Research Spotlight

Posted April 15th 2017

Long-term Duration of First-Line Axitinib Treatment in Advanced Renal Cell Carcinoma.

Thomas Hutson D.O.

Thomas Hutson D.O.

Rini, B. I., V. Gruenwald, E. Jonasch, M. N. Fishman, Y. Tomita, M. D. Michaelson, J. Tarazi, L. Cisar, S. Hariharan, A. H. Bair, B. Rosbrook and T. E. Hutson (2017). “Long-term Duration of First-Line Axitinib Treatment in Advanced Renal Cell Carcinoma.” Target Oncol: 2017 Mar [Epub ahead of print].

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OBJECTIVE: We conducted a retrospective analysis of two clinical trials in treatment-naive patients (n = 402) with advanced renal cell carcinoma (RCC) treated with axitinib. Our objective was to compare duration of treatment (DT) and clinical outcome in patients who achieved DT >18 months (longer DT) versus /=10% tumor shrinkage at first scan (74.8% vs. 55.3%; p = 0.0001) and maximum on-study tumor shrinkage was greater in longer-DT versus shorter-DT group (-51.8% vs. -22.1%; p < 0.0001). Median OS was 32.6 months in the overall population while in the patients with longer DT the median was not reached. Treatment-related adverse events (AEs) grade >/=3 were more frequent in longer-DT versus shorter-DT and included hypertension (25.7% vs. 18.8%), diarrhea (15.1% vs. 4.4%), and weight decrease (11.2% vs. 3.2%); however, these AEs decreased over time in both groups. Eastern Cooperative Oncology Group performance status 0, favorable hematology values, no bone or liver metastases, and baseline tumor burden below the overall median were associated with longer DT. CONCLUSIONS: Longer duration (>18 months) of axitinib treatment was associated with increased frequency of early tumor shrinkage, greater magnitude of tumor shrinkage, and a favorable OS.


Posted April 15th 2017

Cervical sagittal deformity develops after PJK in adult thoracolumbar deformity correction: radiographic analysis utilizing a novel global sagittal angular parameter, the CTPA.

Richard Hostin M.D.

Richard Hostin M.D.

Protopsaltis, T., N. Bronsard, A. Soroceanu, J. K. Henry, R. Lafage, J. Smith, E. Klineberg, G. Mundis, H. J. Kim, R. Hostin, R. Hart, C. Shaffrey, S. Bess and C. Ames (2017). “Cervical sagittal deformity develops after PJK in adult thoracolumbar deformity correction: radiographic analysis utilizing a novel global sagittal angular parameter, the CTPA.” Eur Spine J 26(4): 1111-1120.

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PURPOSE: To describe reciprocal changes in cervical alignment after adult spinal deformity (ASD) correction and subsequent development of proximal junctional kyphosis (PJK). This study also investigated these changes using two novel global sagittal angular parameters, cervical-thoracic pelvic angle (CTPA) and the T1 pelvic angle (TPA). METHODS: Multicenter, retrospective consecutive case series of ASD patients undergoing thoracolumbar three-column osteotomy (3CO) with fusion to the pelvis. Radiographs were analyzed at baseline and 1 year post-operatively. Patients were substratified into upper thoracic (UT; UIV T6 and above) and lower thoracic (LT; UIV below T6). PJK was defined by >10 degrees angle between UIV and UIV + 2 and >10 degrees change in the angle from baseline to post-op. RESULTS: PJK developed in 29 % (78 of 267) of patients. CTPA was linearly correlated with cervical plumbline (CPL) as a measure of cervical sagittal alignment (R = 0.826, p < 0.001). PJK patients had significantly greater post-operative CTPA and SVA than patients without PJK (NPJK) (p = 0.042; p = 0.021). For UT (n = 141) but not LT (n = 136), PJK patients at 1 year had larger CTPA (4.9 degrees vs. 3.7 degrees, p = 0.015) and CPL (5.1 vs. 3.8 cm, p = 0.022) than NPJK patients, despite similar corrections in PT and PI-LL. CONCLUSIONS: The prevalence of PJK was 29 % at 1 year follow-up. CTPA, which correlates with CPL as a global analog of cervical sagittal balance, and TPA describe relative proportions of cervical and thoracolumbar deformities. Patients who develop PJK in the upper thoracic spine after thoracolumbar 3CO also develop concomitant cervical sagittal deformity, with increases in CPL and CTPA.


Posted April 15th 2017

High- versus low-dose leucovorin in the modified FOLFOX6 regimen for first-line treatment of metastatic colorectal cancer.

Jana Reynolds M.D.

Jana Reynolds M.D.

Reynolds, J., A. Chamberland-Tremblay, J. D. Herrington, Y. Munoz Maldonado and L. Wong (2017). “High- versus low-dose leucovorin in the modified FOLFOX6 regimen for first-line treatment of metastatic colorectal cancer.” J Oncol Pharm Pract 23(3): 173-178.

