Efficacy and safety of motesanib, an oral inhibitor of VEGF, PDGF, and Kit receptors, in patients with imatinib-resistant gastrointestinal stromal tumors

Purpose

This multicenter phase 2 study assessed the tolerability and efficacy of motesanib, an oral inhibitor of Kit, platelet-derived growth factor receptor (PDGFR), and vascular endothelial growth factor receptors (VEGFR), in patients with imatinib-resistant gastrointestinal stromal tumors (GIST).

Methods

Patients with advanced GIST who failed imatinib mesylate after ??8?weeks of treatment with ??600?mg daily received motesanib 125?mg orally once daily continuously for 48?weeks or until unacceptable toxicity or disease progression occurred. The primary endpoint was confirmed objective tumor response per RECIST and independent review. Secondary endpoints included progression-free survival (PFS), time to progression (TTP); objective response by ¹⁸FDG-PET and by changes in tumor size and/or density (Choi criteria); pharmacokinetics and safety.

Results

In the patients evaluable for response (N?=?102), the objective response rate was 3%; 59% of patients achieved stable disease, with 14% achieving durable stable disease ??24?weeks; 38% had disease progression. Higher objective response rates were observed per ¹⁸FDG-PET (N?=?91) (30%) and Choi criteria (41%). The median PFS was 16?weeks (95% CI?=?14?C24?weeks); the median TTP was 17?weeks (95% CI?=?15?C24?weeks). The most common motesanib treatment-related grade 3 adverse events included hypertension (23%), fatigue (9%), and diarrhea (5%). Motesanib did not accumulate with daily dosing.

Conclusions

In this study of patients with imatinib-resistant GIST, motesanib treatment resulted in acceptable tolerability and modest tumor control as evident in the proportion of patients who achieved stable disease and durable stable disease.     

Phase I study of cediranib in combination with cisplatin plus fluoropyrimidine (S-1 or capecitabine) in Japanese patients with previously untreated advanced gastric cancer

Purpose

The primary objective of this Phase I study was to assess the safety and tolerability of the vascular endothelial growth factor signalling inhibitor cediranib in combination with cisplatin plus an oral fluoropyrimidine, in Japanese patients with previously untreated advanced gastric cancer.

Methods

Patients received continuous, once-daily oral doses of cediranib 20?mg in combination with either cisplatin (60?mg/m² iv day 1) plus S-1 (40?C60?mg bid, days 1?C21) every 5?weeks for a maximum of eight cycles [Arm A]; or cisplatin (80?mg/m² iv, day 1) plus capecitabine (1,000?mg/m² bid, days 1?C14) every 3?weeks for a maximum of six cycles [Arm B]. In both arms, the assessment period for dose-limiting toxicities (DLTs) was the first 21?days of cycle 1.

Results

Fourteen patients (Arm A, n?=?6; Arm B, n?=?8) were enrolled and received at least one dose of cediranib. One patient in each arm experienced a DLT (Arm A; decreased appetite, grade 3; Arm B, decreased appetite, fatigue and hyponatraemia, all grade 3). Overall, the most common adverse events were decreased appetite, fatigue and nausea (all n?=?13 [92.9%]). Preliminary efficacy evaluation showed one confirmed (Arm A) and three unconfirmed (Arm A, n?=?1; Arm B, n?=?2) partial responses that were ongoing at data cut-off.

Conclusions

Cediranib 20?mg/day in combination with cisplatin and S-1 or capecitabine was tolerable, with no new toxicities identified, and showed preliminary evidence of antitumour activity.     

Association of Type 2 Diabetes and Colon Adenomas

Introduction

Type 2 diabetes mellitus (DM) is associated with hyperinsulinemia, which may lead to increased risk of carcinogenesis by increasing insulin-like growth factor-1 level. In this study, we sought to determine the association between type 2 DM and colon adenomas.

Methods

In this retrospective case?Ccontrol study, all the colonoscopies performed in an urban medical center during a 3-year period were reviewed. Patients with adenomatous polyps were considered as cases (n?=?261). Age- and sex-matched controls with a 2:1 ratio were selected (n?=?522). Among diabetic subjects, the association of different anti-diabetic medications and HbA1C level with high-risk adenoma features was analyzed.

