A multicentre open-label safety and efficacy study of tetrodotoxin for cancer pain.

BACKGROUND: Cancer pain is highly prevalent, and existing treatments are often insufficient to provide adequate relief. OBJECTIVES: We assessed the long-term safety and efficacy of subcutaneous tetrodotoxin treatment in reducing the intensity of chronic cancer-related pain. METHODS: In this multicentre open-label longitudinal trial, 30 µg tetrodotoxin was administered subcutaneously twice daily for 4 days in a heterogeneous cohort of patients with persistent pain despite opioids and other analgesics. "Responder" was defined as a mean reduction of 30% or more in pain intensity from baseline; and "clinical responder" as some pain reduction, but less than 30%, plus agreement on the part of both the patient and the physician that a meaningful analgesic response to treatment had occurred. RESULTS: Of 45 patients who entered the longitudinal trial, 41 had sufficient data for analysis. Of all 45 patients, 21 (47%) met the criteria for "responder" [16 patients (36%)] or "clinical responder" [5 patients (11%)]. Onset of pain relief was typically cumulative over days, and after administration ended, the analgesic effect subsided over the course of a few weeks. No evidence of loss of analgesic effect was observed during subsequent treatments (2526 patient-days in total and a maximum of 400 days in 1 patient). One patient withdrew from the study because of adverse events. Toxicity was usually mild (82%) or moderate (13%), and remained so through subsequent treatment cycles, with no evidence of cumulative toxicity or tolerance. CONCLUSIONS: Long-term treatment with tetrodotoxin is associated with acceptable toxicity and, in a substantial minority of patients, resulted in a sustained analgesic effect. Further study of tetrodotoxin for moderate-to-severe cancer pain is warranted.

Treatment-emergent hypertension and outcomes in patients with advanced non-small-cell lung cancer receiving chemotherapy with or without the vascular endothelial growth factor receptor inhibitor cediranib: NCIC Clinical Trials Group Study BR24.

BACKGROUND: Hypertension (HTN), a recognized adverse effect of angiogenesis inhibitors, may be a potential biomarker of activity of these agents. We conducted a retrospective analysis to examine the incidence and predictors of the development of on-treatment HTN with the vascular endothelial growth factor receptor tyrosine kinase inhibitor cediranib, and the relationship of this adverse event with treatment outcomes. PATIENTS AND METHODS: BR24 was a double-blind placebo-controlled phase II trial of carboplatin/paclitaxel chemotherapy with either daily oral cediranib or placebo in patients (n = 296) with advanced non-small-cell lung cancer (NSCLC). Exploratory analyses characterized relationships between HTN, baseline variables, and efficacy outcomes. RESULTS: New onset or worsening of preexisting HTN (treatment-emergent HTN) was more frequent in patients receiving cediranib (68 versus 45%, P < 0.0001). Factors associated with HTN in all randomized patients were good performance status and treatment with cediranib. In both arms, treatment-emergent HTN was associated with improved efficacy outcomes, but there was no evidence of a differential treatment effect, with nonsignificant interaction P values. CONCLUSIONS: In advanced NSCLC, HTN is frequent in patients receiving chemotherapy, with or without cediranib. The development of HTN was favorably prognostic in these patients, but not predictive of a differential outcome with cediranib.

A dose escalation trial of adjuvant cyclophosphamide and epirubicin in combination with 5-fluorouracil using G-CSF support for premenopausal women with breast cancer involving four or more positive nodes.

BACKGROUND: Dose-dense and dose-intensive regimens have improved the outcome of breast cancer in high-risk women with operable disease. PATIENTS AND METHODS: Sixty-three premenopausal women with Stage 2, 3 breast cancer and > or =4 positive axillary nodes were treated in three successive cohorts with 70 mg/m(2) of epirubicin, 500 mg/m(2) of 5-fluorouracil and G-CSF every 14 days for 12 cycles. Cyclophosphamide (C) was given at 700 mg/m(2), 900 mg/m(2), and 1100 mg/m(2) doses. Patients were evaluated for dose-limiting toxicities (DLTs) in the first four cycles, the primary endpoint of the trial. RESULTS: No DLTs were seen at C 700 mg/m(2); at C 900 mg/m(2) two of 16 patients experienced febrile neutropenia and poor performance status; at C 1100 mg/m(2), 1 of 31 patients experienced poor performance status. Over 6 months, febrile neutropenia, grade 4 thrombocytopenia, grade 3 anemia and severe fatigue were observed. Clinical congestive heart failure occurred in three patients over 4 years. CONCLUSION: A dose-intense and dose-dense regimen of cyclophosphamide, epirubicin and 5-fluorouracil was delivered with G-CSF without apparent increase in acute toxicity. Cyclophosphamide could be increased to more than twice the standard dose at the cost of more anemia and fatigue.

