A retrospective analysis of cardiovascular morbidity in metastatic hormone-refractory prostate cancer patients on high doses of the selective COX-2 inhibitor celecoxib.

This data were previously presented in February 2007 at the American Society of Clinical Oncology's Prostate Cancer Symposium in Orlando, FL, USA. COX-2 inhibition has shown promise in treating prostate cancer, but concerns exist regarding the risk profile associated with this class of drugs. This study analyzes the cardiovascular and cerebral vascular morbidity associated with high doses of the COX-2 inhibitor, celecoxib, in patients with metastatic hormone-refractory prostate cancer (mHRPC). We retrospectively reviewed 67 patients with mHRPC who were treated at our institution between 1999 and 2005. All charts were reviewed for cardiac risk factors and the clinical course whilst on therapy and post-treatment was analyzed. This study included 34 patients who were on protocols that involved celecoxib 400 mg b.i.d.. Treatment ranged from 21 to 355 days, with a median of 118.5 days. There were three myocardial infarctions (MIs)--two in the study group and one in the control group. One patient had a MI while on treatment, but he had a significant cardiac disease history. There were also two cerebral vascular accidents (CVAs) in each group, although none in any patient who was on-study. Although this is a small study, these findings, in the context of other published data, suggest that some patients with advanced malignancies may still benefit from therapies involving COX-2 inhibitors without clinically significant increase in risk for MI or CVA.

A double-blind placebo-controlled randomized phase III trial of 5-fluorouracil and leucovorin, plus or minus trimetrexate, in previously untreated patients with advanced colorectal cancer.

BACKGROUND: Trimetrexate (TMTX) biochemically modulates 5-fluorouracil (5-FU) and leucovorin (LCV). Two phase II trials demonstrated promising activity for TMTX/5-FU/LCV in patients with untreated advanced colorectal cancer (ACC). This trial was designed to demonstrate the safety and efficacy of TMTX/5-FU/LCV as first-line treatment in ACC. PATIENTS AND METHODS: Eligible patients with ACC were randomized in double-blind fashion to receive placebo or TMTX (110 mg/m2) intravenously (i.v.) followed 24 h later by i.v. LCV 200 mg/m2, and 5-FU 500 mg/m2 plus oral LCV rescue. Both schedules were given weekly for 6 weeks every 8 weeks. Patients were evaluated for progression-free survival (PFS), overall survival (OS), tumor response, quality of life (QoL) and toxicity. RESULTS: A total of 382 eligible patients were randomized. Significant toxicities were noted more frequently with TMTX/5-FU/LCV. Diarrhea was the most common grade 3 or 4 side-effect (41% and 28% on the TMTX and placebo arms, respectively). QoL scores and response rates did not differ between treatment arms. PFS was 5.3 months and 4.4 months in the TMTX and placebo arms, respectively (P = 0.77; Wilcoxon). OS was 15.8 months and 16.8 months, respectively (P = 0.73; Wilcoxon). CONCLUSIONS: The addition of TMTX to a weekly regimen of 5-FU/LCV worsened grade 3 or 4 diarrhea. The inclusion of TMTX did not yield any significant improvements in response rate, PFS or OS.

Survival of patients who had salvage castration after failure on bicalutamide monotherapy for stage (D2) prostate cancer.