Results

Type 2 DM was significantly associated with colon adenomas (odds ratio (OR)?=?1.45, 95% confidence interval (CI)?=?1.05?C2.01, p?=?0.024). Exposure to insulin (OR?=?1.734, 95% CI?=?1.13?C2.65, p?=?0.013) and thiazolidinediones (OR?=?2.83, 95% CI?=?1.28?C6.26, p?=?0.01) was associated with developing adenomas. Neither the type of antidiabetic medication nor the level of HbA1C was a predictor for high-risk adenomas. Smoking (OR?=?1.47, 95% CI?=?1.07?C2.02, p?=?0.02), use of aspirin (OR?=?1.59, 95% CI?=?1.15?C2.20, p?=?0.005), and statins (OR?=?1.54, 95% CI?=?1.13?C2.10, p?=?0.007) appeared to increase the risk of adenomas.

Conclusion

This study shows a significant association between type 2 DM and colon adenomas. Establishing this association may lead to inclusion of diabetic patients in the high-risk group for developing colorectal cancer.     

A Phase I study to assess the safety, tolerability, and pharmacokinetics of AZD4877, an intravenous Eg5 inhibitor in patients with advanced solid tumors

Purpose

Inhibition of kinesin spindle protein or Eg5 causes the formation of monoastral mitotic spindles, which leads to cell death. AZD4877 is a specific, potent inhibitor of Eg5.

Methods

This was a Phase I, open-label, two-part study to evaluate the maximum tolerated dose (MTD) and safety and tolerability of AZD4877 in patients with advanced solid malignancies. In part A, the MTD of AZD4877, administered as three weekly 1-h intravenous (iv) infusions in a 28-day schedule, was determined by evaluating dose-limiting toxicity (DLT). In part B, the safety, tolerability, and pharmacokinetic profile of AZD4877 at the MTD were evaluated.

Results

In part A, 29 patients received at least one dose of AZD4877 (5?mg, n?=?4; 7.5?mg, n?=?4; 10?mg, n?=?3; 15?mg, n?=?3; 20?mg, n?=?3; 30?mg, n?=?6; 36?mg, n?=?3; 45?mg, n?=?3). The MTD was defined as 30?mg, with the primary DLT being neutropenia. Although exposures appeared to be similar at the AZD4877 20 and 30?mg doses, dose reductions and omissions were higher in the 30-mg cohort; therefore, an intermediate dose, 25?mg, was evaluated in part B (n?=?14). In part B, neutropenia remained the most commonly reported causally related adverse event. Exposure to AZD4877 was approximately dose proportional. Severity of neutropenia was related to exposure.

Conclusion

The MTD of AZD4877 given as a 1-h iv infusion on days 1, 8, and 15 of a 28-day cycle was 30?mg. At the selected 25?mg dose, AZD4877 had an acceptable safety profile.     

A phase I and pharmacokinetic study of elisidepsin (PM02734) in patients with advanced solid tumors

Purpose

To determine the maximum-tolerated dose (MTD), dose-limiting toxicity (DLT), and recommended phase II dose (RD) of elisidepsin.

Methods

Eligible patients with refractory, advanced solid tumors received elisidepsin as 24-h intravenous infusion every 3?weeks. Pharmacokinetic profiles were analyzed during cycles 1 and 2.

Results

Forty-two patients received elisidepsin at doses from 0.5 to 6.8?mg/m². The MTD was 6.8?mg/m², and the RD was 5.5?mg/m². Cohort expansion at the RD was done at a fixed dose (FD) of 10?mg, considered equivalent to 5.5?mg/m². DLTs (reversible grade 3 transaminase increases) occurred at 6.8?mg/m² (n?=?2 patients), 5.5?mg/m² (n?=?1), and 10?mg FD (n?=?1). One patient with esophageal adenocarcinoma achieved complete response for >38?months, and 12 patients had disease stabilization (8 for ≥3?months). Median time-to-progression for these 12 patients was 4.8?months. Plasma elisidepsin concentrations increased with dose. No drug accumulation between cycles was found. No correlation was observed between body surface area (BSA) and plasma clearance; therefore, elisidepsin was given as flat dose (in mg) in the expansion cohort at the RD and in ongoing clinical trials.

Conclusions

Elisidepsin is well tolerated with predictable reversible transaminase increases. Encouraging preliminary evidence of antitumor activity was observed.     

