Satraplatin is an oral platinum with potential advantages over other platinum agents. This study investigated the combination of satraplatin and docetaxel in a phase 1 study of patients with advanced solid tumor malignancies followed by a phase 1b study in men with chemotherapy naïve metastatic castrate-resistant prostate cancer (CRPC).
In this single institution phase 1/1b study, patients received docetaxel on day 1 and satraplatin on days 1–5 of a 21-day cycle ± granulocyte colony stimulating factor (GCSF). For phase 1b, prednisone 10 mg daily was added.
Twenty-nine patients received treatment. Based on 3 dose limiting toxicities (DLT) (grade 4 neutropenia) in 13 patients at dose levels 1 and −1 (docetaxel 60 mg/m2 plus satraplatin 40 mg/m2 and docetaxel 60 mg/m2 plus satraplatin 50 mg/m2) GCSF was administered with subsequent cohorts. A dose level of docetaxel 60 mg/m2 plus satraplatin 50 mg/m2 with GCSF was the starting dose level for phase 1b. At the highest dose in the phase 1b (docetaxel 75 mg/m2 plus satraplatin 50 mg/m2) there were no DLTs.
The combination of satraplatin and docetaxel is feasible in solid tumor malignancies. In advanced malignancies, the recommended phase 2 dose is docetaxel 60 mg/m2 IV day 1 with satraplatin 40 mg/m2/d PO days 1–5, without G-CSF, and Docetaxel 70 mg/m2 IV day 1 with Satraplatin 50 mg/m2/day PO days 1–5, with G-CSF support, repeated in 3-week cycles. For patients with CRPC the recommended phase 2 dose is docetaxel 75 mg/m2 IV day 1 with satraplatin 50 mg/m2/d PO days 1–-5, with G-CSF and prednisone 10 mg daily, repeated in 3-week cycles.
Satraplatin; Docetaxel; Phase 1; Castrate-resistant; Prostate; Cancer
Adjuvant chemotherapy is typically considered for patients with stage II colon cancer characterized by poor prognostic features, including obstruction, perforation, emergent admission, T4 stage, resection of fewer than 12 lymph nodes, and poor histology. Despite frequent use, the survival advantage conferred on patients with stage II disease by chemotherapy is yet unproven. We sought to determine the overall survival benefit of chemotherapy among patients with stage II colon cancer having poor prognostic features.
Patients and Methods
A total of 43,032 Medicare beneficiaries who underwent colectomy for stage II and III primary colon adenocarcinoma diagnosed from 1992 to 2005 were identified from the Surveillance, Epidemiology, and End Results (SEER) –Medicare database. χ2 and two-way analysis of variance were used to assess differences in patient- and disease-related characteristics. Five-year overall survival was examined using Kaplan-Meier survival analysis and Cox proportional hazards regression with propensity score weighting.
Of the 24,847 patients with stage II cancer, 75% had one or more poor prognostic features. Adjuvant chemotherapy was received by 20% of patients with stage II disease and 57% of patients with stage III disease. After adjustment, 5-year survival benefit from chemotherapy was observed only for patients with stage III disease (hazard ratio[HR], 0.64; 95% CI, 0.60 to 0.67). No survival benefit was observed for patients with stage II cancer with no poor prognostic features (HR, 1.02; 95% CI, 0.84 to 1.25) or stage II cancer with any poor prognostic features (HR, 1.03; 95% CI, 0.94 to 1.13).
Among Medicare patients identified with stage II colon cancer, either with or without poor prognostic features, adjuvant chemotherapy did not substantially improve overall survival. This lack of benefit must be considered in treatment decisions for similar older adults with colon cancer.
Notch1 has been shown to be a tumor suppressor in neuroendocrine tumors. Previous in vitro studies in neuroendocrine tumor cell lines have also suggested that valproic acid, a histone deacetylase inhibitor, can induce Notch1 and that Notch1 activation correlates with a decrease in tumor markers for neuroendocrine tumors. This study showed that valproic acid activates Notch1 signaling in vivo and may have a role in treating low-grade neuroendocrine tumors.