Patients with hormone-naive stage D2 prostate cancer often benefit from castration. This treatment, however, frequently produces many unacceptable physical and psychological side effects, especially in younger and sexually active patients. Bicalutamide is an oral antiandrogen with excellent tolerance and preservation of sexual function. Three institutions participated in phase II and III trials of bicalutamide monotherapy (50 mg daily) as primary therapy in hormone-naive patients with stage D2 prostate cancer. Upon bicalutamide failure, all patients underwent castration and were followed until death. Fifty-four patients received bicalutamide 50 mg orally once a day. One patient (2%) had complete response, 9 patients (17%) had partial response, and 27 patients (50%) had stable disease. Seventeen patients (31%) had progressive disease. The median time to bicalutamide failure was 47.4 weeks, 70.5 weeks for the responders vs. 25.4 weeks for the nonresponders (p < 0.001). The median survival time after the sequential use of bicalutamide and castration was 119.2 weeks for all 54 patients, 162.0 weeks for the responders, and 73.5 weeks for nonresponders (p < 0.0001). The median survival time after initiation of castration was 71.1 weeks for all 54 patients, 91.4 weeks for bicalutamide responders, and 42.1 weeks for nonresponders (p < 0.01). In hormone-naive patients with stage D2 prostate cancer, sequential treatment with bicalutamide monotherapy followed by castration upon failure may produce survival time within the range reported for initial treatment with castration. Thus, considering the favorable quality of life profile of bicalutamide, further studies are needed to define the role of sequential hormonal therapy in younger sexually active patients.

The memorial symptom assessment scale short form (MSAS-SF).

BACKGROUND: The Memorial Symptom Assessment Scale Short Form (MSAS-SF), an abbreviated version of the Memorial Symptom Assessment Scale, measures each of 32 symptoms with respect to distress or frequency alone. A physical symptom subscale (PHYS), psychologic symptom subscale (PSYCH), and global distress index (GDI) can be derived from the Short Form. We validated the MSAS-SF in a population of cancer patients. METHODS: Two hundred ninety-nine cancer patients examined at the Section of Hematology/Oncology completed the MSAS-SF and the Functional Assessment Cancer Therapy (FACT-G). The Karnofsky performance status (KPS), extent of disease (EOD), and demographic data were assessed. The Cronbach alpha coefficient was used to assess internal reliability. MSAS-SF subscales were assessed against subscales of the FACT-G, the KPS, and EOD to determine criterion validity. Test-retest analysis was performed at 1 day and at 1 week. RESULTS: The Cronbach alpha coefficients for the MSAS-SF subscales ranged from 0.76 to 0.87. The MSAS-SF subscales showed convergent validity with FACT subscales. Correlation coefficients were -0.74 (P < 0.001) for the PHYS and FACT-G physical well-being subscales, -0.68 (P < 0.001) for the PSYCH and FACT emotional well-being subscales, and -0.70 (P < 0.001) for GDI and FACT summary of quality-of-life subscales. The MSAS-SF subscales demonstrated convergent validity with performance status, inpatient status, and extent of disease. The test-retest correlation coefficients for the MSAS-SF subscales ranged from 0.86 to 0.94 at 1 day and from 0.40 to 0.84 for the 1 week group. CONCLUSIONS: The MSAS-SF is a valid and easy to use instrument for symptom assessment.

Symptom and quality of life survey of medical oncology patients at a veterans affairs medical center: a role for symptom assessment.

BACKGROUND: The current study was conducted to assess symptom prevalence and symptom intensity and their relation to quality of life in medical oncology patients at a Veterans Affairs medical center. METHODS: Consecutive inpatients and outpatients were asked to complete the Functional Assessment Cancer Therapy (FACT-G), Memorial Symptom Assessment Scale (MSAS), and the Brief Pain Inventory. Symptoms then were analyzed by their relation to Karnofsky performance status (KPS) and quality of life. RESULTS: Two hundred forty patients participated. The median number of symptoms was 8 per patient (range, 0-30 symptoms). The 5 most prevalent symptoms were lack of energy (62%), pain (59%), dry mouth (54%), shortness of breath (50%), and difficulty sleeping (45%). Patients with moderate intensity pain had a median number of 11 symptoms and patients with moderate intensity lack of energy had a median number of 13 symptoms. The number of intense symptoms increased as the KPS decreased (P < 0.001). Patients with moderately intense pain or fatigue also were more likely to experience nausea, dyspnea, and lack of appetite. The number of symptoms rated as present on the MSAS was found to correlate significantly with the FACT-G Sum Quality of Life score. CONCLUSIONS: Intense symptoms were highly prevalent in this population. The presence of pain, lack of energy, or poor performance status should lead to comprehensive symptom assessment. Patients free of disease nevertheless still may experience intense symptoms. The number of symptoms present may be a helpful guide to quality of life. Routine comprehensive symptom assessment may identify a significant fraction of patients who urgently require intensive symptom palliation.

