor suppressor gene in human lung adenocarcinoma, is commonly co-mutated with KRAS, and leads to more aggressive, treatment-resistant tumors in mouse models. The identification of druggable signaling molecules that result from specific alterations in LKB1 could result in a personalized clinical strategy to target this high-risk patient population. We have previously published that LKB1 acts to limit focal adhesion kinase (FAK) activity in human lung cancer cells to restrict cell adhesion and migration. Based on our prior published data we hypothesize that FAK pathway inhibition will suppress invasion and metastasis in LKB1-mutant tumors in vivo. To investigate our hypothesis, we have designed the first rolling-enrollment pre-clinical mouse trial to target invasion and metastasis using a small-molecule FAK inhibitor. To enroll mice with early-stage lung adenocarcinoma, we developed a novel lentiviral-Cre induced KrasG12D; Lkb1fl/fl genetically engineered mouse model (GEMM) (KLLLenti) that develops 100% adenocarcinomas, expresses a luciferase reporter gene, and has elevated levels of active FAK in late stage invasive tumors. Importantly, short-term treatment of KLLLenti mice with a pharmacologic FAK inhibitor potently suppresses the invasive progression of primary tumors. Moreover, long-term treatment results in improved progression-free survival, and delays metastatic spread to the lymph nodes. We further pursue mechanistic studies to investigate how LKB1-mutant tumor tissue gains a metastatic advantage in vivo, and using a combination of 3D tumor spheroid assays, and multiphoton microscopy, present results that LKB1-mutant tumors use a unique form of hybrid invasion that relies both on cell:cell and cell-matrix adhesion, and in doing so, are equipped to more efficiently invade into the collagen-dense microenvironment of the lung. We will also present data that similar molecular and cell biologic phenotypes can be found in a subset of KRAS, LKB1-mutant human clinical samples. Our studies suggest that when used early, FAK inhibitors may be a viable clinical strategy to prevent or delay metastasis in the KRAS, LKB1-mutant patient population, and begin to define alternate escape pathways by which this highly invasive cell population may escape first-line therapy. Citation Format: Melissa Gilbert-Ross, Jessica Konen, Junghui Koo, John Shupe, Gabriel L. Sica, Zhengjia Chen, Brian S. Robinson, Madhusmita Behera, Michael R. Rossi, Geoffrey H. Smith, Charles E. Hill, Suresh M. Ramalingam, Haian Fu, Fadlo R. Khuri, Wei Zhou, Adam Marcus. Developing a personalized anti-metastatic therapy to treat KRAS, LKB1-mutant lung adenocarcinoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-348.