Phase Ib Trial of mFOLFOX6 and Everolimus (NSC-733504) in Patients with Metastatic Gastroesophageal Adenocarcinoma.

OBJECTIVES: Based upon preclinical data showing synergy with mTOR inhibition and platinum chemotherapy, this study explores the safety and tolerability of combining everolimus with mFOLFOX6 for patients with metastatic gastroesophageal adenocarcinoma. METHODS: Eligible patients with metastatic gastroesophageal adenocarcinoma received standard-dose mFOLFOX6 chemotherapy in combination with escalating doses of everolimus. RESULTS: Six patients were accrued to the first dose level of 2.5 mg everolimus daily with mFOLFOX6. Overall, the toxicity profile was manageable with expected grade 3 toxicities of mucositis and neutropenia. The dose-limiting toxicity (DLT) included a week delay in therapy greater than 7 days as a result of the first 2 courses of mFOLFOX6. Two patients experienced DLTs at the first dose level due to delays in their treatment caused by prolonged grade 2 neutropenia and fever with fatigue. They were allowed to continue with a dose reduction of their chemotherapy. The median overall survival and progression-free survival were 20.3 and 14.5 months, respectively. CONCLUSIONS: The combination of mFOLFOX6 and everolimus is an active regimen with 83% of the patients experiencing a partial response. p53 mutations were found in the 5 samples analyzed.

Pilot study of an interdisciplinary supportive care planning intervention in pancreatic cancer.

PURPOSE: A diagnosis of pancreatic cancer is often associated with higher symptom burden, lower functional status, and worse quality of life (QOL). To date, few interventions have focused on the unique QOL needs of patients with pancreatic cancer. The purpose of this pilot study is to determine the feasibility of an interdisciplinary supportive care planning intervention in patients with pancreatic cancer during disease-focused treatments. METHODS: Patients enrolled in this prospective, pre- and post-intervention pilot study received a supportive care intervention that included the following three components: comprehensive QOL assessment, case presentation at interdisciplinary care meetings, and two nurse-administered educational sessions on QOL concerns. Patients completed outcome measures that included the FACT-Hep, FACIT-Sp-12, and self-report of finances and out-of-pocket costs since diagnosis. Measures were completed at baseline prior to receiving the intervention, and follow-up occurred at 1 and 2 months post-intervention. RESULTS: A total of 10 patients were enrolled during a 4-month period who provided informed consent, received the intervention, and completed the study (58 % accrual). Examination of pre- and post-intervention QOL outcomes revealed changes across the three evaluation time points that were not statistically significant. Patients were highly satisfied with the intervention, with 80 % reporting that the intervention was "excellent." Discussions during the interdisciplinary care meetings and educational sessions were largely focused on physical and psychosocial needs. CONCLUSIONS: An interdisciplinary supportive care planning intervention was potentially feasible and acceptable for pancreatic cancer patients in an ambulatory care setting.

Rectal Cancer, Version 2.2015.

The NCCN Guidelines for Rectal Cancer begin with the clinical presentation of the patient to the primary care physician or gastroenterologist and address diagnosis, pathologic staging, surgical management, perioperative treatment, posttreatment surveillance, management of recurrent and metastatic disease, and survivorship. The NCCN Rectal Cancer Panel meets at least annually to review comments from reviewers within their institutions, examine relevant new data from publications and abstracts, and reevaluate and update their recommendations. These NCCN Guidelines Insights summarize major discussion points from the 2015 NCCN Rectal Cancer Panel meeting. Major discussion topics this year were perioperative therapy options and surveillance for patients with stage I through III disease.

Colon cancer, version 3.2014.

The NCCN Guidelines for Colon Cancer address diagnosis, pathologic staging, surgical management, perioperative treatment, posttreatment surveillance, management of recurrent and metastatic disease,and survivorship. This portion of the guidelines focuses on the use of systemic therapy in metastatic disease. The management of metastatic colorectal cancer involves a continuum of care in which patients are exposed sequentially to a variety of active agents, either in combinations or as single agents. Choice of therapy is based on the goals of treatment, the type and timing of prior therapy, the different efficacy and toxicity profiles of the drugs, the mutational status of the tumor, and patient preference.