Notch1 has been shown to be a tumor suppressor in neuroendocrine tumors (NETs). Previous in vitro studies in NET cell lines have also suggested that valproic acid (VPA), a histone deacetylase inhibitor, can induce Notch1 and that Notch1 activation correlates with a decrease in tumor markers for NETs. Thus, this study aimed to evaluate the role of VPA in treating NETs and to determine whether VPA induced the Notch signaling pathway signaling in vivo.
Patients and Methods.
Eight patients with low-grade NETs (carcinoid and pancreatic) were treated with 500 mg of oral VPA twice a day with dosing adjusted to maintain a goal VPA level between 50 and 100 μg/mL. All patients were followed for 12 months or until disease progression.
Notch1 signaling was absent in all tumors prior to treatment and was upregulated with VPA. One patient had an unconfirmed partial response and was noted to have a 40-fold increase in Notch1 mRNA levels. Four patients had stable disease as best response. Tumor markers improved in 5 out of 7 patients. Overall, treatment with VPA was well tolerated.
VPA activates Notch1 signaling in vivo and may have a role in treating low-grade NETs.
Neuroendocrine tumors; Valproic acid; Histone deacetylase inhibitor; Pancreatic carcinoid; Notch signaling
Prognosis remains poor after progression on first-line chemotherapy for colorectal adenocarcinoma, and inactivation of the EGFR pathway with monoclonal antibodies is an effective treatment strategy in selected patients with metastatic disease. Lapatinib is an oral EGFR and HER-2 dual tyrosine kinase inhibitor that has not shown significant activity in metastatic colorectal cancer. However, lapatinib may act synergistically with capecitabine in anticancer effects.
This was an open-label, non-randomized phase II study of lapatinib 1,250 mg orally daily and capecitabine 2,000 mg/m2 by mouth split into twice-daily dosing for 14 days of a 21 days cycle. Inclusion criteria included metastatic or locally advanced adenocarcinoma of the colon or rectum with progression by RECIST on or within six months of receiving a fluoridopyrimidine-, oxaliplatin- or irinotecan-containing regimen. Prior EGFR monoclonal antibody was permitted. K-ras testing was not routinely performed and was not a part of the study protocol.
Twenty nine patients (16 M; 13 F) were enrolled in this study. There were no complete or partial responses. 41.4% of patients achieved stable disease as a best response. Median overall survival was 6.8 months, with a 1-year survival rate of 22%, and median progression-free survival was 2.1 months. The combination produced few grade 3 and no grade 4 toxicities. No grade 3 toxicity occurred in more than 10% of patients.
Although capecitabine and lapatinib is well tolerated, it is not an effective regimen in patients with refractory colorectal adenocarcinoma.
Colorectal cancer; capecitabine; lapatinib; EGFR; Her-2
Notch1 has been shown to be a tumor suppressor in neuroendocrine tumors (NETs). Previous in-vitro studies in NET cell lines have also suggested that valproic acid (VPA), a histone deacetylase inhibitor, can induce Notch1, and that Notch1 activation correlates with a decrease in tumor markers for NET. Thus, this study aimed to evaluate the role of valproic acid in treating NETs and if VPA induced the Notch signaling pathway signaling in-vivo‥
Patients & Methods
Eight patients with low grade NETs (carcinoid and pancreatic) were treated with valproic acid 500 mg orally twice a day with dosing adjusted to maintain a goal VPA level between 50–100 mcg/mL. All patients were followed for 12 months or until disease progression.
Notch1 signaling was absent in all tumors prior to treatment, and was upregulated with VPA. One patient had an unconfirmed PR and was noted to have a 40-fold increase in Notch1 mRNA levels. Four patients had stable disease as best response. Tumor markers improved in 5/7 patients. Overall, treatment with VPA was well tolerated.