Comparison of oral capecitabine versus intravenous fluorouracil plus leucovorin as first-line treatment in 605 patients with metastatic colorectal cancer: results of a randomized phase III study.

PURPOSE: To compare the response rate, efficacy parameters, and toxicity profile of oral capecitabine with bolus intravenous (IV) fluorouracil plus leucovorin (5-FU/LV) as first-line treatment in patients with metastatic colorectal cancer. PATIENTS AND METHODS: We prospectively randomized 605 patients to treatment with oral capecitabine for 14 days every 3 weeks or 5-FU/LV by rapid IV injection daily for 5 days in 4-week cycles. RESULTS: The overall objective tumor response rate among all randomized patients was significantly higher in the capecitabine group (24.8%) than in the 5-FU/LV group (15.5%; P =.005). In the capecitabine and 5-FU/LV groups, median times to disease progression were 4.3 and 4.7 months (log-rank P =.72), median times to treatment failure were 4.1 and 3.1 months (P =.19), and median overall survival times were 12.5 and 13.3 months (P =.974), respectively. Capecitabine, compared with bolus 5-FU/LV treatment, produced a significantly lower incidence (P <.0002) of diarrhea, stomatitis, nausea, and alopecia. Patients treated with capecitabine also displayed lower incidences of grade 3/4 stomatitis and grade 3/4 neutropenia (P <.0001) leading to significantly less neutropenic fever/sepsis. Grade 3 hand-foot syndrome (P <.00001) and grade 3/4 hyperbilirubinemia were the only toxicities more frequently associated with capecitabine than with 5-FU/LV treatment. CONCLUSION: Oral capecitabine was more active than 5-FU/LV in the induction of objective tumor responses. Time to disease progression and survival were at least equivalent for capecitabine compared with the 5-FU/LV arm. Capecitabine also demonstrated clinically meaningful benefits over bolus 5-FU/LV in terms of tolerability.

Randomized study of CODE versus alternating CAV/EP for extensive-stage small-cell lung cancer: an Intergroup Study of the National Cancer Institute of Canada Clinical Trials Group and the Southwest Oncology Group.

PURPOSE: To determine whether an intensive weekly chemotherapy regimen plus thoracic irradiation is superior to standard chemotherapy in the treatment of extensive-stage small-cell lung cancer (ESCLC). PATIENTS AND METHODS: Patients with ESCLC were considered eligible for the study if they were younger than 68 years, had a performance status of 0 to 2, and were free of brain metastases. Patients were randomized to receive cisplatin, vincristine, doxorubicin, and etoposide (CODE) or alternating cyclophosphamide, doxorubicin, vincristine/etoposide and cisplatin (CAV/EP). Consolidative thoracic irradiation and prophylactic cranial irradiation were given to patients responding to CODE and according to investigator discretion on the CAV/EP arm. RESULTS: The fidelity of drug delivery on both drug regimens was equal, and more than 70% of all patients received the intended protocol chemotherapy. Although rates of neutropenic fever were similar, nine (8.2%) of 110 patients on the CODE arm died during chemotherapy, whereas one (0.9%) of 109 patients died on the CAV/EP arm. Response rates after chemotherapy were higher (P =.006) with CODE (87%) than with CAV/EP (70%). However, progression-free survival (median of 0.66 years on both arms) and overall survival (median, 0.98 years for CODE and 0. 91 years for CAV/EP) were not statistically different. CONCLUSION: The CODE regimen increased two-fold the received dose-intensity of four of the most active drugs in small-cell lung cancer compared with the standard CAV/EP regimen while maintaining an approximately equal total dose. Despite supportive care (but not routine prophylactic use of granulocyte colony-stimulating factor), there was excessive toxic mortality with the CODE regimen. The response rate with CODE was higher than that of CAV/EP, but progression-free and overall survival were not significantly improved. In view of increased toxicity and similar efficacy, the CODE chemotherapy regimen is not recommended for treatment of ESCLC.

Rivizor--a new third-generation aromatase inhibitor for the treatment of advanced breast cancer after tamoxifen failure.