Synchronous metastatic rectal cancer completely resected after multidisciplinary planning and treatment: a case report.

Colorectal cancer is a common and significant public health concern. The liver is the most common site of metastasis, and colorectal cancer liver metastases (CRLM) may affect up to 60% of patients at some time during the course of their disease. Approximately 25% of patients are found to have synchronous CRLM at the time of diagnosis, and these patients have a worse prognosis than those who develop metastases later in their disease course. In the absence of extrahepatic disease, resection of CRLM with negative margins along with chemotherapy can lead to a 5-year overall survival rate of up to 60%. This report presents the case of a 48-year-old man diagnosed with rectal cancer and synchronous liver metastases that a multidisciplinary tumor board initially deemed to be unresectable because of large size and insufficient future liver remnant. The patient underwent FOLFOX chemotherapy with bevacizumab and experienced conversion to resectable hepatic disease. After neoadjuvant short-course radiation treatment to the rectum, the patient underwent combined low anterior resection of the rectum and a right hepatectomy and was rendered disease-free. The management of the patient's clinical course with correlation to the NCCN Clinical Practice Guidelines in Oncology for Rectal Cancer is presented in this report, including discussion of the role of chemotherapy in the conversion of CRLM to resectable status, the role of surgical metastasectomy, and postoperative surveillance of patients with colorectal cancer.

Metastatic colon cancer, version 3.2013: featured updates to the NCCN Guidelines.

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Colon Cancer begin with the clinical presentation of the patient to the primary care physician or gastroenterologist and address diagnosis, pathologic staging, surgical management, perioperative treatment, patient surveillance, management of recurrent and metastatic disease, and survivorship. The NCCN Colon Cancer Panel meets annually to review comments from reviewers within their institutions and to reevaluate and update their recommendations. In addition, the panel has interim conferences as new data necessitate. These NCCN Guidelines Insights summarize the NCCN Colon Cancer Panel's discussions surrounding metastatic colorectal cancer for the 2013 update of the guidelines. Importantly, changes were made to the continuum of care for patients with advanced or metastatic disease, including new drugs and an additional line of therapy.

Localized colon cancer, version 3.2013: featured updates to the NCCN Guidelines.

The NCCN Clinical Practice Guidelines in Oncology for Colon Cancer begin with the clinical presentation of the patient to the primary care physician or gastroenterologist and address diagnosis, pathologic staging, surgical management, perioperative treatment, patient surveillance, management of recurrent and metastatic disease, and survivorship. The NCCN Colon Cancer Panel meets annually to review comments from reviewers within their institutions and to reevaluate and update their recommendations. In addition, the panel has interim conferences as new data necessitate. These NCCN Guidelines Insights summarize the NCCN Colon Cancer Panel's discussions regarding the treatment of localized disease for the 2013 update of the guidelines.

Angiogenesis inhibitors in the treatment of epithelial ovarian cancer.

Treatment of epithelial ovarian cancer involves surgical management with staging or debulking surgery and chemotherapy with a platinum and taxane-containing regimen. Despite achieving a 70-80 % complete remission, patients often will recur. Novel therapies are needed to improve the treatment of ovarian cancers. Tumor angiogenesis is a critical process involved in the growth and metastasis of ovarian cancer. Numerous phase II trials with angiogenesis inhibitors have been reported and have led to the development and completion of several recent phase III trials in both upfront and recurrent ovarian cancers. Future studies will need to focus on how and when to incorporate angiogenesis inhibitors in the treatment armamentarium for ovarian cancers.

Enhancing quality improvements in cancer care through CME activities at a nationally recognized cancer center.