Valproic acid activates Notch1 signaling in-vivo and may have a role in treating low grade NET.
Neuroendocrine tumors; Valproic Acid; histone deacetylase inhibitor; pancreatic carcinoid; Notch signaling
Erlotinib has prolonged survival in unselected patients with advanced non-small cell lung cancer, whereas sunitinib has yielded promising rates of disease control in previously treated patients. We conducted a dose escalation study of this combination to determine the maximum tolerated dose of sunitinib in combination with a fixed dose of erlotinib and to evaluate the toxicities of this combination.
Patients with advanced nonsquamous non-small cell lung cancer were treated at two dose levels: sunitinib at either 25 mg or 37.5 mg, with erlotinib 150 mg. Both drugs were given once daily, continuously.
Eleven patients enrolled from November 2007 to October 2009. No dose-limiting toxicities occurred. Grade 3/4 adverse events at least possibly related to treatment were seen in seven patients (64%). Six patients (54%) required dose modifications, and three (27%) discontinued study treatment due to toxicity. Rates of grade 3 diarrhea and mucositis exceeded those seen with single-agent erlotinib or sunitinib. One patient (9%) attained a partial response lasting 16.3 months.
Although no dose-limiting toxicities occurred, it is difficult to recommend erlotinib 150 mg and sunitinib 37.5 mg daily as the phase II dose for this combination due to the high rate of adverse events. Because of the overlapping toxicity profile of each agent, this combination was poorly tolerated in our population.
Phase I clinical trial; Non-small cell lung cancer; Epidermal growth factor receptor; Vascular endothelial growth factor receptors; Receptor protein-tyrosine kinases
The efficacy of lithium chloride in patients with low-grade neuroendocrine tumors was evaluated and it was found to be ineffective in obtaining radiographic responses.
Low-grade neuroendocrine tumors (NETs) respond poorly to chemotherapy; effective, less toxic therapies are needed. Glycogen synthase kinase (GSK)-3β has been shown to regulate growth and hormone production in NETs. Use of lithium chloride in murine models suppressed carcinoid cell growth, reduced GSK-3β levels, and reduced expression of chromogranin A. This study assessed the efficacy of lithium chloride in patients with NETs.
Eligible patients had low-grade NETs. A single-arm, open-label phase II design was used. Lithium was dosed at 300 mg orally three times daily, titrated to serum levels of 0.8–1.0 mmol/L. The primary endpoint was objective tumor response by the Response Evaluation Criteria in Solid Tumors. Secondary endpoints included overall survival, progression-free survival, GSK-3β phosphorylation, and toxicity.
Fifteen patients were enrolled between October 3, 2007 and July 17, 2008, six men and nine women. The median age was 58 years. Patient diagnoses were carcinoid tumor for eight patients, islet cell tumor for five patients, and two unknown primary sites. Eastern Cooperative Oncology Group performance status scores were 0 or 1. Two patients came off study because of side effects. The median progression-free survival interval was 4.50 months. There were no radiographic responses. Because of an early stopping rule requiring at least one objective response in the first 13 evaluable patients, the study was closed to further accrual. Patients had pre- and post-therapy biopsies.
Lithium chloride was ineffective at obtaining radiographic responses in our 13 patients who were treated as part of this study. Based on the pre- and post-treatment tumor biopsies, lithium did not potently inhibit GSK-3β at serum levels used to treat bipolar disorders.
Neuroendocrine tumors; Lithium chloride; Glycogen synthase kinase-3β; Chemotherapy; Carcinoid tumors
We have undertaken the current study to evaluate factors that correlate with postoperative complications in older patients undergoing surgery for colon cancer.
Patients and Methods
The database of the American College of Surgeons (ACS) National Surgical Quality Improvement Program (NSQIP) from years 2005 to 2008 was accessed. Patients age 65 and older were included according to Current Procedural Terminology and International Classification of Disease-9 codes. Preoperative and operative variables were examined and postoperative complications assessed using a combination of univariate and multivariate statistical models. Propensity score matching was used to control for nonrandomization of the database.