Retrospective analysis of cetuximab monotherapy for patients with irinotecan-intolerant metastatic colorectal cancer

Background

The efficacy and safety of cetuximab for irinotecan-intolerant patients has not yet been evaluated in detail.

Methods

We retrospectively analyzed the efficacy and safety of cetuximab monotherapy for patients with metastatic colorectal cancer (MCRC) that was intolerant to irinotecan.

Results

Among 105 patients who received cetuximab-containing chemotherapy until March 2010, 22 patients were treated with cetuximab monotherapy due to irinotecan intolerance. Cetuximab was given at the approved dosage to all patients. The performance status was 2 or 3 in 17 patients (77%). All but 1 patient had wild-type KRAS tumors. The causes of irinotecan intolerance were icterus (n?=?9; 41%; median serum total bilirubin, 6.3?mg/dl), symptomatic peritoneal metastasis or obstruction (n?=?8; 36%), and thrombocytopenia (n?=?1; 5%). Four patients (18%) refused irinotecan due to previous irinotecan-associated toxicity. Two patients achieved a partial response with an apparent drop of serum bilirubin, for a response rate of 9.1%. The median progression-free survival and overall survival were 1.6 and 3.5?months, respectively. No grade 3 or 4 adverse events or treatment-related deaths were experienced.

Conclusion

Cetuximab monotherapy for irinotecan-intolerant MCRC is feasible. However, the overall efficacy was modest in the present cohort, despite the fact that most of the patients had wild-type KRAS tumors; further effective therapies should be evaluated to improve the prognosis of this patient population.     

A phase I study of sunitinib combined with modified FOLFOX6 in patients with advanced solid tumors

Purpose

This phase I study assessed the safety, tolerability, maximum tolerated dose (MTD), pharmacokinetics, and preliminary antitumor effects of sunitinib combined with modified FOLFOX6 (mFOLFOX6).

Methods

Patients with advanced solid malignancies received mFOLFOX6 in 2-week cycles with escalating sunitinib doses (25, 37.5, and 50?mg/day) on three schedules: 2?weeks on, 2?weeks off (2/2); 4?weeks on, 2?weeks off (4/2); or continuous daily dosing (CDD). Patients received up to 8 treatment cycles (Schedule 2/2 and CDD schedule) or 6 cycles (Schedule 4/2). An expansion cohort enrolled patients with metastatic colorectal cancer at the Schedule 2/2 MTD.

Results

Overall, 53 patients were enrolled, with 43 evaluable for dose-limiting toxicity (DLT). On Schedule 2/2 (n?=?18), DLTs occurred in three patients at 50?mg/day (grade 4 neutropenia [n?=?1]; grades 3 and 4 thrombocytopenia [n?=?2]) and two patients achieved partial responses (PRs). On Schedule 4/2 (n?=?13), 37.5?mg/day exceeded the MTD with two DLTs (febrile neutropenia and grade 4 hypokalemia, respectively). On the CDD schedule (n?=?12), the MTD was 25?mg/day; one DLT (grade 3 stomatitis) was reported and two patients achieved PRs. The most common adverse events were neutropenia, fatigue, and thrombocytopenia. No clinically significant drug?Cdrug interactions were apparent between sunitinib, its metabolite SU12662, and mFOLFOX6.

Conclusions

Sunitinib combined with mFOLFOX6 had acceptable tolerability. The MTDs were sunitinib 50?mg/day on Schedule 2/2 and 25?mg/day on the CDD schedule. A MTD for Schedule 4/2 was not established.     

CDC73 mutations and parafibromin immunohistochemistry in parathyroid tumors: clinical correlations in a single-centre patient cohort

Objective

To determine if molecular and immunohistochemical (IHC) features of the HRPT2/CDC73 gene and its product, parafibromin, predict the natural history of parathyroid malignancy, particularly atypical adenoma, as seen in a single-centre patient cohort.

Methods

Matched tumor and non-tumor tissues were obtained from 46 patients with parathyroid carcinoma (CA) (n?=?15), atypical adenoma (AA) (n?=?14) and typical adenoma (TA) (n?=?17), as defined by standardized histopathological criteria. Exons and exon-intron boundaries of the CDC73 gene were sequenced to identify germline or somatic mutations. IHC staining for parafibromin was performed and scored as positive if nuclear staining was at least partially IHC-positive.