Phase II study of trimetrexate, fluorouracil, and leucovorin for advanced colorectal cancer.

PURPOSE: A phase II study to evaluate the response rate and toxicities of a trimetrexate, fluorouracil (5FU), and leucovorin regimen in patients with advanced incurable colorectal cancer. PATIENTS AND METHODS: Thirty-six patients with unresectable or metastatic colorectal cancer who had not been treated for advanced disease received the following chemotherapy regimen weekly for six courses every 8 weeks: trimetrexate 110 mg/m2 intravenously (I.V.) on day 1, leucovorin 200 mg/m2 I.V. on day 2 (24 hours later), 5FU 500 mg/m2 on day 2 immediately following leucovorin, and oral leucovorin 15 mg every 6 hours for seven doses starting 6 hours after 5FU. Patients were treated until progression or unacceptable toxicity. RESULTS: Thirty patients were assessable for response, and all 36 were assessable for toxicity. Two patients (7%) achieved a complete response (CR) and 13 (43%) a partial response (PR), for an overall response (OR) rate of 50% (95% confidence interval [CI], 32% to 68%). Analysis by intent to treat demonstrated a 42% OR rate (95% CI, 26% to 58%). At final analysis, 16 patients were alive. The median survival duration for the entire cohort was 53.4 weeks. Gastrointestinal toxicity was most common, with 21 patients (58%) having grade 3/4 diarrhea and 12 patients (34%) grade 3/4 nausea. Hematologic toxicity was generally low grade, although two patients died of sepsis. CONCLUSION: The combination of trimetrexate with 5FU and leucovorin is active in metastatic colorectal cancer. Gastrointestinal toxicity with this regimen is most prominent, but is manageable.

A double-blind, randomized study of two different dosage regimens of intravenous dolasetron in patients receiving high-dose cisplatin chemotherapy.

This study compared the antiemetic efficacy and safety of two different intravenous (i.v.) dolasetron dosing regimens in patients receiving their first course of high-dose (> or = 80 mg/m2) cisplatin. Of 30 patients enrolled, 14 received a single i.v. dolasetron dose (0.6 mg/kg) before cisplatin and 16 received a multiple i.v. dose regimen (0.6 mg/kg x 3) given before and after cisplatin. Complete plus major responses were achieved by 71% (10/14) of patients who received single-dose dolasetron and by 50% (8/16) of those who received the multiple-dose regimen. Forty-three percent (6/14) of patients who received the single dose had a complete response compared with 25% (4/16) who received multiple doses. Multiple doses resulted in less nausea at 24 hr following cisplatin; however, differences were not statistically significant. Both regimens were well tolerated, with mild headache (33%) and diarrhea (13%) the most common adverse events. This study demonstrated that a single 0.6-mg/kg dose of dolasetron given before chemotherapy provides equivalent antiemetic efficacy to three 0.6-mg/kg doses given before and after high-dose cisplatin chemotherapy; thus, there was no additional antiemetic benefit by using the multiple-dose regimen.

Single-agent therapy with bicalutamide: a comparison with medical or surgical castration in the treatment of advanced prostate carcinoma.

