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
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
Use of sentinel lymph node biopsy (SLNB) is under-reported by cancer registries’ “Scope of Regional Lymph Node Surgery” variable. In 2011, the Surveillance Epidemiology and End Results (SEER) Program recommended against its use to determine extent of axillary surgery, leaving a gap in the utilization of claims data for breast cancer research. The objective was to develop an algorithm using SEER registry and claims data to classify extent of axillary surgery for breast cancer.
We analyzed data for 24,534 breast cancer patients. CPT codes and number of examined lymph nodes classified the extent of axillary surgery. The final algorithm was validated by comparing the algorithm derived extent of axillary surgery to direct chart review for 100 breast cancer patients treated at our breast center.
Using the algorithm, 13% had no axillary surgery, 56% SLNB and 31% axillary lymph node dissection (ALND). SLNB was performed in 77% of node negative patients and ALND in 72% of node positive. In our validation study, concordance between algorithm and direct chart review was 97%.
Given recognized inaccuracies in cancer registries’ “Scope of Regional Lymph Node Surgery” variable, these findings have high utility for health services researchers studying breast cancer treatment. J. Surg. Oncol. ß 2014 Wiley Periodicals, Inc.
breast cancer; SEER-Medicare; axillary surgery
Survival benefit from adjuvant chemotherapy is established for stage III colon cancer; however, uncertainty exists for stage II patients. Tumor heterogeneity, specifically microsatellite instability (MSI) which is more common in right-sided cancers, may be the reason for this observation. We examined the relationship between adjuvant chemotherapy and overall 5-year mortality for stage II colon cancer by location (right- versus left-side) as a surrogate for MSI.
Using Surveillance, Epidemiology, and End Results (SEER)-Medicare data, we identified Medicare beneficiaries from 1992 to 2005 with AJCC stage II (n=23,578) and III (n=17,148) primary adenocarcinoma of the colon who underwent surgery for curative intent. Overall 5-year mortality was examined with Kaplan-Meier survival analysis and Cox proportional hazards regression with propensity score weighting.
Eighteen percent (n=2,941) of stage II patients with right-sided cancer and 22% (n=1,693) with left-sided cancer received adjuvant chemotherapy. After adjustment, overall 5-year survival benefit from chemotherapy was observed only for stage III patients (right-sided: HR 0.64; 95% CI, 0.59–0.68, p<0.001 and left-sided: HR 0.61; 95% CI, 0.56–0.68, p<0.001). No survival benefit was observed for stage II patients with either right-sided (HR 0.97; 95% CI, 0.87–1.09, p=0.64) or left-sided cancer (HR 0.97; 95% CI, 0.84–1.12, p=0.68).
Among Medicare patients with stage II colon cancer, a substantial number receive adjuvant chemotherapy. Adjuvant chemotherapy did not improve overall 5-year survival for either right- or left-sided colon cancers. Our results reinforce existing guidelines and should be considered in treatment algorithms for older adults with stage II colon cancer.
Psychological distress among cancer survivors is common. It is unknown if symptoms predate diagnosis or differ from patients without cancer because studies are limited to patient follow-up. Linked cohort (Wisconsin Longitudinal Study) and tumor registry records were used to assess the psychological distress response pre- to post-cancer diagnosis. Adjusted predicted probabilities of being in one of five categories of change for three psychological distress measures (depression, anxiety, well-being) were compared for participants diagnosed with cancer between 1993–1994 and 2004–2005 and participants without cancer (N=5,162). Cancer survivors were more likely to experience clinically significant increases (≥0.8 standard deviation) in depression (15%,95%CI=12–18%) and anxiety (19%, CI=16–22%) compared to their no-cancer counterparts (10%, CI=10–11%; 11%, CI=11–12%). Cancer survivors <5 years from diagnosis were more likely to experience worsening depression. Survivors ≥5 years were more likely to experience worsening anxiety. No significant results were found for well-being. Characterizing the psychological distress response is a prerequisite for identifying at-risk patients and communicating expected symptoms, allowing for proactive resource provision.
cancer; oncology; depression; anxiety; quality of life; psychological well-being
Chemotherapy has yielded minimal clinical benefit in pancreatic and biliary tract cancer. A high-dose, short course capecitabine schedule with oxaliplatin, has shown some efficacy with a lower incidence of palmar-plantar erythrodysesthesia. Achieving high exposures of the targeted agent sorafenib may be possible with this shorter schedule of capecitabine by avoiding dermatologic toxicity. All patients had pancreatic or biliary tract cancer. Patients in both cohorts received oxaliplatin 85 mg/m2 followed by capecitabine 2250 mg/m2 PO every 8 hours × 6 doses starting on days 1 and 15 of a 28 day cycle, or 2DOC (2 Day Oxaliplatin/Capecitabine). Cohort 1 used sorafenib 200 mg BID, and cohort 2 used sorafenib 400 mg BID. Sixteen patients were enrolled. Across all cycles the most common grade 1 or 2 adverse events were fatigue (10 pts), diarrhea (10 pts), nausea (9 pts), vomiting (8 pts), sensory neuropathy (8 pts), thrombocytopenia (7 pts), neutropenia (5 pts), and hand-foot syndrome (5 pts). Grade 3 toxicites included neutropenia, mucositis, fatigue, vomiting and diarrhea. Cohort 1 represented the MTD. Two partial responses were seen, one each in pancreatic and biliary tract cancers. The recommended phase II dose of sorafenib in combination with 2DOC is 200 mg BID. There were infrequent grade 3 toxicities, most evident with sorafenib at 400 mg BID.
