Comparison of response evaluation criteria in solid tumors with volumetric measurements for estimation of tumor burden in pancreatic adenocarcinoma and hepatocellular carcinoma.

BACKGROUND: Response evaluation criteria in solid tumors (RECIST) is the accepted method for determining tumor progression. However, RECIST may not estimate disease burden accurately because the axial plane often does not produce the actual longest diameter. Volumetric measurements may be an alternative to better determine tumor size. Our aim was to compare volumetric measurements with RECIST in pancreatic ductal adenocarcinomas (PDA) and hepatocellular carcinomas (HCC). METHODS: RECIST and volumetric measurements were determined in 9 patients with metastatic PDA and 17 patients with HCC who subsequently underwent liver transplantation. Gross pathologic measurements after hepatectomy also were analyzed for volumes. RESULTS: Three-dimensional diameter in volumetric analysis was 38% and 36% higher than RECIST diameter in PDA and HCC, respectively (P \u3c .01). However, RECIST yielded 78% and 23% larger estimated tumor volumes than volumetric analysis in PDA and HCC, respectively (P \u3c .01). Gross pathologic volume in HCC showed a linear correlation with both volumetric analysis (r = .95; P \u3c .01) and RECIST (r = .96; P \u3c .01) but RECIST significantly overestimated gross pathologic volume by an average of 28% (P \u3c .01) whereas volumetric analysis was similar to gross pathologic volume (P = .56). In categorizing treatment response in PDA, RECIST and volumetric analysis were in moderate agreement (κ = .49). CONCLUSIONS: RECIST significantly may overestimate tumor burden compared with volumetric measurements in both PDA and HCC. Volumetric analysis may be the preferred method to detect tumor progression

Signaling pathways in adenoid cystic cancers: implications for treatment.

Adenoid cystic cancers (ACC) in the head and neck are rare yet present a clinical dilemma. Although 5-y survivals are excellent, they have a propensity for late recurrences. Most of these cancers are initially treated with surgery followed by radiation. When recurrences happen, treatment options are limited both by the morbidity and low efficacy of re-irradiation and repeated surgical resection. Reported response rates to chemotherapy are low and targeted therapies may be one option. We, therefore, investigated signaling pathways that may be active in adenoid cystic cancers. Tissues from the last nine ACC patients resected at the University of Iowa were immunohistochemically stained with antibodies for EGFR, phosphorylated (P) Akt, and P-MAPK in order to molecularly characterize these tumors. An ACC cell line (ACC3) was also characterized by western blot. We found that seven of the nine tumor samples had strong expression of P-Akt and 5/9 had P-MAPK. None of them had EGFR expression. In the ACC3 cell line, similar data was found in that there was P-Akt and P-MAPK but no EGFR expression. We tested the HIV protease inhibitor nelfinavir (NFV) which has been shown to inhibit Akt signaling to see its effect on ACC3 cells. Both P-Akt and P-MAPK were inhibited with NFV in ACC3 cells and this resulted in growth inhibition and clonogenic death. In patients where re-irradiation or further surgery is not an option, a trial of NFV may be warranted

Accrual Patterns for Clinical Studies Involving Quantitative Imaging: Results of an NCI Quantitative Imaging Network (QIN) Survey.

Patient accrual is essential for the success of oncology clinical trials. Recruitment for trials involving the development of quantitative imaging biomarkers may face different challenges than treatment trials. This study surveyed investigators and study personnel for evaluating accrual performance and perceived barriers to accrual and for soliciting solutions to these accrual challenges that are specific to quantitative imaging-based trials. Responses for 25 prospective studies were received from 12 sites. The median percent annual accrual attained was 94.5% (range, 3%-350%). The most commonly selected barrier to recruitment (n = 11/25, 44%) was that patients decline participation, followed by too few eligible patients (n = 10/25, 40%). In a forced choice for the single greatest recruitment challenge, too few eligible patients was the most common response (n = 8/25, 32%). Quantitative analysis and qualitative responses suggested that interactions among institutional, physician, and patient factors contributed to accrual success and challenges. Multidisciplinary collaboration in trial design and execution is essential to accrual success, with attention paid to ensuring and communicating potential trial benefits to enrolled and future patients

Once Daily High-dose Radiation (≥60 Gy) Treatment in Limited Stage Small Cell Lung Cancer.