OBJECTIVES: Single-agent therapy with bicalutamide, a nonsteroidal antiandrogen, was compared with castration, either surgical or medical, in patients with untreated Stage D2 prostate cancer. METHODS: In an open, randomized, multicenter trial, patients were randomized to treatment with 50 mg bicalutamide (n = 243) once daily or to castration (n = 243), either orchiectomy or depot injection of goserelin acetate every 28 days. Primary efficacy endpoints were times to treatment failure and objective disease progression and survival. Assessments included review of measurable metastases, prostate dimensions, Eastern Cooperative Oncology Group performance status, pain, analgesic requirements, and quality of life responses. RESULTS: The median duration of therapy was 39 weeks for bicalutamide-treated patients and 42 weeks for castrated patients; treatment failure occurred in 53% and 42% and disease progression in 43% and 33%, respectively. Treatment effects favored castration for both endpoints (P < or = 0.002), with hazard ratios (bicalutamide:castration) of 1.54 (95% confidence interval [CI], 1.18 to 2.00) for time to treatment failure and 1.6 (95% CI, 1.19 to 2.15) for time to disease progression. From the 1-year survival analysis, the hazard ratio for probability of death was 1.29 (95% CI, 0.96 to 1.72). Thus far, with a median follow-up of 86 weeks, median survival has not been reached in either group. Changes from baseline in several quality of life variables were significantly different (P < or = 0.01) between treatment groups periodically from months 1 to 6, and all favored bicalutamide. Overall, the antiandrogen was well tolerated compared with castration; with bicalutamide, hot flushes occurred less often and breast tenderness and gynecomastia more often. CONCLUSIONS: Although a dosage of 50 mg of bicalutamide once daily was not as effective as castration, the favorable quality of life outcomes and the low incidence of nonhormonal adverse events provide reasons to evaluate bicalutamide, as a single therapeutic agent, at higher doses.

Case report: primary choriocarcinoma of the stomach.

An 80-year-old man with gastrointestinal hemorrhage was found to have primary choriocarcinoma of the stomach with liver metastases. Review of the literature revealed that this patient had the highest reported level of beta human chorionic gonadotrophin.

A phase II trial of alternating chemotherapy in patients with inoperable non-small cell lung cancer.

We assessed the efficacy and toxicity of alternating non-cross-resistant chemotherapy in the treatment of advanced NSCLC. Cycles of cisplatin, methotrexate, doxorubicin, and cyclophosphamide were alternated monthly with cisplatin and etoposide. Patients had measurable disease, ECOG performance status 0-3, no previous chemotherapy, and stage II (inoperable), III, or IV disease without brain metastases. Between 1988 and 1990, 28 patients were entered in the study: 20 patients (71%) had stage IV disease, 19 (68%) were evaluable for response and toxicity; 4 (21%) responded. There were 3 partial responders (16%) and 1 complete responder (5%). The mean duration of response was 60.5 weeks (range: 32-105+ weeks), and the median time to progression was 12 weeks (range: 8-105+ weeks). The median survival time for all 28 patients was 24 weeks (range: 3-153+ weeks). The most significant toxicity was grade 3-4 leukopenia experienced by 63% of patients, but there were no episodes of sepsis and no treatment-related deaths. This regimen of alternating cycles of cisplatin-containing chemotherapy is safe, but its efficacy is not superior to other combination chemotherapy regimens.

Taxol in advanced, hormone-refractory carcinoma of the prostate. A phase II trial of the Eastern Cooperative Oncology Group.

BACKGROUND: Recent clinical trials have documented activity for combinations of chemotherapeutic agents that target the microtubular apparatus in patients with hormone-refractory prostate cancer. Taxol has a novel antimicrotubular mechanism, acting by stabilizing polymerized tubulin. METHODS: Twenty-three patients with hormone-refractory prostate cancer and bidimensionally measurable disease were treated with Taxol by 24-hour continuous infusion at 135-170 mg/M2 every 21 days for a maximum of 6 cycles. RESULTS: Eighty-five courses of Taxol were administered to 23 patients. One patient (4.3%) experienced a partial response lasting 9 months, and four other patients with radiographically stable disease had minor reductions in the serum prostate-specific antigen (PSA) of 16-24%. Eleven patients (47.8%) had stable disease, and progressive disease developed in 9 patients (39.1%) during therapy. Median survival was 9 months. Leukopenia was the dose-limiting toxicity with 13% of patients having Grade 3 and 61% having Grade 4 toxicity, and granulocytopenic fever developed in 26%. Three patients experienced sudden cardiovascular events while participating in the study, including one patient with a nonfatal, non-Q-wave myocardial infarction that occurred during a taxol infusion, and two patients who had sudden deaths 9 days and 30 days after receiving their last taxol dose, respectively. CONCLUSIONS: In the subset of patients with hormone-refractory prostate cancer and bidimensionally measurable disease, Taxol at this dosage has only minor activity.