Results

Mutations of CDC73 were observed in 9/15 (60?%) CA, 2/14 (14?%) AA, and 1/17 (6?%) TA tumors. A recurrent two basepair mutation in exon 7 -- c.679_680delAG -- accounted for half of all identified mutations. Absence of parafibromin nuclear staining was noted in 8/12 (67?%) CA, 2/13 (15?%) AA, and 3/17 (18?%) TA tumors. Median follow up times were 88?months for CA, 76?months for AA, and 104?months for TA patients. One patient, a member of a previously reported multiplex family with a germline CDC73 mutation was found to have a second adenoma after removal of an atypical adenoma.

Conclusions

Molecular screening and IHC are both useful tools in the differential diagnosis of parathyroid tumors, but both have limited sensitivity and specificity. CDC73 mutations and negative immunostaining were common in atypical adenomas, but no local recurrence was observed in any case with successful surgical removal after follow-up periods of 27 to 210?months.     

A phase I open-label study evaluating the cardiovascular safety of sorafenib in patients with advanced cancer

Purpose

To characterize the cardiovascular profile of sorafenib, a multitargeted kinase inhibitor, in patients with advanced cancer.

Methods

Fifty-three patients with advanced cancer received oral sorafenib 400?mg bid in continuous 28-day cycles in this open-label study. Left ventricular ejection fraction (LVEF) was evaluated using multigated acquisition scanning at baseline and after 2 and 4 cycles of sorafenib. QT/QTc interval on the electrocardiograph (ECG) was measured in triplicate with a Holter 12-lead ECG at baseline and after 1 cycle of sorafenib. Heart rate (HR) and blood pressure (BP) were obtained in duplicate at baseline and after 1 and 4 cycles of sorafenib. Plasma pharmacokinetic data were obtained for sorafenib and its 3 main metabolites after 1 and 4 cycles of sorafenib.

Results

LVEF (SD) mean change from baseline was ?0.8 (±8.6) LVEF(%) after 2 cycles (n?=?31) and ?1.2 (±7.8) LVEF(%) after 4 cycles of sorafenib (n?=?24). The QT/QTc mean changes from baseline observed at maximum sorafenib concentrations (t _max) after 1 cycle (n?=?31) were small (QTcB: 4.2?ms; QTcF: 9.0?ms). Mean changes observed after 1 cycle in BP (n?=?31) and HR (n?=?30) at maximum sorafenib concentrations (t _max) were moderate (up to 11.7?mm Hg and ?6.6?bpm, respectively). No correlation was found between the AUC and C _max of sorafenib and its main metabolites and any cardiovascular parameters.

Conclusions

The effects of sorafenib on changes in QT/QTc interval on the ECG, LVEF, BP, and HR were modest and unlikely to be of clinical significance in the setting of advanced cancer treatment.     

A multicenter phase II trial of docetaxel and capecitabine as salvage treatment in anthracycline- and taxane-pretreated patients with metastatic breast cancer

Objective

To evaluate the efficacy and safety of docetaxel plus capecitabine (DC) combination as salvage treatment in anthracycline- and taxane-pretreated patients with metastatic breast cancer (MBC).

Patients and treatment

Patients with MBC who had disease progression after initial chemotherapy with anthracyclines (n?=?29; 100?%) and taxanes (n?=?11; 37.9?%) were treated with oral capecitabine 950?mg/m² twice daily on days 1?C14 and docetaxel 75?mg/m² on day 1 every 3?weeks. Nineteen (65.5?%) patients received this regimen as second line and 10 (34.5?%) as???3rd line of therapy. All patients were evaluable for response and toxicity.

Results

Complete response occurred in two (6.9?%) patients and partial response in eleven (37.9?%) for an overall response rate of 44.8?% (95?% CI 26.7?C62.9?%). Eleven women (37.9?%) had stable disease and five (17.2?%) progressive disease. Of the eleven patients previously treated with anthracyclines and taxanes, five (45.5?%) responded to DC combination. The median duration of response was 5.7?months (range 3.4?C64.2), the median time to disease progression 9.3?months (range 1.2?C58), and the median overall survival 25.5?months. No toxic death occurred. Neutropenia grade 4 occurred in 58.6?% of patients and three of them (10.3?%) developed neutropenic fever. Non-hematological toxicities were manageable with grade 3 hand-foot syndrome occurring in 6.9?% of the patients, fatigue in 3.4?%, and neurotoxicity in 3.4?%.