Rivizor (vorozole) is a new, highly potent and selective third-generation aromatase inhibitor for treatment of advanced breast cancer. In an open-label study, 30 postmenopausal women failing tamoxifen therapy received Rivizor 2.5 mg once daily until disease progression. Rivizor produced clinical benefit (partial response or no change) in 16 of 27 evaluable patients (59.3%). Five patients (18.5%) had a partial response (UICC criteria) which lasted for a median of 15 months (range 14-42.5 months), 11 patients had disease stabilization for a median of 14 months (7-24 months), and 11 patients had disease progression. Median time to first response was 3.9 months (3-27.5 months): estimated median survival time for all patients was 22.8 months (2-52.8 months) and estimated median time to disease progression was 10.8 months (1.4-42.4 months). Estradiol levels decreased to below limits of detection from 1st month of treatment until study end. Androstenedione, 17alpha-hydroxyprogesterone, dehydroepiandrosterone, and free-testosterone levels were unaffected by Rivizor. ACTH stimulation tests demonstrated that Rivizor does not interfere with adrenal mineralocorticoid and glucocorticoid steroid synthesis. Adverse events were mild-to-moderate. Rivizor might be an effective and well-tolerated alternative treatment for postmenopausal advanced breast cancer patients following tamoxifen failure.

Use of dexamethasone and granisetron in the control of delayed emesis for patients who receive highly emetogenic chemotherapy. National Cancer Institute of Canada Clinical Trials Group.

PURPOSE: To evaluate the roles of granisetron and dexamethasone for emesis control on days 2 through 7 after the administration of cisplatin in doses of 50 mg/m2 or greater to patients who had not previously received chemotherapy. PATIENTS AND METHODS: Four hundred thirty-five eligible and assessable patients were randomized to one of two arms in a double-blind fashion: arm A; granisetron 3 mg intravenous (i.v.) plus dexamethasone 10 mg i.v. prechemotherapy followed by granisetron 1 mg orally at 6 and 12 hours, then granisetron 1 mg orally and dexamethasone 8 mg orally twice daily on days 2 through 7 (219 patients); arm B; as in arm A but with placebo substituted for granisetron on days 2 through 7 (216 patients). All patients completed diaries in which episodes of emesis and severity of nausea were recorded. RESULTS: The addition of granisetron on days 2 through 7 had no discernable impact on nausea and vomiting during this period. CONCLUSION: The administration of a 5-hydroxytryptamine3, receptor (5-HT3) antagonist, in this case granisetron, after 24 hours conferred no benefit. This negative result needs to be assessed in light of conflicting literature, but at present it does not appear that the routine use of these drugs in this setting is justified.

Phase III double-blind comparison of dolasetron mesylate and ondansetron and an evaluation of the additive role of dexamethasone in the prevention of acute and delayed nausea and vomiting due to moderately emetogenic chemotherapy.

PURPOSE: To compare the efficacy of dolasetron and ondansetron in controlling nausea and vomiting in the first 24 hours; to evaluate the efficacy when dexamethasone is added to either drug in the first 24 hours; and to extend these comparisons over 7 days in patients receiving moderately emetogenic chemotherapy. PATIENTS AND METHODS: This was a multicenter, double-blind, randomized study with six parallel arms that used a 2 x 2 factorial design in chemotherapy-naive patients. In arm 1, dolasetron (2.4 mg/kg) was given intravenously (I.V.) prechemotherapy, followed 24 hours later by oral dolasetron (200 mg once daily) for 6 days. Arms 2 and 3 consisted of dolasetron and dexamethasone 8 mg I.V., followed 24 hours later by oral dexamethasone (8 mg once daily) in one arm, and oral dexamethasone and dolasetron in the other, also for 6 days. In arms 4, 5, and 6, ondansetron (32 mg I.V. or 8 mg orally twice daily) was administered in a similar manner to arms 1, 2, and 3 before and 24 hours after chemotherapy. Mean nausea severity (MNS) was assessed on a visual analog scale (VAS) in a daily diary. RESULTS: Of 703 patients enrolled, 696 were eligible. There were 343 dolasetron- and 353 ondansetron-treated patients; 57% of dolasetron-treated patients had complete protection in the first 24 hours versus 67% of patients who received ondansetron (P = .013). MNS was also more pronounced on the dolasetron arm (P = .051). Sixty-seven percent of patients who received added dexamethasone in the first 24 hours had complete protection, compared with 55% without dexamethasone (P < .001). MNS was significantly reduced with the addition of dexamethasone (P < .001). At 7 days, dolasetron and ondansetron had equivalent complete protection rates (36% and 39%, respectively). With the addition of dexamethasone, 48% of patients compared with 28% had complete protection (P < .001). MNS was significantly improved with added dexamethasone (P < .001). CONCLUSION: At the doses used, dolasetron was significantly less effective than ondansetron at controlling nausea and vomiting in the first 24 hours in patients receiving moderately emetogenic chemotherapy, but there was no demonstrable difference between both drugs over 7 days. The addition of dexamethasone significantly improved the efficacy of both drugs in the first 24 hours and over 7 days.

The role of the 5-HT3 antagonists ondansetron and dolasetron in the control of delayed onset nausea and vomiting in patients receiving moderately emetogenic chemotherapy.