Changing healthcare policy will undoubtedly affect the healthcare environment in which providers function. The current Fee for Service reimbursement model will be replaced by Value-Based Purchasing, where higher quality and more efficient care will be emphasized. Because of this, large healthcare organizations and individual providers must adapt to incorporate performance outcomes into patient care. Here, we present a Continuing Medical Education (CME)-based initiative at the City of Hope National Cancer Center that we believe can serve as a model for using CME as a value added component to achieving such a goal.

Phase II trial of bryostatin-1 in combination with cisplatin in patients with recurrent or persistent epithelial ovarian cancer: a California cancer consortium study.

BACKGROUND: The California Cancer Consortium has performed a Phase II trial of infusional bryostatin, a protein kinase C inhibitor isolated from the marine invertebrate bryozoan, Bugula Neritina, a member of the phylum Ectoprocta, in combination with cisplatin, in patients (pts) with recurrent platinum-sensitive or resistant ovarian cancer (OC). METHODS: Pts received bryostatin 45 mcg/m(2) as a 72 h continuous infusion followed by cisplatin 50 mg/m(2). Cycles were repeated every 3 weeks. Dosages were chosen based on phase I data obtained by the CCC in a population of pts with mixed tumor types. RESULTS: Eight pts with recurrent or persistent epithelial OC received 23 cycles of treatment. All pts had received previous platinum-based chemotherapy; two pts had received one prior course, five had received two prior courses, and one had received three prior courses of chemotherapy. The median age was 64 (range 32-72), and Karnofsky performance status 90 (range 80-100). A median of 3 cycles of chemotherapy were delivered (range: 1-5). The median progression-free and overall survivals were 3 and 8.2 months respectively. Best responses included two partial responses (one in a platinum-resistant pt), three pts with stable disease, and three progressions. All pts experienced Grade 3 or 4 toxicities including severe myalgias/pain/fatigue/asthenia in six pts, and severe nausea/vomiting/constipation in two other pts. One pt experienced a seizure and liver function tests were elevated in one other. CONCLUSIONS: A modest response rate is observed in pts with recurrent or persistent ovarian cancer treated with the combination of bryostatin and cisplatin. The toxicity profile, however, observed in this pt population (primarily severe myalgias), precludes tolerability and prevents this combination from further investigation at this dose and schedule. It is possible that platinum pre-exposure in OC patients exacerbates observed toxicity. Phase II dosages of investigational agents in OC pts that are determined by phase I trials in pts with other tumor types should be chosen cautiously.

Rectal cancer.

These NCCN Clinical Practice Guidelines in Oncology provide recommendations for the management of rectal cancer, beginning with the clinical presentation of the patient to the primary care physician or gastroenterologist through diagnosis, pathologic staging, neoadjuvant treatment, surgical management, adjuvant treatment, surveillance, management of recurrent and metastatic disease, and survivorship. This discussion focuses on localized disease. The NCCN Rectal Cancer Panel believes that a multidisciplinary approach, including representation from gastroenterology, medical oncology, surgical oncology, radiation oncology, and radiology, is necessary for treating patients with rectal cancer.

Anal Carcinoma, Version 2.2012: featured updates to the NCCN guidelines.

The workup and management of squamous cell anal carcinoma, which represents the most common histologic form of the disease, are addressed in the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Anal Carcinoma. These NCCN Guidelines Insights provide a summary of major discussion points of the 2012 NCCN Anal Carcinoma Panel meeting. In summary, the panel made 4 significant changes to the 2012 NCCN Guidelines for Anal Carcinoma: 1) local radiation therapy was added as an option for the treatment of patients with metastatic disease; 2) multifield technique is now preferred over anteroposterior-posteroanterior (AP-PA) technique for radiation delivery and the AP-PA technique is no longer recommended as the standard of care; 3) PET/CT should now be considered for radiation therapy planning; and 4) a section on risk reduction was added to the discussion section. In addition, the panel discussed the use of PET/CT for the workup of anal canal cancer and decided to maintain the recommendation that it can be considered in this setting. They also discussed the use of PET/CT for the workup of anal margin cancer and for the assessment of treatment response. They reaffirmed their recommendation that PET/CT is not appropriate in these settings.