Conclusion

The DC combination is a valuable regimen as salvage treatment in anthracycline- or anthracycline and taxane-pretreated patients with MBC.     

The effect of different etiologies of hepatic impairment on the pharmacokinetics of gefitinib

Purpose

We investigated whether the pharmacokinetics and tolerability of gefitinib were altered in patients with hepatic impairment due to cirrhosis or hepatic metastases in two open, parallel-group, multicenter studies.

Methods

In Study 1, subjects with normal hepatic function or mild, moderate, or severe hepatic impairment (Child-Pugh criteria) due to cirrhosis received single-dose gefitinib 250?mg (n?=?10 per group). In Study 2, patients with solid malignant tumors with normal liver biochemistry (n?=?18), moderate (n?=?16), or severe (n?=?7) hepatic impairment (liver biochemistry tests) due to metastases received gefitinib 250?mg daily for 28?days.

Results

In Study 1, the geometric mean area under the plasma concentration?Ctime curve (AUC) for gefitinib was significantly higher in patients with hepatic impairment compared with healthy subjects; hepatic impairment was associated with reduced gefitinib plasma clearance, longer half-life, and reduced plasma metabolite levels. In Study 2, the geometric mean gefitinib steady-state AUC during the 24-h dosing interval was slightly, but not significantly, higher in patients with moderate hepatic impairment; there were, however, no significant differences between groups in gefitinib and metabolite pharmacokinetic parameters. In both studies, gefitinib was well tolerated across all cohorts.

Conclusions

We conclude that the effect of hepatic impairment on gefitinib pharmacokinetics depends on the underlying etiology of that impairment and its classification.     

Efficacy of EGFR tyrosine kinase inhibitors for non-adenocarcinoma NSCLC patients with EGFR mutation

Purpose

The epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) gefitinib and erlotinib have shown dramatic response rate (RR) and significant prolongation of progression-free survival (PFS) in non-small-cell lung cancer (NSCLC) patients with EGFR mutation. Since only a few patients with non-adenocarcinoma histology have been enrolled in clinical trials, the efficacy of EGFR TKIs in non-adenocarcinoma NSCLC patients with EGFR mutation has not yet been fully determined.

Methods

We retrospectively analyzed clinical outcomes, including RR, PFS, and OS, in patients who were treated with the EGFR TKIs gefitinib or erlotinib and compared the results with those of adenocarcinoma patients with EGFR mutation and non-adenocarcinoma patients with wild-type EGFR.

Results

Among 250 patients with non-adenocarcinoma of the lung who underwent EGFR mutation genotyping, 21 were found to have an EGFR mutation (8.4?%). Twelve of the 21 patients were treated with the EGFR TKIs gefitinib (n?=?6) or erlotinib (n?=?6). The most common mutation was exon 19 deletion (n?=?7). The RR and disease control rate for 12 patients receiving EGFR TKIs were 50 and 75?%, respectively. The median PFS was 3.67?months (95?% CI: 1.34?C5.99), which was significantly lower than that of 269 adenocarcinoma patients with EGFR mutation (13.53?months) but better than that of 32 non-adenocarcinoma patients with wild-type EGFR (1.83?months) who were treated with EGFR TKIs.

Conclusions

The results of this study show that the EGFR mutation rate in Korean patients with non-adenocarcinoma of the lung is relatively high and that the clinical outcomes of EGFR TKIs are modest.     

Reproductive factors and lymphoid neoplasms in Europe: findings from the EpiLymph case–control study

Background

The study of lymphomagenesis has rarely focused on hormonal factors. Higher incidence rates are observed for many lymphoma subtypes in men compared with women suggesting an underlying association. Our goal was to investigate the association between reproductive factors and lymphomas.

Methods

The Epilymph study is a multicenter case?Ccontrol study carried out in six European countries from 1998 to 2004. Female cases of mature T-cell neoplasms (n?=?52), Hodgkin lymphoma (n?=?147), and mature B-cell neoplasms (n?=?795), including its common subtypes, and their respective controls (n?=?1,141) frequency matched by age, gender, and center were considered.