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Background In response to the national leucovorin shortage in 2008, our institution adjusted the modified FOLFOX6 (leucovorin, fluorouracil, and oxaliplatin) protocol to utilize a lower dose of leucovorin (20 mg/m2). This adjustment was based on prospective studies suggesting that lower doses of leucovorin may be equally effective in other fluorouracil containing regimens. This retrospective study evaluates outcomes in metastatic colorectal cancer (mCRC) patients treated with low- (20 mg/m2) vs. high-dose (400 mg/m2) leucovorin in the FOLFOX6 regimen for mCRC. Methods This retrospective analysis included consecutive mCRC patients from 2004 to 2011 if they received at least one cycle of modified FOLFOX6 as first line therapy. Patients who received an initial leucovorin dose other than 20 mg/m2 or 400 mg/m2 on their first cycle were excluded. Patient characteristics included demographics, metastatic site at initial diagnosis, and treatment history including chemotherapy and surgery. Primary outcome was date of death or last contact. Cox proportional hazards regression analysis and Kaplan-Meier survival curves were utilized to evaluate the effect of leucovorin dose on overall survival. Log-rank tests were used to compare median survival times by dose group. Results Of the 93 mCRC patients who received first line modified FOLFOX6, leucovorin 400 mg/m2 was administered to 47 (51%) patients and 20 mg/m2 to 46 (49%) patients. There were no differences of baseline characteristics between the groups with exception of primary site of cancer ( p = 0.038). The overall survival time was 22.5 months (95% CI 16.6-29.6). The median survival time in the leucovorin 400 mg/m2 group was 23.1 months (95% CI 16.2-35.7) compared to leucovorin 20 mg/m2 which was 20.5 months (95% CI 14.2-34.2); p = 0.573. The median survival times in patients with one versus two or more sites with metastasis were statistically different (26.9 vs. 16.2 months, p = 0.009). Metastatic site removal or ablation showed differences in the median survival, 34.2 months (95% CI 20.8-50.9) vs. 16.6 months (95% CI 14.1-23.6) without metastatic disease removal ( p = 0.004). The odds of dying for patients with two metastatic sites was higher compared with the odds of those patients with one site, HR 1.8 (95% CI 1.08-3.0). Patients without metastatic site removal or ablation had higher odds of dying compared to those patients without this procedure, HR 0.47 (95% CI 0.27-0.81). Conclusion In this single center retrospective study, there was no difference in overall survival for mCRC patients treated with first line FOLFOX6 with low- vs. high-dose leucovorin.


Posted April 15th 2017

HBV Reactivation During DAA Treatment of Chronic Hepatitis C: A Hidden Danger of an Otherwise Major Success Story.

Robert P. Perrillo M.D.

Robert P. Perrillo M.D.

Perrillo, R. P. (2017). “HBV Reactivation During DAA Treatment of Chronic Hepatitis C: A Hidden Danger of an Otherwise Major Success Story.” Hepatology: 2017 Mar [Epub ahead of print].

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It has been estimated that 250 million and 170 million people worldwide are infected with hepatitis B virus (HBV) and hepatitis C virus (HCV), respectively. Co-infection is relatively common in regions where both viruses are endemic and transmission is facilitated by common routes of exposure. In a recent study of 1287 New York City residents with hepatitis C, most of whom were born in United States, 62% had resolved HBV infection and 6% were HBsAg positive. Dual infection with HBV and HCV leads to accelerated liver disease and a higher risk for cirrhosis and hepatocellular carcinoma. Treatment of coinfected patients is controversial, but it is a common practice to treat the virus that genomic testing reveals to be dominant. The intracellular interactions of the two viruses are unclear. Cross sectional studies have shown that co-infected individuals often have high levels of HCV RNA, low or non-detectable HBV DNA, anti-HBe reactivity, and lower levels of HBsAg when compared to HBV mono infection. Thus, HCV is most often the primary target of antiviral therapy. However, longitudinal studies have demonstrated that the levels of HBV DNA and HCV RNA may fluctuate with time suggesting that competitive interactions between the two viruses is more dynamic than previously thought.


Posted April 15th 2017

Effect of everolimus on the pharmacokinetics of octreotide long-acting repeatable in patients with advanced neuroendocrine tumors: An analysis of the randomized phase III RADIANT-2 trial.

Carlos Becerra M.D.

Carlos Becerra M.D.

Pavel, M. E., C. Becerra, K. Grosch, W. Cheung, J. Hasskarl and J. C. Yao (2017). “Effect of everolimus on the pharmacokinetics of octreotide long-acting repeatable in patients with advanced neuroendocrine tumors: An analysis of the randomized phase III RADIANT-2 trial.” Clin Pharmacol Ther 101(4): 462-468.

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In the RADIANT-2 trial, addition of everolimus to octreotide long-acting repeatable (LAR) exhibited a clinically meaningful 5.1-month improvement in progression-free survival (PFS) in patients with advanced functional neuroendocrine tumors. In this study, we characterized the effects of everolimus co-administration on octreotide LAR pharmacokinetics and its relationship with efficacy and safety. At least one evaluable blood everolimus and plasma octreotide predose minimum concentration (Cmin ) was available for 182 patients and 294 patients, respectively. Concomitant everolimus administration increased octreotide Cmin with a geometric mean ratio (everolimus/placebo) of 1.47 (90% confidence interval [CI] = 1.32-1.64). Risk for progression was consistently reduced when everolimus Cmin was increased twofold, regardless of octreotide exposure (hazard ratio [HR] = 0.74; 95% CI = 0.46-1.18; HR = 0.54; 95% CI = 0.32-0.92 for 6 ng/mL and 4 ng/mL octreotide, respectively). Risk for pulmonary or metabolic events was associated with increased everolimus Cmin . Co-administration of everolimus plus octreotide LAR increased octreotide Cmin , which did not impact efficacy.