We found that patients undergoing laparoscopic (n = 2113) and open (n = 3801) surgery for the diagnosis of colon cancer were similar in age and gender. However, patients undergoing laparoscopic surgery were generally at lower risk for developing postoperative complications (16.1% vs. 25.4%, P < 0.005). Statistical models controlling for preoperative and operative variables demonstrated patients with elevated body mass index (odds ratio [OR] = 1.26), a history of chronic obstructive pulmonary disease (OR = 1.63), over age 85 (OR = 1.35), a surgery lasting longer than 4 hours (OR = 1.48), or having undergone an open operation (OR = 1.53) to have increased risk for developing postoperative complications. Propensity score match analysis confirmed these results.
Identification of preoperative factors that predispose patients to postoperative complications could allow for the institution of protocols that may decrease these events. Furthermore, expanding the role of laparoscopy in the treatment of older patients with colon cancer may decrease rates of postoperative complications.
Low-grade neuroendocrine tumors (NETs) respond poorly to chemotherapy; effective, less toxic therapies are needed. Glycogen synthase kinase (GSK)-3β has been shown to regulate growth and hormone production in NETs. Use of lithium chloride in murine models suppressed carcinoid cell growth, reduced GSK-3β levels and reduced expression of chromogranin A. This study assessed the efficacy of lithium chloride in patients with NETs.
Eligible patients had low-grade NETs. A single-arm, open-label phase II design was used. Lithium was dosed at 300mg orally TID, titrated to serum levels of 0.8–1.0mmol/L. The primary endpoint was objective tumor response by RECIST. Secondary endpoints included overall survival, progression-free survival, GSK-3β phosphorylation, and toxicity.
15 patients were enrolled between 10/3/07 and 7/17/08; 6 men, 9 women. The median age was 58. Patients’ diagnoses were carcinoid tumor for 8 pts, islet cell tumor for 5 pts, and 2 unknown primary sites. ECOG PS was 0 or 1. Two pts came off study due to side effects. Median progression-free survival was 4.50 months. There were no radiographic responses. Due to an early stopping rule requiring at least 1 objective response in the first 13 evaluable pts, the study was closed to further accrual. Patients had pre- and post-therapy biopsies.
Lithium chloride was ineffective at obtaining radiographic responses in our 13 patients who were treated as part of this study. Based on the pre- and post- treatment tumor biopsies, lithium did not potently inhibit GSK-3β at serum levels utilized to treat bipolar disorders.
Neuroendocrine tumors; lithium chloride; glycogen synthase kinase-3 beta; chemotherapy; carcinoid tumors
Biliary cancers overexpress epidermal growth factor receptor (EGFR), and angiogenesis has been correlated with poor outcome. Erlotinib, an EGFR tyrosine kinase inhibitor, and bevacizumab, a vascular endothelial growth factor (VEGF) inhibitor have each been shown to have activity in biliary cancer. The primary objective of this study was to evaluate the response rate by Response Evaluation Criteria in Solid Tumors (RECIST). Secondary end points included overall survival (OS), time to progression (TTP), VEGF levels, and molecular studies of EGFR and k-ras.
Patients and Methods
Eligible patients had advanced cholangiocarcinoma or gallbladder cancer. Patients were treated with bevacizumab 5 mg/kg intravenously on days 1 and 15 and erlotinib 150 mg by mouth daily on days 1 through 28. Responses were evaluated by RECIST. VEGF levels were collected, and samples were analyzed for EGFR mutation by polymerase chain reaction.
Fifty-three eligible patients were enrolled at eight sites. Of 49 evaluable patients, six (12%; 95% CI, 6% to 27%) had a confirmed partial response. Stable disease was documented in another 25 patients (51%). Rash was the most common grade 3 toxicity. Four patients had grade 4 toxicities. Median OS was 9.9 months, and TTP was 4.4 months. Low repeats (< 16) in EGFR intron 1 polymorphism and G>G k-ras Q38 genotype (wild type) were associated with improved outcomes.