BACKGROUND: To investigate outcomes and prognostic factors in patients treated with once daily high-dose (≥60 Gy) radiation therapy (HDRT) and concurrent platinum-based chemotherapy in limited stage small cell lung cancer (LS-SCLC). While we await current phase III trials to determine optimal radiation dose fractionation schemes in LS-SCLC, we report our experience in LS-SCLC with once daily HDRT. We hypothesized that HDRT would achieve similar efficacy and tolerability as twice daily therapy. METHODS: We conducted a single institution retrospective review of all patients with LS-SCLC who underwent curative intent treatment from 2005-2013. Patients treated with HDRT (≥60 Gy) and concurrent chemotherapy (cisplatin or carboplatin and etoposide) were included in our analysis. Clinicopathologic variables assessed include gender, performance status, time to treatment, response to treatment, toxicity, volumetric tumor response at 3 months, and use of prophylactic cranial irradiation (PCI). RESULTS: 42 patients with LS-SCLC who initiated concurrent chemoradiation from 2005 to 2013 were included in the analysis. 38 patients (90%) completed definitive treatment to the lung; 16 (38%) also completed PCI. Median failure free survival (FFS) and overall survival (OS) were 11.9 and 23.1 months, respectively. Two-year and 5-year OS rates were 47% (CI=30-62%) and 21% (CI=7-38%), respectively. On univariate analysis, PCI was associated with improved FFS but this was not significant (p=0.18). Gender was the only co-variate significantly associated with statistical differences in FFS (p=0.03) and OS (p=0.02). Grade 3 and 4 esophagitis were 10.5% and 2.6%, respectively. Pre-HDRT tumor volume and 3-month post-treatment tumor volume were both associated with FFS (p CONCLUSIONS: In this single institution series, daily HDRT demonstrated a 2-year OS of 47% in LS-SCLC. This compares well to the historical survival of daily fractionation (47%) from INT 0096 reported by Turris

Pharmacologic Ascorbate Reduces Radiation-Induced Normal Tissue Toxicity and Enhances Tumor Radiosensitization in Pancreatic Cancer.

Chemoradiation therapy is the mainstay for treatment of locally advanced, borderline resectable pancreatic cancer. Pharmacologic ascorbate (P-AscH-, i.e., intravenous infusions of ascorbic acid, vitamin C), but not oral ascorbate, produces high plasma concentrations capable of selective cytotoxicity to tumor cells. In doses achievable in humans, P-AscH- decreases the viability and proliferative capacity of pancreatic cancer via a hydrogen peroxide (H2O2)-mediated mechanism. In this study, we demonstrate that P-AscH- radiosensitizes pancreatic cancer cells but inhibits radiation-induced damage to normal cells. Specifically, radiation-induced decreases in clonogenic survival and double-stranded DNA breaks in tumor cells, but not in normal cells, were enhanced by P-AscH-, while radiation-induced intestinal damage, collagen deposition, and oxidative stress were also reduced with P-AscH- in normal tissue. We also report on our first-in-human phase I trial that infused P-AscH- during the radiotherapy beam on. Specifically, treatment with P-AscH- increased median overall survival compared with our institutional average (21.7 vs. 12.7 months, P = 0.08) and the E4201 trial (21.7 vs. 11.1 months). Progression-free survival in P-AscH--treated subjects was also greater than our institutional average (13.7 vs. 4.6 months, P \u3c 0.05) and the E4201 trial (6.0 months). Results indicated that P-AscH- in combination with gemcitabine and radiotherapy for locally advanced pancreatic adenocarcinoma is safe and well tolerated with suggestions of efficacy. Because of the potential effect size and minimal toxicity, our findings suggest that investigation of P-AscH- efficacy is warranted in a phase II clinical trial. SIGNIFICANCE: These findings demonstrate that pharmacologic ascorbate enhances pancreatic tumor cell radiation cytotoxicity in addition to offering potential protection from radiation damage in normal surrounding tissue, making it an optimal agent for improving treatment of locally advanced pancreatic adenocarcinoma