Oligometastatic Breast Cancer Patients Treated with High-Dose Chemotherapy and Targeted Radiation: Long-Term Follow-Up of a Phase II Trial.

BACKGROUND: Patients with oligometastatic breast cancer (oMBC) may benefit from aggressive local therapy. We sought to assess the effects of consolidative radiation therapy (RT) on outcomes in oMBC patients treated on a prospective phase II trial of high-dose chemotherapy (HDCT). METHODS: Between 2005 and 2009, 12 patients with oMBC (≤3 metastatic sites) cancer were treated on protocol. Patients were to receive tandem HDCT supported by hematopoietic cell rescue (HCR). All radiographically identifiable oligometastatic sites received targeted radiation. RESULTS: HDCT was initiated at a median of 6.7 (3.5-12.7) months after diagnosis of oMBC. Hormone receptors (HR) were positive in 91.6% of patients, and HER2 was overexpressed in 25% of patients. Median radiation dose (EQD2) was 41.2 (37.9-48.7) Gy. Median follow-up was 13.1 (6.8-15.1) years for living patients. Ten-year PFS and OS were 33% (95%CI, 10-59%) and 55% (95%CI, 22-79%), respectively. Durable local control of treated lesions was 87.5%. At the last follow up, two patients remained progression free and two more were without evidence of disease following additional salvage treatment. CONCLUSIONS: Although modern systemic therapies have obviated the use of HDC, aggressive local therapy warrants further evaluation and fractionated radiotherapy is a viable alternative if SBRT is not available.

A phase I study of a combination of yttrium-90-labeled anti-carcinoembryonic antigen (CEA) antibody and gemcitabine in patients with CEA-producing advanced malignancies.

PURPOSE: To determine the maximum tolerated dose of combined therapy using an yttrium-90-labeled anti-carcinoembryonic antigen (CEA) antibody with gemcitabine in patients with advanced CEA-producing solid tumors. EXPERIMENTAL DESIGN: The chimeric human/murine cT84.66 is an anti-CEA intact IgG1, with high affinity and specificity to CEA. This was given at a fixed yttrium-90-labeled dose of 16.6 mCi/m(2) to subjects who had and an elevated CEA in serum or in tumor by immunohistochemistry. Also required was a tumor that imaged with an (111)In-labeled cT84.66 antibody. Patients were treated with escalating doses of gemcitabine given i.v. over 30 minutes on day 1 and 3 after the infusion of the yttrium-90-labeled antibody. Patients were treated in cohorts of 3. The maximum tolerated dose was determined as the highest level at which no >1 of 6 patients experienced a dose limiting toxicity. RESULTS: A total of 36 patients were enrolled, and all but one had prior systemic therapy. The maximum tolerated dose of gemcitabine in this combination was 150 mg/m(2). Dose limiting toxicities at a gemcitabine dose of 165 mg/m(2) included a grade 3 rash and grade 4 neutropenia. One partial response was seen in a patient with colorectal cancer, and 4 patients had a >50% decrease in baseline CEA levels associated with stable disease. Human antichimeric antibody responses were the primary reason for stopping treatment in 12 patients. CONCLUSIONS: Feasibility of combining gemcitabine with an yttrium-90-labeled anti-CEA antibody is shown with preliminary evidence of clinical response.

A phase II trial of vorinostat (suberoylanilide hydroxamic acid) in metastatic breast cancer: a California Cancer Consortium study.

