S. Gertler

A Selective N-Type Ca2+-Channel Blocker Prevents CA1 Injury 24 h following Severe Forebrain Ischemia and Reduces Infarction following Focal Ischemia

SNX-111 (NEUREX Corporation, Menlo Park, CA, U.S.A.) an ω-conopeptide, was tested for cytoprotection following normothermic ischemia using both a four-vessel occlusion model of severe forebrain ischemia and a model of transient middle cerebral artery occlusion focal ischemia. Adult male Wistar rats were subjected to 10 min of forebrain ischemia followed by 7 days of reperfusion. A single dose of SNX-111 (5 mg/kg) was injected intravenously following delays of either 6 or 24 h after reperfusion. For 11 rats treated with saline, there was 78 ± 13% CA1 neuronal injury (mean ± SD); for 11 given SNX-111 delayed by 6 h, injury was reduced to 35 ± 30% (p < 0.01); and remarkably, treatment delayed by 24 h (n = 10), still resulted in protection, with only 50 ± 29% injury (p < 0.05). Adult male spontaneously hypertensive rats had transient occlusion of the right middle cerebral artery of 1.5- or 2-h duration followed by 22.5 or 22 h of reperfusion, respectively. Rats were randomly assigned to receive either saline or SNX-111 (5 mg/kg i.v.), with treatment starting immediately after reperfusion (1.5-h ischemic group) or at 1 h following the onset of ischemia (2-h ischemic group). In the 1.5-h ischemic group, saline-treated animals sustained 138 ± 32 mm3 of neocortical infarction (n = 9), and SNX-111 treatment resulted in an infarct reduction to 76 ± 25 mm3 (n = 9; p < 0.001). In the 2-h ischemic group, saline-treated controls sustained 211 ± 51 mm3 (n = 6) of infarction, and SNX-111 infusion attenuated the infarct size to 126 ± 50 mm3 (n = 5; p < 0.05). Because of the hypotensive effects of SNX-111, an additional SNX-111-treated group with intravenous norepinephrine blood pressure support was studied, using 2 h of focal ischemia and 22 h of reperfusion. In this group, combined treatment resulted in 141 ± 22 mm3 of infarction (n = 5; p < 0.05). These data suggest that Ca2+ fluxes through ω-conopeptide-sensitive N-type Ca2+ channels are critically involved in the pathogenesis of selective neuronal death up to 24 h after ischemia in the hippocampus and that this conopeptide protection extends, even when given late, to neocortical infarct reduction.

Use of Conjoint Analysis to Assess Breast Cancer Patient Preferences for Chemotherapy Side Effects

OBJECTIVE Our objective was to evaluate preferences associated with grade I/II and grade III/IV chemotherapy side effects among breast cancer patients receiving chemotherapy. We also assessed trade-offs that patients are willing to make between treatment side effects and the route and schedule of treatment administration. METHODS In this cross-sectional study, patients receiving chemotherapy for breast cancer completed a one-time Web survey. Conjoint analysis was used to elicit preferences for 17 grade I/II and III/IV side effects associated with available chemotherapies and regimens. In the analysis, the risk of each side effect was increased by 5%, holding all others constant, and the respective impact on patient preferences was identified. RESULTS A total of 102 women participated (mean age 54 ± 11). Among the grade I/II side effects, a 5% reduction in the risk of sensory neuropathy, nausea, and motor neuropathy had the highest impact on preferences. Among grade III/IV side effects, motor neuropathy, nausea/vomiting, and myalgia made the most difference. An oral twice-daily regimen was most preferred; however, patients were willing to receive an intravenous regimen relative to oral to avoid an increased risk of 5% in the majority of side effects. Avoiding an increased chance of grade III/IV motor neuropathy was associated with willingness to tolerate one of the least preferred administration schedules. CONCLUSION This study identified relative preferences among both mild/moderate to severe side effects from the patient perspective. Patients appear to be willing to make trade-offs between side effects and different regimens. These findings may help to inform medical decision-making processes.

