Paul D. Savage

Phase I trial of twice-weekly gemcitabine and concurrent radiation in patients with advanced pancreatic cancer

PURPOSE To determine the maximum-tolerated dose, dose-limiting toxicities, and potential antitumor activity of twice-weekly gemcitabine and concurrent radiation in patients with locally advanced pancreatic cancer. PATIENTS AND METHODS Nineteen patients with histologically confirmed adenocarcinoma of the pancreas were studied at the Wake Forest University Baptist Medical Center and the University of North Carolina at Chapel Hill. The initial dose of gemcitabine was 20 mg/m(2) by 30-minute intravenous infusion each Monday and Thursday for 5 weeks concurrent with 50.4 Gy of radiation to the pancreas. Gemcitabine doses were escalated in 20-mg/m(2) increments in successive cohorts of three to six additional patients until dose-limiting toxicity was observed. RESULTS The dose-limiting toxicities at 60 mg/m(2) given twice-weekly were nausea/vomiting, neutropenia, and thrombocytopenia. Twice-weekly gemcitabine at a 40-mg/m(2) dose was well tolerated. Of the eight patients eligible for a minimum follow-up of 12 months, three remain alive, one of whom has no evidence of disease progression. CONCLUSION A dose of twice-weekly gemcitabine at 40 mg/m(2) produced mild thrombocytopenia, neutropenia, nausea, and vomiting when delivered with concurrent radiation to the upper abdomen in patients with advanced pancreatic cancer. These data suggest this regimen is well tolerated and may possess significant activity. These data and other observations have resulted in a phase II Cancer and Leukemia Group B study to ascertain the efficacy of this treatment regimen in patients with locally advanced pancreatic cancer.

Reducing distress in cancer patients with an orientation program.

The purpose of this study was to test a brief orientation program for reducing anxiety, depressive symptoms, and overall distress in cancer patients at their initial clinic visit. One hundred and fifty consecutively referred patients seen in an oncology outpatient clinic were randomly assigned to an intervention or usual care control group. The intervention group received a clinic tour, general information about clinic operations, and a question and answer session with an oncology counselor. Outcome measures included the State‐Trait Anxiety Inventory (STAI), the Brief Profile of Mood States (POMS), the Center for Epidemiologic Studies‐Depression (CES‐D) Scale, and an oncology clinic questionnaire which were administered at the initial clinic visit and follow‐up. There were no statistically significant clinical or demographic differences between groups at initial assessment. At follow‐up, the intervention group had lower state anxiety, lower overall distress, and fewer patients reporting depressive symptoms. Patients in the intervention group demonstrated significantly more knowledge about clinic operations and greater satisfaction with care. These data provide evidence that anxiety, distress and depressive symptoms can be reduced with an orientation program. This finding has particular relevance in the early stages of diagnosis where patients may suffer symptoms of anxiety and depression.

Cystic changes in hepatic and peritoneal metastases from gastrointestinal stromal tumors treated with Gleevec.

AbstractBackground: Tyrosine kinase inhibitor (Gleevec or STI-571) must be considered the treatment of choice for metastatic gastrointestinal stromal tumors (GISTs). The purpose of this article is to address and illustrate a long-term follow-up of computed tomographic (CT) radiologic findings in patients with metastases from GIST after Gleevec treatment. Methods: We performed a retrospective review of seven patients (four male, three female) with unresectable metastases from GIST who were treated with STI-571 in a 1-year period. Patients were followed every 2–4 months by contrast-enhanced CT for up to 12 months. The size and attenuation of hepatic and peritoneal metastases on CT were measured and correlated. Results: Hepatic metastases from GISTs showed significant decreased attenuation from a mean of 60 HU to a mean of 32 HU (p < 0.01) in the first 2 months and continued decreasing attenuation to 23 HU at the 12-month follow-up. These metastases superficially resembled simple cysts. Most metastases became smaller, with more defined borders, after treatment. Histologic examination in a resected specimen revealed hepatic cyst with no residual tumor cells, regression of omental lesions, and extensive necrosis. Conclusions: CT findings of unresectable hepatic and peritoneal metastases from GIST displayed decreasing, near cystic attenuation and size as an effective regression in response to STI-571 treatment.

Inflammatory Myofibroblastic Tumor With Bone Marrow Involvement A Case Report and Review of the Literature

Inflammatory myofibroblastic tumor, also referred to as inflammatory fibrosarcoma, is a rare tumor composed of myofibroblastic spindle cells of uncertain etiology and disputed nosology. We report a case of inflammatory myofibroblastic tumor of the omentum with involvement of the bone marrow in an 18-year-old man. Histologic and immunohistochemical studies of the abdominal mass and bone marrow were consistent with inflammatory myofibroblastic tumor. Additionally, fluorescence in situ hybridization using a probe specific for the ALK gene showed disruption of the gene. The literature is reviewed with emphasis on the ability of inflammatory myofibroblastic tumor to recur, metastasize, and cause mortality.

Fine-Needle Aspiration Biopsy of Sarcomas and Related Tumors

BACKGROUND Largely due to a lack of experience, familiarity, and/or confidence, few centers rely on simple fine-needle aspiration biopsy (FNAB) for the diagnosis of sarcomas and related tumors. METHODS The authors have reviewed their own experience in more than 200 cases of FNAB of bone and soft-tissue tumors, as well as cases reported in the literature. RESULTS FNAB has proven to be accurate and useful in 8 consecutive years of clinical experience. No serious complications have occurred. CONCLUSIONS FNAB is recommended as an integral part of the initial evaluation of amenable orthopaedic tumors, including sarcomas, especially in cases with classic clinical and radiographic findings.