Carcinoid syndrome in the absence of liver metastasis: a case report and review of literature.

A patient with carcinoid tumor of the head of pancreas and carcinoid syndrome presented without liver metastasis. The patient had retroperitoneal lymphadenopathy. He had symptoms of flushing, diarrhea and abdominal pain. 5-Hydroxyindoleacetic acid (5-HIAA) was elevated. Absence of liver metastasis was documented not only by the negative computed tomography (CT) scan and liver/spleen scan, but also by autopsy. Except for carcinoid arising from ovary, testis, or bronchi, the other carcinoid tumors rarely cause carcinoid syndrome without liver metastasis. The literature was reviewed, and the findings are presented.

A single-blind comparison of intravenous ondansetron, a selective serotonin antagonist, with intravenous metoclopramide in the prevention of nausea and vomiting associated with high-dose cisplatin chemotherapy.

Ondansetron (GR 38032F), a selective antagonist of serotonin subtype 3 receptors, is effective in the prevention of emesis associated with cisplatin as well as other chemotherapeutic agents. In this randomized, single-blind, multicenter, parallel group study, we compared the efficacy and safety of intravenous (IV) ondansetron with IV metoclopramide in the prevention of nausea and vomiting associated with high-dose (greater than or equal to 100 mg/m2) cisplatin chemotherapy. Three hundred seven patients receiving their first dose of cisplatin, either alone or in combination with other antineoplastic agents, were randomized to receive ondansetron 0.15 mg/kg IV every 4 hours for three doses or metoclopramide 2 mg/kg IV every 2 hours for three doses, then every 3 hours for three additional doses. The study prohibited the concurrent administration of other antiemetics or dexamethasone. Patients receiving ondansetron had a higher rate of complete protection from emesis (40% v 30%, P = .07), a higher complete plus major response rate (65% v 51%, P = .016), a lower rate of failure (21% v 36%, P = .007), and a lower median number of emetic episodes (one v two, P = .005) than did those receiving metoclopramide. The median time to the first emetic episode was longer on ondansetron (20.5 v 4.3 hours, P less than .001). Adverse events occurred in 48% of patients receiving ondansetron and 69% of those receiving metoclopramide (P less than .001). Akathisia and acute dystonic reactions occurred only on metoclopramide; headache (controlled with acetaminophen) was significantly more frequent with ondansetron. Ondansetron is more effective, produces fewer adverse events, and is easier to administer than metoclopramide for the prevention of emesis associated with high-dose cisplatin chemotherapy.

Good tolerance to high-dose hepatic arterial infusion therapy.

A pilot study was designed to evaluate the efficacy of high-dose FUDR administered through the hepatic artery for the treatment of cancer involving the liver. Three dose schedules were used beginning with a dose of 0.5 mg FUDR/kg/day for 2 weeks followed by normal saline infusion for 2 weeks (schedule A). Elevation of serum bilirubin was the sole indication to deescalate to schedule B (0.3 mg FUDR/kg/day for two weeks followed by saline infusion for 4 weeks). Tolerance to this schedule escalated the patient to schedule C (0.5 mg FUDR/kg/day for 2 weeks followed by normal saline infusion for 4 weeks). Eighteen patients were treated, sixteen with metastatic colon cancer, one with metastatic leiomyosarcoma, and one with hepatoma. The patient with hepatoma developed progressive disease after one cycle of therapy. Of the 17 patients with metastatic cancer only 5 patients failed therapy yielding a 70% response rate. High-dose FUDR was well tolerated with only six patients requiring deescalation to schedule B. Elevation of alkaline phosphatase and glutamic oxaloacetic transaminase was universal. Two patients developed peptic ulceration. Sclerosing cholangitis was not observed. We conclude that high-dose FUDR administered through the hepatic artery is as safe as conventional dose infusion therapy but probably not more effective. The safety of high-dose FUDR infusion therapy suggests that sclerosing cholangitis is association with hepatic arterial infusion therapy is not related to the FUDR dose.