Paclitaxel plus hydroxyurea as second line therapy for non-small cell lung cancer

We tested paclitaxel (Taxol) and low dose hydroxyurea as second line therapy in 30 patients with non-small cell lung cancer since both drugs are active against non-small cell lung cancer in other settings, and since hydroxyurea may reverse chemotherapy resistance by disrupting double minute chromosomes. Hydroxyurea 500 mg was given orally each Monday, Wednesday, Friday starting 1 week before paclitaxel, and continuing until removal from study. Paclitaxel 135 mg/m2 was given i.v. over > or = 1 h every 3 weeks with dexamethasone, diphenhydramine, and ranitidine. Patients could have paclitaxel doses escalated to 175 mg/m2 in course 2 and to 200 mg/m2 in course 3, where tolerated. Sixteen males and 14 females were treated. All patients had previously received a single cisplatin-based chemotherapy regimen and 23 had previously received radiotherapy. Twelve patients had adenocarcinomas, six had squamous cell carcinomas, and 12 had large cell carcinomas. Eight patients had Stage IIIb cancers and 22 had Stage IV. Paclitaxel doses were 135 mg/m2 in 56 courses, 175 mg/m2 in 24, and 200 mg/m2 in 15. Treatment was well tolerated. Median granulocyte nadirs were 2.5 (x 10(9)/l) for paclitaxel 135 mg/m2, 1.8 for 175 mg/m2, and 1.3 for 200 mg/m2. No patient developed febrile neutropenia, and none required a dose reduction. Two patients had reversible anaphylaxis. Other toxicities were quite tolerable. They included fatigue, myalgias, dizziness, paresthesias, diarrhea, alopecia, mucositis, flushing, headache, swollen red hands, and anxiety. One patient had a partial remission and 15 had stable disease (including six with minor responses). Median survival was 20 (95% CI, 12-34) weeks, with 19% of patients remaining alive at 1 year from initiation of treatment. This is a well-tolerated regimen with modest activity as second line chemotherapy for patients with non-small cell lung cancer previously treated with cisplatin regimens. Higher doses would be feasible and other strategies are now being explored.

Phase II study of a one hour paclitaxel infusion in combination with carboplatin for advanced non-small cell lung cancer

PURPOSE To determine the activity, toxicity, and optimal dose of paclitaxel when given by one hour infusion combined with carboplatin in advanced non-small cell lung cancer (NSCLC). PATIENTS AND METHODS Thirty-seven previously untreated patients with stage IIIB or IV NSCLC were enrolled. Paclitaxel was administered by one hour infusion at a dose of 175 mg/m2 for the first cycle, and was escalated up to 255 mg/m2 over successive cycles if tolerated. In the absence of toxicity, the carboplatin dose was kept constant at an area under the concentration-time curve (AUC) of 6. Cycles were repeated at 3-week intervals until progression or intolerable toxicity occurred. RESULTS Thirty-six patients were evaluable for toxicity and survival, and thirty-five for responses. The partial response rate was 10 of 35 (29%) and there were no complete responses. The median duration of response was 4.8 months (range 0.5-11.7 months). The median survival duration was 6.5 months, and 1 year survival was 31%. The mean paclitaxel dose was 188 mg/m2. Treatment was generally well tolerated. Four patients (11%) had febrile neutropenia. Five patients (14%) had grade 3 neuropathy, and 4 (11%) had grade 3 nausea and vomiting. Minor toxicities included alopecia, myalgias, arthralgias and stomatitis. CONCLUSIONS Paclitaxel and carboplatin is a well-tolerated regimen that can safely be given by a one hour paclitaxel infusion. The modest response rate observed in this study may be due to either the low dose-intensity of paclitaxel or the short infusion duration. Further trials to optimize the relative doses of paclitaxel and carboplatin are needed.

A phase I study of gemcitabine/cisplatin/etoposide in the treatment of small-cell lung cancer

PURPOSE To define the maximum tolerated dose and toxicity of combined cisplatin, etoposide, and gemcitabine in patients with small-cell lung cancer. METHODS We undertook a phase I study in patients with either extensive small-cell lung cancer with or without prior chemotherapy, or limited disease who had progressed or recurred despite prior treatment. Patients received cisplatin 75 mg/m2 i.v. day 1, etoposide 50-100 mg/m2 i.v. day 1 followed by oral administration of 50-100 mg/m2 days 2 5, and gemcitabine at either 800 or 1000 mg/m2 i.v. days 1 and 8, on a 3 weekly cycle. RESULTS We treated 20 patients, 14 at the 800 mg/m2 gemcitabine dose level, and six at the 1000 mg/m2 dose level. The protocol initially used an etoposide dose of 100 mg/m2 etoposide daily (i.v. day 1 and orally days 2-5), but the first two patients died of septic complications. With reduction of the etoposide dose to 50 mg/m2 daily x 5, the regimen was well tolerated. At this etoposide dose, neutropenia, mucositis, and gastrointestinal toxicity occurred in one patient at each of the two gemcitabine dose levels. In addition, one patient receiving gemcitabine at the 1000 mg/m2 level experienced a possible allergic reaction. The overall response rate was 54%. Patients on gemcitabine at the 800 mg/m2 level who had not received prior chemotherapy had the highest response rate, at 75%. CONCLUSION The recommended phase II doses for this regimen are cisplatin 75 mg/m2 i.v. day 1, etoposide 50 mg/m2 i.v. day 1 and orally days 2-5, and gemcitabine 800 mg/m2 i.v. days 1 and 8. Future trials should further examine the optimal relative doses and schedule of gemcitabine and etoposide.