Results

An odds reduction of 29% (95% CI ?46 to ?6%) was observed for mature T-cell neoplasms for each child increase among parous women and of 13% (95% CI ?19 to ?7%) for mature B-cell neoplasms; while no association was observed for Hodgkin lymphoma. By B-cell neoplasm subtypes, these associations were found for chronic lymphocytic leukemia/small lymphocytic lymphoma (?21%, 95% CI ?31 to ?9%) and diffuse large B-cell lymphoma (DLBCL; ?14%; 95% CI ?23 to ?3%). Overall, no associations were observed with age at first and last pregnancy, and ever use of hormonal contraceptives and lymphoma. Higher odds ratios for a short-term use of hormonal contraceptives (<5?years), but not for a long-term use, were observed for mature B-cell neoplasms, DLBCL, and follicular lymphoma compared with never use.

Conclusion

These data support the hypothesis that increased parity confers a protective effect against lymphoma. Less clearly, our results also indicate that hormonal contraceptives could play a role.     

Single- and multiple-dose pharmacokinetics, safety and tolerability of zibotentan (ZD4054) in Chinese men with advanced solid tumors

Purpose

The endothelin axis and the endothelin A (ET_A) receptor have been implicated in tumor development and bone metastasis. This study aimed to investigate the pharmacokinetic (PK) and safety profiles of the specific ET_A receptor antagonist, zibotentan, in elderly, male Chinese patients with advanced solid tumors. The PK data generated in these Chinese patients were further compared with those previously reported in Japanese and Caucasian patient populations.

Methods

In this Phase I, open-label study, patients received a single dose of zibotentan 10?mg on Day 1, followed by a 72-h washout period and 12 consecutive days of once-daily zibotentan 10?mg.

Results

Fifteen patients received at least one dose of zibotentan 10?mg. Exposure was demonstrated in all patients and the PK profiles following single dosing and multiple dosing showed relatively rapid absorption, decline in a monophasic manner, a modest amount of accumulation, and relatively low apparent clearance and volume of distribution. Zibotentan was well tolerated with no new safety concerns. Adverse events reported in >1 patient were pyrexia (n?=?4), constipation (n?=?3), headache (n?=?3) and peripheral edema (n?=?2). Comparative analysis found no evidence of significant differences in zibotentan exposure between the Chinese patients in our study, and the previous Japanese and Caucasian studies.

Conclusions

The PK and safety profiles of zibotentan determined in this Chinese patient population are similar to those previously reported. Our findings suggest no clinically relevant inter-ethnic differences in zibotentan disposition between the patient populations analyzed.     

Effects of famotidine or an antacid preparation on the pharmacokinetics of nilotinib in healthy volunteers

Purpose

This study evaluated the effects of either famotidine or antacid on the pharmacokinetics of nilotinib in healthy subjects, with the specific focus to explore different dosing separation schemes leading to a minimized drug–drug interaction.

Methods

Fifty-two subjects were randomized to receive the following treatments in a crossover manner: (A) single oral nilotinib 400 mg alone; (B) famotidine 20 mg twice a day for 3 days, followed by a single administration of nilotinib 400 mg and famotidine 20 mg on Day 4, where famotidine was given 2 h after nilotinib; (C) single oral nilotinib 400 mg and antacid suspension 20 mL, where antacid was given 2 h before nilotinib; (D) single oral nilotinib 400 mg and antacid suspension 20 mL, where antacid was given 2 h after nilotinib.

Results

Comparing Treatment B to Treatment A, the geometric mean ratios of nilotinib C _max, AUC_0-tlast, and AUC_0-inf were 0.966, 0.984, and 0.911, respectively (90 % confidence intervals (CIs), 0.875–1.066, 0.905–1.069, and 0.798–1.039, respectively). Nilotinib pharmacokinetic parameters following Treatment C or Treatment D were similar to those after Treatment A; the corresponding 90 % CIs of the geometric mean ratios of C _max, AUC_0-tlast, and AUC_0-inf all fell within the bioequivalence range of 0.8–1.25.

Conclusions

Neither famotidine nor antacid significantly affected nilotinib pharmacokinetics. When concurrent use of an H2 blocker or an antacid is necessary, the H2 blocker may be administered 10 h before and 2 h after nilotinib dose, or the antacid may be administered 2 h before or 2 h after nilotinib dose.     