PURPOSE: The primary goal of this trial was to determine the response rate of single-agent vorinostat in patients with metastatic breast cancer. The secondary goals included assessment of time to progression, evaluation of toxicities, and overall survival. EXPERIMENTAL DESIGN: From June 2005 to March 2006, 14 patients received vorinostat, 200 mg p.o., twice daily for 14 days of each 21 day cycle. Response and progression were evaluated using Response Evaluation Criteria in Solid Tumors (RECIST) criteria. RESULTS: The median age for all patients was 60.5 years (range, 37-88). Eight patients were estrogen receptor and/or progesterone positive, four were Her-2 positive. Sites of metastatic disease included brain, liver, lungs, bones, pelvis, pleura, chest wall, and distant lymph nodes. Patients received a median of 1.5 prior (range, 0-2) chemotherapeutic regimens for metastatic disease. Fatigue, nausea, diarrhea, and lymphopenia were the most frequent clinically significant adverse effects. The median number of cycles delivered was 2 (range, 1-20). There were no complete or partial responses, and the study was terminated after the first stage; however, 4 patients were observed with stable disease with time to progression of 4, 8, 9, and 14 months. The median number of months that patients received treatment on this study was 1.7 (range, 0.5-14). CONCLUSIONS: Although not meeting the RECIST response criteria for adequate single-agent activity, the observed tolerable toxicities and the potential for clinical benefit in terms of stable disease suggest that further assessment of vorinostat as a part of combination therapy with either chemotherapeutic or targeted agents in metastatic breast might be undertaken.

A phase I trial of intraperitoneal nab-paclitaxel in the treatment of advanced malignancies primarily confined to the peritoneal cavity.

PURPOSE: To evaluate intraperitoneal (IP) nab-paclitaxel in patients with advanced malignancies that are primarily confined to the peritoneal cavity in a phase I trial. METHODS: Using a 3 + 3 dose escalation of IP nab-paclitaxel on days 1, 8, and 15 of a 28-day cycle, we evaluated six dose levels (35-175 mg/m2/dose). Maximum tolerated dose (MTD) and pharmacokinetics (PK) of IP nab-paclitaxel were determined. RESULTS: There were no dose-limiting toxicities (DLTs) in cohorts 1-3. There was a DLT in one of six patients in cohort 4 (112.5 mg/m2) (grade 3 neutropenia causing treatment delay > 15 days) and a DLT in one of three patients in cohort 6 (175 mg/m2) (grade 4 neutropenia and grade 3 abdominal pain). A second patient in cohort 6 experienced a serious adverse event (cycle 1, grade 4 ANC ≤ 7 days, cycle 4, grade 2 left ventricular dysfunction). This dose level was determined to be above the MTD. No DLTs were seen in seven patients treated in cohort 5 (140 mg/m2). The MTD of IP nab-paclitaxel was established at 140 mg/m2 on days 1, 8, and 15 of a 28-day cycle. There was a PK advantage for IP nab-paclitaxel, with an IP plasma area under the concentration-time curve (AUC) ratio of 147-fold (range 50-403) and therapeutic range systemic drug levels. Eight of 27 enrolled patients had progression-free survival ≥ 6 months. One patient experienced complete response, and one patient experienced partial response. Six patients had stable disease. CONCLUSIONS: Weekly IP nab-paclitaxel has a favorable toxicity profile, a significant pharmacologic advantage, and promising clinical activity. CLINICAL TRIAL REGISTRATION: NCT00825201.

Randomized trial of oral cyclophosphamide versus oral cyclophosphamide with celecoxib for recurrent epithelial ovarian, fallopian tube, and primary peritoneal cancer.