Combination chemotherapy with bevacizumab and erlotinib showed clinical activity with infrequent grade 3 and 4 adverse effects in patients with advanced biliary cancers. On the basis of preliminary molecular analysis, presence of a k-ras mutation may alter erlotinib efficacy. The combination of bevacizumab and erlotinib may be a therapeutic alternative in patients with advanced biliary cancer.
To measure disparities between African Americans and whites in colorectal cancer incidence and mortality rates between 1995-2006 in Wisconsin.
Cancer incidence data were obtained from the Wisconsin Cancer Reporting System. Cancer mortality data were accessed from the SEER. Trends in incidence and mortality rates were calculated and changes in relative disparity were measured using rate ratios.
The relative disparity in incidence grew from 1.0 in 1995 and 1.3 in 2006. The relative disparity in death rates for African Americans widened as well, from 1.2 to 1.5.
A persistent and widening colorectal cancer racial disparity exists.
colorectal cancer; epidemiology; disparities
Capecitabine has shown similar efficacy to 5-fluorouracil (5-FU); a regimen containing 2 weeks of capecitabine/oxaliplatin (CapOx) has demonstrated noninferiority to infusional 5-FU/oxaliplatin/leucovorin (FOLFOX) for the treatment of metastatic colorectal cancer (mCRC). This phase II study explores the efficacy and safety of a 2-day course of oxaliplatin/capecitabine (2DOC), with oxaliplatin given on day 1 and capecitabine given orally every 8 hours in high doses over 6 doses, mimicking FOLFOX6.
Patients and Methods
This phase II study was conducted by the University of Wisconsin Carbone Cancer Center. Eligible patients with mCRC received oxaliplatin 100 mg/m2 intravenously (I.V.) over 2 hours followed by leucovorin 20 mg/m2 I.V. bolus and 5-FU 400 mg/m2 I.V. bolus on day 1 and day 15. Capecitabine was administered at 1500 mg/m2 orally every 8 hours over 6 doses starting on day 1 and day 15.
A total of 45 patients were enrolled; 44 were evaluated for response. Seventeen patients (39%) had objective responses. Median time to progression was 6.8 months, and median overall survival (OS) was 17.5 months. The most common side effects were grade 1/2 neuropathy, fatigue, and nausea. Severe hand-foot syndrome (HFS) was rare.
The overall response rate with the 2DOC regimen is similar to published CapOx regimens, and time to progression and OS are similar. The incidence of HFS, diarrhea, and mucositis were lower compared with published results of 2-week schedules of capecitabine. The 2DOC regimen merits further study as a more convenient regimen than infusional 5-FU with less HFS when compared with a 2-week administration of capecitabine.
2DOC; FOLFOX6; Irinotecan; Neutropenia; Thrombocytopenia
There are no clear predictors clinicians can use to determine who is more likely to experience dose limiting toxicity (DLT) in phase I chemotherapy clinical trials. Many providers are reluctant to refer older adults to phase I trials because of concerns about the development of toxicity. The goal of this study was to identify clinical and nonclinical factors which were associated with the development of DLT in phase I studies
Patients (pts) were included if they were treated at maximally tolerated dose (MTD) and above. Studies were included only if MTD was reached. Data collected included age, comorbidity (Cumulative Illness Rating Score-Geriatrics), labs at enrollment, height, weight, performance status, cancer type, duration of diagnosis, prior treatment, drug level, smoking status, marital status, mean income, percent of population high school educated as determined by ZIP code, and distance to the phase I trial hospital. Those who did and did not have DLT were compared by bivariate and then multivariate analysis.