Pancreatic cancer; bile duct cancer; oxaliplatin; sorafenib; capecitabine; chemotherapy
Age-related disparities in colon cancer treatment exist, with older patients less likely to receive recommended therapy. However, few studies have focused on receipt of surgery. The objective was to describe patterns of surgery in colon cancer patients ≥80 years and examine outcomes with and without colectomy.
Medicare beneficiaries ≥80 years with colon cancer diagnosed from 1992–2005 were identified from the Surveillance, Epidemiology and End Results- Medicare database. Multivariable logistic regression analysis was utilized to assess factors associated with non-operative management. Kaplan-Meier survival analysis determined one-year overall and colon cancer-specific survival.
Of 31,574 patients, 80% underwent colectomy. 46% occurred during an urgent/emergent admission, with decreased 1-year overall survival (70% vs. 86% during an elective admission). Factors most predictive of non-operative management include older age, black race, more hospital admissions, use of home oxygen, use of a wheel chair, being frail and dementia. For both operative and non-operative patients, one-year overall survival was lower than colon cancer-specific survival (colectomy 78% vs. 89%; no colectomy 58% vs. 78%).
Most older colon cancer patients are receiving surgery, with improved outcomes compared to non-operative management. However, many patients not selected for surgery die of unrelated causes, reflecting good surgical selection. Patients undergoing surgery during an urgent/emergent admission have an increased short-term mortality. As earlier detection of colon cancer may increase the proportion of older patients undergoing elective surgery, these findings have policy implications for colon cancer screening and suggest that age should not be the only factor driving cancer screening recommendations.
colon cancer; elderly; colectomy; octogenarian; nonagenarian; aged
American College of Surgeons Oncology Group (ACOSOG) Z0011 demonstrated that eligible breast cancer patients with positive sentinel lymph nodes (SLN) could be spared an axillary lymph node dissection (ALND) without sacrificing survival or local control. Although heralded as a “practice-changing trial”, some argue that the stringent inclusion criteria limit the trial’s clinical significance. The objective was to assess the potential impact of ACOSOG Z0011 on axillary surgical management of Medicare patients and examine current practice patterns.
Medicare beneficiaries aged ≥66 with non-metastatic invasive breast cancer diagnosed from 2001–2007 were identified from the Surveillance, Epidemiology and End Results-Medicare database (n=59,431). Eligibility for ACOSOG Z0011 was determined: SLN mapping, tumor <5 cm, no neoadjuvant treatment, breast conservation; number of positive nodes was determined. Actual surgical axillary management for eligible patients was assessed.
12% (6,942/59,431) underwent SLN mapping and were node positive. Overall, 2,637 patients (4.4% (2,637/59,431) of the total cohort but 38% (2,637/6,942) of patients with SLN mapping and positive nodes) met inclusion criteria for ACOSOG Z0011, had 1 or 2 positive lymph nodes, and could have been spared an ALND. Of these 2,637 patients, 46% received a completion ALND and 54% received only SLN biopsy.
Widespread implementation of ACOSOG Z0011 trial results could potentially spare 38% of older breast cancer patients who undergo SLN mapping with positive lymph nodes an ALND. However, 54% of these patients are already managed with SLN biopsy alone, lessening the impact of this trial on clinical practice in older breast cancer patients.
Although recommendations for breast cancer follow-up frequency exist, current follow-up guidelines are standardized, without consideration of individual patient characteristics. Some studies suggest oncologists are using these characteristics to tailor follow-up recommendations, but it is unclear how this is translating into practice. The objective was to examine current patterns of oncologist breast cancer follow-up and determine the association between patient and tumor characteristics and follow-up frequency.
The Surveillance, Epidemiology and End Results (SEER)-Medicare database was used to identify stage I-III breast cancer patients diagnosed 2000-2007 (n=39,241). Oncologist follow-up visits were defined using Medicare specialty provider codes and the linked AMA Masterfile. Multinomial logistic regression determined the association between patient and tumor characteristics and oncologist follow-up visit frequency.
Younger age (p<0.001), positive nodes (p<0.001), ER/PR positivity (p<0.001), and increasing treatment intensity (p<0.001) were most strongly associated with more frequent follow-up. However, after accounting for these characteristics, significant variation in follow-up frequency was observed. In addition to patient factors, the number and types of oncologists involved in follow-up was associated with follow-up frequency (p<0.001). Types of oncologists providing follow-up varied, with medical oncologists the sole providers of follow-up for 19-51% of breast cancer survivors. Overall, 58% of patients received surgical oncology and 51% undergoing radiation received radiation oncology follow-up, usually in combination with medical oncology.