Treatment for gastric carcinoma in the oldest old patients

Background

The strategy for treating extremely aged patients with gastric carcinoma is controversial. This study reviews the prognoses of patients aged 85?years and older who were diagnosed with gastric carcinoma.

Methods

One hundred seventeen patients aged 85?years and older were diagnosed as having gastric carcinoma after 1969 in our institution. After excluding those at stage IV, 36 cases underwent curative resection and 30 cases received best supportive care (BSC), which we reviewed retrospectively.

Results

Surgical methods included distal gastrectomy for 28 cases, total gastrectomy for five cases, and other procedures for three cases. Postoperatively, pneumonia developed in four cases, anastomotic leakage in two cases, and pancreatic fistula in one case. Two patients died of pneumonia within 1?month of surgery. Univariate analysis demonstrated that age, surgery, performance status, and sodium level were statistically significant prognostic factors. Multivariate analysis demonstrated that surgery was the only independent prognostic factor. When patients with a performance status of 4 were excluded, the clinical characteristics of the surgery group (n?=?36) and BSC group (n?=?20) were statistically identical, and the overall survival was significantly better in the surgery group (p?=?0.0078).

Conclusions

Postoperative outcomes were relatively acceptable. Surgery may be feasible and beneficial even for extremely aged patients 85?years and older, except for those with a performance status of 4.     

Unmet information and support needs in newly diagnosed thyroid cancer: comparison of adolescents/young adults (AYA) and older patients

Purpose

Thyroid cancer (TC) is the most common cancer in adolescent and young adult (AYA) females ages 15–29 and second for 30–39. However, little research details the unmet support needs and survivorship concerns of TC patients.

Methods

TC patients ≥15 years of age at diagnosis completed online surveys through the thyroid cancer survivor (ThyCa) website. Survivors rated the importance of medical/physical (M/Ph), practical, and emotional/psychological (E/Ps) realms of information during diagnosis and treatment, as well as recollection of receiving such information. Comparison was made between AYAs and those ≥40 years at diagnosis.

Results

Of 1,113 respondents, most were female (88.3 %), part Caucasian (92.3 %), and treated in academic or private urban settings. More than 80 % of patients rated receiving information about most M/Ph matters very or extremely important and >70 % for most E/Ps concerns. However, few recalled receiving any information besides the surrounding surgery and radioiodine (RAI). AYAs were more often female, non-white, Hispanic, married with children, living with a spouse/significant other, and unemployed at diagnosis (p?<?0.001). Significant differences were noted in the importance AYAs placed on many M/Ph and practical matters, but not E/Ps ones. AYAs less commonly recalled receiving information on recurrence (p?=?0.038), long-term side effects (p?=?0.024), coping strategies (p?=?0.049), support groups (p?=?0.019), opportunities for meeting other survivors (p?=?0.009), or help with treatment decisions (p?=?0.036); they reported receiving less overall care for E/Ps concerns (p?=?0.016).

Conclusion

TC patients place high importance on receiving information regarding most aspects of TC treatment and survivorship care. However, these information needs and survivorship concerns are largely unmet, especially among AYAs.

Implications for Cancer Survivors

Participating in multidisciplinary and survivorship-focused TC care may alleviate some of these unmet information and support needs.     

Early metabolic response to neoadjuvant letrozole, measured by FDG PET/CT, is correlated with a decrease in the Ki67 labeling index in patients with hormone receptor-positive primary breast cancer: a pilot study

Purpose

To assess whether the early metabolic response evaluated by ¹⁸F-fluorodeoxy-glucose positron emission combined with computed tomography (FDG PET/CT) predicts the morphological, pathological, and cell-cycle responses to neoadjuvant endocrine therapy of hormone receptor-positive primary breast cancer.

Study design

Eleven patients (12 tumors) with estrogen receptor-positive (Allred score 7 or 8) primary breast cancer were enrolled. All patients received a daily dose (2.5?mg) of letrozole for 12?weeks followed by surgery. Sequential FDG PET/CT scans were performed before treatment (baseline), at 4?weeks after the initiation of endocrine therapy (PET2), and prior to surgery (PET3). Tumors showing a 40% or more reduction and those showing a less than 40% reduction in the standardized uptake value maximum (SUV_max) at PET2 compared with the baseline PET were defined as metabolic responders and metabolic nonresponders, respectively. Change in tumor size as measured by ultrasound (morphological response), pathological response, and change in the Ki67 labeling index in tumor tissue (cell-cycle response) during the neoadjuvant letrozole therapy were compared between the metabolic responders and nonresponders.