Phase I Study of Lenalidomide in Solid Tumors

Background: The primary objectives of this phase I study were to define a tolerable dose and to describe the toxicity of lenalidomide administered as a daily oral dose for 4 weeks followed by a 2-week rest period (6-week cycle) in patients with solid tumors that were refractory to standard treatment. The secondary objective was to document any antitumor activity. Methods: Key eligibility criteria included a performance status of 0–2 and acceptable hematologic, hepatic, and renal function. The dose was escalated from 5 to 10 to 25 mg/day. Nine cycles (54 weeks) were planned unless the patient developed intolerable toxicity or experienced tumor progression. Dose-limiting toxicity was defined as nonhematologic toxicity of grade 3 or higher and hematologic toxicity of grade 4 or higher occurring in cycle 1. Results: Overall, 20 patients were enrolled. One patient was ineligible due to a thromboembolic event within the preceding 6 months, but this was not known at enrollment and this patient was included in the analysis. Three, five, and 12 patients were treated with 5, 10, and 25 mg/day, respectively. One patient on 25 mg/day developed grade 3 motor neuropathy in cycle 1, and this was the only dose-limiting toxicity. Moderate dose-dependent and reversible hematologic toxicity was observed. The nonhematologic toxicities were otherwise mild to moderate over multiple cycles of lenalidomide. One patient had a partial response, and three patients had stable disease; three of these patients had non-small cell lung cancer. Conclusion: The recommended dose of lenalidomide for further studies in patients with solid tumors is 25 mg/day for 4 weeks followed by a 2-week rest period.

Schedule-selective biochemical modulation of 5-fluorouracil in advanced colorectal cancer – a phase II study

Background5-fluorouracil remains the standard therapy for patients with advanced/metastatic colorectal cancer. Pre-clinical studies have demonstrated the biological modulation of 5-fluorouracil by methotrexate and leucovorin. This phase II study was initiated to determine the activity and toxicity of sequential methotrexate – leucovorin and 5-fluorouracil chemotherapy in patients with advanced colorectal cancer.MethodsNinety-seven patients with metastatic colorectal cancer were enrolled onto the study. Methotrexate – 30 mg/m2 was administered every 6 hours for 6 doses followed by a 2 hour infusion of LV – 500 mg/m2. Midway through the leucovorin infusion, patients received 5-fluorouracil – 600 mg/m2. This constituted a cycle of therapy and was repeated every 2 weeks until progression.ResultsThe median age was 64 yrs (34–84) and the Eastern Cooperative Group Oncology performance score was 0 in 37%, 1 in 55% and 2 in 8% of patients. Partial and complete responses were seen in 31% of patients with a median duration of response of 6.4 months. The overall median survival was 13.0 months. The estimated 1-year survival was 53.7%. Grade III and IV toxic effects were modest and included mucositis, nausea and vomiting.ConclusionsThis phase II study supports previously reported data demonstrating the modest clinical benefit of 5-FU modulation utilizing methotrexate and leucovorin in patients with metastatic colorectal cancer. Ongoing studies evaluating 5-fluorouracil modulation with more novel agents (Irinotecan and/or oxaliplatin) are in progress and may prove encouraging.

MEDICAL MANAGEMENT OF METASTATIC SKELETAL DISEASE

The medical management of metastatic disease generally includes chemotherapy, hormonal therapy, and metabolic pharmacologic manipulations with medications, such as bisphosphonates as well as nonoperative physical measures, such as orthoses and ambulatory or mobility aids. This comprehensive complex care is best coordinated with the medical oncologist. If well planned and coordinated, such care can improve the life of the cancer patient greatly.

Reverse translation of phase I biomarker findings links the activity of angiotensin-(1-7) to repression of hypoxia inducible factor-1α in vascular sarcomas.

BackgroundIn a phase I study of angiotensin-(1–7) [Ang-(1–7)], clinical benefit was associated with reduction in plasma placental growth factor (PlGF) concentrations. The current study examines Ang-(1–7) induced changes in biomarkers according to cancer type and investigates mechanisms of action engaged in vitro.MethodsPlasma biomarkers were measured prior to Ang-(1–7) administration as well as 1, 2, 3, 4, and 6 hours after treatment. Tests for interaction were performed to determine the impact of cancer type on angiogenic hormone levels. If a positive interaction was detected, treatment-induced biomarker changes for individual cancer types were assessed. To investigate mechanisms of action, in vitro growth assays were performed using a murine endothelioma cell line (EOMA). PCR arrays were performed to identify and statistically validate genes that were altered by Ang-(1–7) treatment in these cells.ResultsTests for interaction controlled for dose cohort and clinical response indicated a significant impact of cancer type on post-treatment VEGF and PlGF levels. Following treatment, PlGF levels decreased over time in patients with sarcoma (P = .007). Treatment of EOMA cells with increasing doses of Ang-(1–7) led to significant growth suppression at doses as low as 100 nM. PCR arrays identified 18 genes that appeared to have altered expression after Ang-(1–7) treatment. Replicate analyses confirmed significant changes in 8 genes including reduction in PlGF (P = .04) and hypoxia inducible factor 1α (HIF-1α) expression (P < .001).ConclusionsAng-(1–7) has clinical and pre-clinical activity for vascular sarcomas that is linked to reduced HIF-1α and PlGF expression.

Primary osteosarcoma of the spermatic cord with synchronous bilateral renal cell carcinoma

Primary extraskeletal osteosarcoma of the spermatic cord is an extremely rare tumor with only two other cases being reported in the world literature. We describe a patient with this lesion who also had concomitant bilateral renal cell carcinoma. The management of this case and a review of this subject are presented.