Significant variation in breast cancer follow-up frequency exists. Developing follow-up guidelines tailored for patient, tumor, and treatment characteristics, while also providing guidance on who should provide follow-up, has the potential to increase clinical efficiency.
Individuals ≥80 years of age represent an increasing proportion of colon cancer diagnoses. Selecting these patients for elective surgery is challenging due to diminished overall health, functional decline, and limited data to guide decisions. The objective was to identify overall health measures that are predictive of poor survival after elective surgery in these oldest-old colon cancer patients.
Medicare beneficiaries ≥80 years who underwent elective colectomy for stage I-III colon cancer from 1992-2005 were identified from the Surveillance, Epidemiology and End Results(SEER)-Medicare database. Kaplan-Meier survival analysis determined 90-day and 1-year overall survival. Multivariable logistic regression assessed factors associated with short-term post-operative survival.
Overall survival for the 12,979 oldest-old patients undergoing elective colectomy for colon cancer was 93.4% and 85.7%, at 90-days and 1-year. Older age, male gender, frailty, increased hospitalizations in prior year, and dementia were most strongly associated with decreased survival. In addition, AJCC stage III (versus stage I) disease and widowed (versus married) were highly associated with decreased survival at 1-year. Although only 4.4% of patients were considered frail, this had the strongest association with mortality, with an odds ratio of 8.4 (95% confidence interval 6.4-11.1).
Although most oldest-old colon cancer patients do well after elective colectomy, a significant proportion (6.6%) dies by post-operative day 90 and frailty is the strongest predictor. The ability to identify frailty through billing claims is intriguing and suggests the potential to prospectively identify, through the electronic medical record, patients at highest risk of decreased survival.
Although 64% of cancer survivors are expected to live at least five years beyond diagnosis, the receipt of cancer screening by this population is unclear. The study objective is to assess the relation between a cancer diagnosis and future cancer screening, exploring provider, patient, and cancer-specific factors that explain observed relationships.
The Wisconsin Longitudinal Study (WLS) and Wisconsin Tumor Registry were used to identify two participant groups: 415 diagnosed with non-metastatic cancer between 1992-1993 (pre-cancer) and 2003-2004 (post-cancer) and 4,680 no-cancer controls. Adjusted average predicted probabilities of cancer screening were estimated with models that first did not include and then included, provider (provider relationship length), participant (depressive symptoms (CES-D)) and cancer-specific (time since diagnosis) factors. Participants with a history of the cancer associated with a given screening test were then excluded to assess whether relationships are explained by screening for recurrence versus second cancers.
Female cancer survivors were more likely than no-cancer controls to undergo pelvic/pap (70%, 95% confidence interval (CI)=63-76% and 61%,CI=59-63%) and mammography screening (86%,CI=78-90% and 76%,CI=74-77%), though male cancer survivors were not more likely to receive prostate exams (76%,CI=70-82% and 69%,CI=67-71%). After excluding people with a history of the cancer being screened for, there were few significant differences in cancer screening between short or long-term survivors (>5 years) and no-cancer controls. Relationships were not sensitive to adjustment for provider or participant factors.
The significant positive differences in cancer screening between people with and without cancer can be explained by screening for recurrence. Long-term cancer survivors are not more likely to receive follow-up screening for second cancers. This information should be used by providers to ensure patients receive recommended follow-up preventive care.
Cancer Screening; Cancer Survivorship; Primary Care; Preventive Care
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
Colorectal cancer is the fourth most commonly diagnosed cancer and the second leading cause of cancer-related death in Wisconsin. Incidence and mortality rates for colorectal cancer vary by age, race/ethnicity, geography, and socioeconomic status. From 2010 through 2012, the Wisconsin Comprehensive Cancer Control Program awarded grants to 5 regional health systems for the purpose of planning and implementing events to increase colorectal cancer screening rates in underserved communities.
Grantees were chosen for their ability to engage community partners in reaching underserved groups including African American, Hispanic/Latino, Hmong, rural, and uninsured populations in their service areas.
Grantees identified target populations for proposed screening events, designated institutional planning teams, engaged appropriate local partner organizations, and created plans for follow-up. All grantees implemented 1 or more colorectal cancer screening events within 6 months of receiving their awards. Events were conducted in 2 phases.
Participating health systems organized 36 screening events and distributed 633 individual test kits; 506 kits were returned, of which 57 (9%) tested positive for colorectal abnormalities. Of attendees who received screening, 63% were uninsured or underinsured, 55% had no previous screening, 46% were of a racial/ethnic minority group, 22% had a family history of cancer, and 13% were rural residents. This project strengthened partnerships between health systems and local organizations.
An effective strategy for improving colorectal cancer screening rates, particularly among underserved populations, is to award health systems grants for implementing community-based screening events in conjunction with community partners.
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.
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
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
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.