Relationship between changes in the histologic subtype of small cell carcinoma of the lung and the response to chemotherapy.

It has been documented that changes in the histopathologic subtype of small cell carcinoma of the lung (SCCL) may occur after chemotherapy. The significance of such changes with respect to response to treatment has not yet been studied. In a retrospective review of 25 patients, we correlated their response from chemotherapy with morphologic changes seen in subsequent histologic material. Eleven patients responded to therapy and 14 failed to respond. A difference in original histologic subtype was found in 10 (71%) of the nonresponders and in only two (18%) of the responders. The difference was statistically significant (p less than 0.05). We conclude that patients with "pure" SCCL in the initial biopsy specimen who fail to respond to chemotherapy are likely to have mixed or combined histologic subtypes in subsequent tissue specimens, although we cannot preclude their pre-existence. An attempt to search for different histologic subtypes is warranted in patients who do not respond to chemotherapy regimens considered to be efficacious in SCCL.

Cyclophosphamide versus 5-fluorouracil, doxorubicin, and mitomycin C (FAM') in the treatment of hormone-resistant metastatic carcinoma of the prostate: a preliminary report of a randomized trial.

There is no evidence that combination chemotherapy is superior to single agents in the treatment of advanced, hormone-resistant carcinoma of the prostate. We are reporting the preliminary results of a randomized trial comparing cyclophosphamide (CTX) with a combination of 5-fluorouracil, doxorubicin and mitomycin C (FAM'). Thirty-one patients were randomized and 30 of them were evaluable for response. Sixteen patients were treated with CTX and 14 with FAM'. On the CTX arm, eight (50%) of the patients had stable disease (SD) and eight (50%) had progressive disease (PD). On the FAM' arm, one (7%) patient had partial response (PR), five (36%) patients had SD and eight (57%) failed to respond. The difference in response rates between the two regimens was not significant (P greater than .72). The median time to progression (MTP) of all patients treated with CTX was six weeks and the MTP of patients treated with FAM' was 16 weeks (P less than .007). This difference in MTP could be explained in part by the unequal time to reevaluation between the two regimens. The MTP of the responders on CTX however, was 13 weeks, while for FAM' it was 33 weeks (P = .014). This difference suggests that FAM' has superior activity to CTX. Pain alleviation was seen in 25% of patients treated with CTX and in 64% of those treated with FAM' (P less than .01). Toxicity was tolerable on both regimens. We conclude that CTX and FAM' have similar response rates. Patients treated with FAM' enjoyed longer MTP and greater pain alleviation than those treated with CTX.

Combination chemotherapy with 5-fluorouracil, CCNU, and vincristine in metastatic colorectal carcinoma.

Twenty-four patients with metastatic colorectal carcinoma were treated with a chemotherapeutic regimen consisting of 5-fluorouracil, CCNU, and vincristine (FCV). Twenty patients were evaluable for response and 22 were evaluable for drug toxicity. One patient (5%) showed partial response, eight patients (40%) had stabilization of disease, and the remaining 11 patients (55%) had progression of disease. There was no statistically significant difference between the median survivals of patients with stabilization and of those with progression of their disease (p greater than 0.01). We were unable to demonstrate objective efficacy of the FCV regimen in the schedule used.