BACKGROUND: Oral metronomic chemotherapy, which has low toxicity, has demonstrated promising anti-tumor and anti-angiogenic properties that may lead to prolonged progression-free survival and improved response rates in patients with recurrent epithelial ovarian cancer (EOC). These effects may be enhanced by the co-administration of anti-angiogenic agents. METHODS: We conducted a randomized phase II clinical trial to evaluate the therapeutic benefit of oral metronomic cyclophosphamide (CTX) alone and with the anti-angiogenic drug celecoxib in patients with gynecological malignancies. 52 patients were randomly assigned to two treatments arms: 50 mg oral CTX daily alone (Arm A) or with 400 mg celecoxib twice daily (Arm B). The primary endpoint was response rate. Secondary endpoints included toxicity, time to treatment failure, and overall survival. RESULTS: In Arm A (n = 26), 3 patients (12%) had stable disease >6 months and 1 (4%) had a partial response. In Arm B, 5 (19%) had stable disease >6 months and 1 patient (4%) had a partial response. There were no significant between-group differences in overall survival (9.69 months [95% CI 3.84-13.18] vs. 12.55 months [6.67-17.61]) or in median time to treatment failure (1.84 months [1.68-2.76] vs. 1.92 months [1.64-5.22]). The most common adverse events were nausea, vomiting, and abdominal pain. CONCLUSIONS: Oral metronomic CTX has activity with no major toxicities in heavily pretreated recurrent gynecological cancers and may be considered in patients with indolent disease. We did not observe any additional benefit of celecoxib treatment, though this may be due to small sample sizes.

Phase I trial of intraperitoneal gemcitabine in the treatment of advanced malignancies primarily confined to the peritoneal cavity.

PURPOSE: To determine the maximally tolerated dose, toxicity, and pharmacokinetics of i.p. gemcitabine. EXPERIMENTAL DESIGN: Patients had peritoneal carcinomatosis. Gemcitabine (40, 80, 120, or 160 mg/m(2)) was administered into the peritoneal cavity in 2 L of warmed saline on days 1, 4, 8, and 12 of a 28-day cycle. RESULTS: Thirty patients received 63 (median, 2; range, 0-6) courses. Tumors included ovary (14), uterus (2), colon (6), pancreas (3), and others (5). Dose-limiting toxicity included nausea, vomiting, diarrhea, dyspnea, fatal respiratory failure, and grade 3 elevation of alanine aminotransferase in three patients. Hematologic toxicity and pain were

p53-Reactive T Cells Are Associated with Clinical Benefit in Patients with Platinum-Resistant Epithelial Ovarian Cancer After Treatment with a p53 Vaccine and Gemcitabine Chemotherapy.

Purpose: To conduct a phase I trial of a Modified Vaccinia Ankara vaccine delivering wild-type human p53 (p53MVA) in combination with gemcitabine chemotherapy in patients with platinum-resistant ovarian cancer.Experimental Design: Patients received gemcitabine on days 1 and 8 and p53MVA vaccine on day 15, during the first 3 cycles of chemotherapy. Toxicity was classified using the NCI Common Toxicity Criteria and clinical response assessed by CT scan. Peripheral blood samples were collected for immunophenotyping and monitoring of anti-p53 immune responses.Results: Eleven patients were evaluated for p53MVA/gemcitabine toxicity, clinical outcome, and immunologic response. TOXICITY: there were no DLTs, but 3 of 11 patients came off study early due to gemcitabine-attributed adverse events (AE). Minimal AEs were attributed to p53MVA vaccination. Immunologic and clinical response: enhanced in vitro recognition of p53 peptides was detectable after immunization in both the CD4+ and CD8+ T-cell compartments in 5 of 11 and 6 of 11 patients, respectively. Changes in peripheral T regulatory cells (Tregs) and myeloid-derived suppressor cells (MDSC) did not correlate significantly with vaccine response or progression-free survival (PFS). Patients with the greatest expansion of p53-reactive T cells had significantly longer PFS than patients with lower p53-reactivity after therapy. Tumor shrinkage or disease stabilization occurred in 4 patients.Conclusions: p53MVA was well tolerated, but gemcitabine without steroid pretreatment was intolerable in some patients. However, elevated p53-reactive CD4+ and CD8+ T-cell responses after therapy correlated with longer PFS. Therefore, if responses to p53MVA can be enhanced with alternative agents, superior clinical responses may be achievable. Clin Cancer Res; 24(6); 1315-25. ©2018 AACR.