Results

The average decreases in SUV_max at PET2 compared with the baseline PET in the metabolic responders (n?=?6) and the metabolic nonresponders (n?=?6) were 60.9% (??21.3 SD) and 14.2% (??12.0 SD), respectively. At PET3 compared with the baseline PET, the metabolic responders showed a significantly higher decrease of 64.5% (??18.7 SD) (p?=?0.0004), whereas the nonresponders showed a nonsignificant decrease of 16.7% (??14.1 SD) (p?=?0.06). The morphological and pathological responses after letrozole therapy did not differ between the metabolic responders and nonresponders. The metabolic responders showed a marked decrease in the Ki67 labeling index at 2?weeks after the initiation of treatment (62.9%, ??35.9 SD, p?=?0.04) and at surgery (91.7%, ??10.7 SD, p?=?0.03) compared with the baseline values. In contrast, metabolic nonresponders showed no significant change in the Ki67 index either after 2?weeks of therapy or at surgery.

Conclusion

Cell-cycle response monitored by the Ki67 labeling index correlates with metabolic response monitored by tumor SUV_max. Monitoring of tumor SUV_max using FDG PET/CT may be feasible to predict cell-cycle response to neoadjuvant endocrine therapy of primary breast cancer.     

Prospective study of cytomegalovirus serostatus and prostate cancer risk in the Prostate Cancer Prevention Trial

Purpose

To investigate serologic evidence of infection by cytomegalovirus (CMV), a herpesvirus with known oncogenic potential that has been detected in malignant prostate tissue, in relation to prostate cancer (PCa) risk in a large case–control study nested in the Prostate Cancer Prevention Trial (PCPT).

Methods

Cases were men with a confirmed diagnosis of PCa after visit 2 (n?=?614), and controls were men not diagnosed with PCa during the trial who also had a negative end-of-study biopsy (n?=?616). Controls were frequency-matched to cases by age, treatment arm, and family history of PCa. Sera from visit 2 were tested for CMV IgG antibodies.

Results

No association was observed between CMV serostatus and PCa risk (adjusted CMV seroprevalence?=?67.9?% for cases and 65.2?% for controls, odds ratio?=?1.13, 95?% CI 0.89–1.45).

Conclusions

Considering our null findings in the context of the full CMV literature, CMV infection, as measured by serostatus, does not appear to increase PCa risk.     

In vitro testing of drug combinations employing nilotinib and alkylating agents with regard to pretransplant conditioning treatment of advanced-phase chronic myeloid leukemia

Purpose

The prognosis of patients with advanced-phase chronic myeloid leukemia (CML) remains dismal despite the availability of targeted therapies and allogeneic stem cell transplantation (allo-SCT). Increasing the antileukemic efficacy of the pretransplant conditioning regimen may be a strategy to increase remission rates and duration. We therefore investigated the antiproliferative effects of nilotinib in combination with drugs that are usually used for conditioning: the alkylating agents mafosfamide, treosulfan, and busulfan.

Methods

Drug combinations were tested in vitro in different imatinib-sensitive and imatinib-resistant BCR–ABL-positive cell lines. A tetrazolium-based MTT assay was used for the assessment and quantification of growth inhibition after exposure to alkylating agents alone or to combinations with nilotinib. Drug interaction was analyzed using the median-effect method of Chou and Talalay, and combination index (CI) values were calculated according to the classic isobologram equation.

Results

Treatment of imatinib-sensitive, BCR–ABL-positive K562 and LAMA84 cells with nilotinib in combination with mafosfamide, treosulfan, or busulfan resulted in synergistic (CI < 1), additive (CI ~ 1), and predominantly antagonistic (CI > 1) effects, respectively. In imatinib-resistant K562-R and LAMA84-R cells, all applied drug combinations were synergistic (CI < 1) at higher growth inhibition levels.

Conclusions

Our in vitro data warrant further investigation and may provide the basis for nilotinib-supplemented conditioning regimens for allo-SCT in advanced-phase CML.