242 charts were reviewed, from 24 cytotoxic chemotherapy studies, and 27 different types of cancer were represented. On bivariate analysis, mean age, household income (higher), weight, body surface area, dose of drug, alkaline phosphatase, hemoglobin, and LDH were significantly associated with DLT (p<0.05). CIRS-G score was not associated with DLT. In multivariate analysis dose level (p=0.004) and distance from the phase I trial hospital (p=0.04) were still significant predictors of DLT. Age did not predict for severity of DLT.
Age and comorbidity did not predict for development of DLT in phase I chemotherapy trials. Many of these pts were very fit, with relatively low CIRS-G scores, so the impact of comorbidity may not have been fully evaluated. Several social and clinical factors may predict for development of DLT. A prospective study is being planned to confirm these results.
Early hospital readmission is a common and costly problem in the Medicare population. In 2009, the Centers for Medicaid and Medicare Services began mandating hospital reporting of disease-specific readmission rates. We sought to determine the rate and predictors of readmission after colectomy for cancer, as well as the association between readmission and mortality.
Medicare beneficiaries who underwent colectomy for stage I-III colon adenocarcinoma from 1992–2002 were identified from the SEER-Medicare database. Multivariate logistic regression identified predictors of early readmission and one-year mortality. Odds ratios were adjusted for multiple factors, including measures of comorbidity, socioeconomic status, and disease severity.
Of 42,348 patients who were discharged, 4,662 (11.0%) were readmitted within 30 days. The most common causes of rehospitalization were ileus/obstruction and infection. Significant predictors of readmission included male gender, comorbidity, emergent admission, prolonged hospital stay, blood transfusion, ostomy, and discharge to nursing home. Readmission was inversely associated with hospital procedure volume, but not surgeon volume. After adjusting for potential confounding variables, the predicted probability of one-year mortality was 16% for readmitted patients, compared to 7% for those not readmitted. This difference in mortality was significant for all stages of cancer.
Early readmission after colectomy for cancer is common and due in part to modifiable factors. There is a remarkable association between readmission and one-year mortality. Early readmission is therefore an important quality-of-care indicator for colon cancer surgery. These findings may facilitate the development of targeted interventions that will decrease readmissions and improve patient outcomes.
Colon Cancer; Surgery; Colectomy; Readmission; Rehospitalization; Mortality; Hospital Discharge; Risk Factors; Outcomes
To evaluate the maximum tolerated dose (MTD), safety, and antitumor activity of sunitinib combined with paclitaxel and carboplatin.
Successive cohorts of patients with advanced solid tumors received oral sunitinib (25, 37.5, or 50 mg) for 2 consecutive weeks of a 3-week cycle (Schedule 2/1) or as a continuous daily dose for 3-week cycles (CDD schedule) in combination with paclitaxel (175–200 mg/m2) plus carboplatin (AUC 6 mg•min/mL) on day 1 of each of 4 cycles. Dose-limiting toxicities (DLTs) and adverse events (AEs) were evaluated to determine the MTD. Efficacy parameters were analyzed in patients with measurable disease.
Forty-three patients were enrolled (n = 25 Schedule 2/1; n = 18 CDD schedule). Across all doses, 6 DLTs were observed (grade 4 papilledema, grade 5 GI hemorrhage, grade 3 neutropenic infection, grade 4 thrombocytopenia [n = 3]). The MTD for Schedule 2/1 was sunitinib 25 mg plus paclitaxel 175 mg/m2 and carboplatin AUC 6 mg•min/mL. The MTD was not determined for the CDD schedule. Treatment-related AEs included neutropenia (77%), thrombocytopenia (56%), and fatigue (47%). Of 38 evaluable patients, 4 (11%) had partial responses and 12 (32%) had stable disease. PK data indicated an increase in maximum and total plasma exposures to sunitinib and its active metabolite when given with paclitaxel and carboplatin compared with sunitinib monotherapy.
Myelosuppression resulting in prolonged dose delays and frequent interruptions was observed, suggesting that this treatment combination is not feasible in the general cancer population.
Sunitinib; Phase I; Solid tumor; NSCLC; Antiangiogenesis; Chemotherapy