BACKGROUND: 5-HT3 antagonists are effective in reducing the acute nausea and vomiting caused by cancer chemotherapy. However, it is not clear whether continuing these agents beyond twenty four hours is useful in controlling emesis on days two to seven after chemotherapy. PATIENTS AND METHODS: Four hundred seven patients receiving moderately emetogenic chemotherapy who had been given dexamethasone 8 mg i.v. and either ondansetron 32 mg i.v. or dolasetron 2.4 mg/kg i.v. were randomized to continue either an oral form of their 5-HT3 antagonist (ondansetron 8 mg b.i.d. or dolasetron 200 mg daily) plus dexamethasone 8 mg p.o. daily or dexamethasone alone for days two to seven. Endpoints assessed by self-report were: 1) complete control (no vomiting, no rescue medications, no missing data) of emesis; 2) nausea severity; and 3) quality-of-life as measured by the EORTC QLQ-C30. RESULTS: Continuation of 5-HT3 antagonists improved slightly, but not significantly, the complete control rate (47% vs. 41%: P = 0.24 one-sided) after chemotherapy. However, mean nausea severity was significantly (P = 0.015 one sided) reduced (by 3 mm on a 10 cm scale) on the combined arm. Minimal differences in quality of life were observed. CONCLUSION: The benefit of continuing 5-HT3 antagonists beyond 24 hours is modest and the merits of routine use in these circumstances debatable.

Dexamethasone improves the efficacy of granisetron in the first 24 h following high-dose cisplatin chemotherapy.

The object of the study was to determine whether dexamethasone improved the efficacy of the serotonin receptor (5-HT3) antagonist granisetron in controlling acute (within 24 h) emesis in cancer patients receiving high-dose cisplatin chemotherapy and to ascertain whether continuation of granisetron after 24 h reduces the occurrence of delayed emesis. This randomised, double-blind, multicentre, three-arm study was conducted at 21 medical centres. A group of 292 nausea- and emesis-free patients with cancer, who had never had chemotherapy and were scheduled to receive at least 50 mg/m2 cisplatin, were given 3 mg granisetron i.v. in a 15-min infusion with or without 10 mg dexamethasone i.v. completed 5 min prior to high-dose cisplatin and 1 mg granisetron p.o. at +6 h and +12 h. Primary study end-points were control of emesis and nausea. Patients completed a self-report diary every 6 h for the first 24 h. At the end of the 24-h period, the patients who received dexamethasone had a significantly higher complete protection rate from emesis (64% compared to 39%) than those who received no steroid. Similarly, the dexamethasone-treated group had a significantly higher complete plus partial (0-2 emetic episodes) protection rate (84% compared to 64%). This study shows that dexamethasone markedly enhances the antiemetic efficacy of granisetron for acute-onset emesis in high-dose cisplatin chemotherapy.

Phase II study of vorozole (R83842), a new aromatase inhibitor, in postmenopausal women with advanced breast cancer in progression on tamoxifen.

This Phase II study was designed to determine the efficacy and tolerability of vorozole (R83842), a new nonsteroidal aromatase inhibitor, in postmenopausal women with advanced breast cancer in progression being treated with tamoxifen, and to correlate these effects with the hormonal profile and plasma drug levels. Twenty-nine eligible women with estrogen receptor-positive or unknown disease were treated with 2.5 mg vorozole once daily p.o. until disease progression. All 29 are evaluable for toxicity and 27 for response as assessed by International Union Against Cancer (UICC) criteria. After a median follow-up of 8 months, 3 patients (11%) had partial remission of their disease for 14, 15, and 16 months and 14 patients had disease stabilization for 7-24 months (median, 12). Patients with a normal carcinoembryonic antigen level (

A phase II study of menogaril in low-grade non-Hodgkin's lymphoma. An NCI Canada Clinical Trials Group study.

The NCI Canada Clinical Trials Group conducted a phase II study of menogaril given intravenously every 4 weeks in low-grade non-Hodgkin's lymphoma. Fifteen of 26 eligible patients had had no prior therapy. Partial responses were seen in 9 patients (35%). Toxicity was moderate including myelosuppression, nausea, phlebitis, alopecia, and lethargy. This drug has only modest activity in this potentially responsive group of patients.

Hyperosmolar non-ketotic diabetic coma: with particular reference to vascular complications.

Two West Indian men with no previous history of diabetes mellitus developed hyperosmolar non-ketotic diabetic coma. Intra-abdominal catastrophes secondary to mesenteric thrombosis played a major part in the death of these patients, in both of whom control of the hyperosmolar state had been achieved. Both patients had evidence of infarction of intestine at necropsy. Vascular thromboses are a major complication of this form of coma and must be considered when such patients develop signs of an acute abdomen.