High dose doxorubicin plus cisplatin in the treatment of unresectable mesotheliomas: report of four cases

Only a very small proportion of all patients with mesotheliomas can be cured surgically. Both radiotherapy and standard chemotherapy are generally considered to be of only limited usefulness. In this paper, we report four patients with unresectable mesotheliomas treated with the combination of cisplatin 105-120 mg/m2 plus doxorubicin 90 mg/m2. Toxicity was substantial, in that all four patients developed neutropenic sepsis and other grade 3 toxicity, but there were no treatment-related deaths. There were two patients with complete remissions (one persisting at > 4 years), one partial remission, and one stable disease with marked symptomatic improvement. This combination is toxic, but the anecdotal evidence of efficacy is suggestive that it may possibly be more active than lower doses of chemotherapy. It warrants further study in good performance status patients with unresectable mesotheliomas.

Can the referring surgeon enhance accrual of breast cancer patients to medical and radiation oncology trials? The ENHANCE study

INTRODUCTION The accrual rate to clinical trials in oncology remains low. In this exploratory pilot study, we prospectively assessed the role that engaging a referring surgeon plays in enhancing nonsurgical oncologic clinical trial accrual. METHODS Newly diagnosed breast cancer patients were seen by a surgeon who actively introduced specific patient-and physician-centred strategies to increase clinical trial accrual. Patient-centred strategies included providing patients, before their oncology appointment, with information about specific clinical trials for which they might be eligible, as evaluated by the surgeon. The attitudes of the patients about clinical trials and the interventions used to improve accrual were assessed at the end of the study. The primary outcome was the clinical trial accrual rate during the study period. RESULTS Overall clinical trial enrolment during the study period among the 34 participating patients was 15% (5 of 34), which is greater than the institutions historical average of 7%. All patients found the information delivered by the surgeon before the oncology appointment to be very helpful. Almost three quarters of the patients (73%) were informed about clinical trials by their oncologist. The top reasons for nonparticipation reported by the patients who did not participate in clinical trials included lack of interest (35%), failure of the oncologist to mention clinical trials (33%), and inconvenience (19%). CONCLUSIONS Accrual of patients to clinical trials is a complex multistep process with multiple potential barriers. The findings of this exploratory pilot study demonstrate a potential role for the referring surgeon in enhancing nonsurgical clinical trial accrual.

A randomized, double-blind trial evaluating the palliative benefit of either continuing pamidronate or switching to zoledronate in patients with high-risk bone metastases from breast cancer (The Odyssey Study).

155 Background: Questions remain around the optimal use of bone-targeted agents (BTA) in patients with bone metastases (BM) from breast cancer (BC). In Canada pamidronate (PAM) is the most commonly used BTA in BC.We explored whether a switch to a more potent BTA, like zoledronic acid (ZA), in patients who remain at high risk of skeletal related events (SREs) despite PAM use is associated with significant palliative benefit. METHODS BC patients with high risk BM (prior SRE, bone progression, bone pain or levels of bone turnover marker serum C-telopeptide (sCTX) >400ng/L) despite >3 months of PAM use were eligible. Patients were randomized in a double-blind manner to either switch to ZA or continue on PAM every 4 weeks for 12 weeks. Primary outcome was the proportion of patients achieving a fall in sCTX at 12 weeks. Secondary outcomes were pain control (BPI and FACT-BP) and toxicity. Results 73 patients completed the study. Median age 61 years (range 37 - 87), prior duration of PAM use 10 months (range 3 - 118). sCTX levels for all patients at baseline, 372+/- 471, week 12, 209 +/-290. Proportion of patients achieving a fall in sCTX from week 0 to week 12, 26/31 (84%) in ZA arm, 17/30 (57%) in PA arm, p=0.0262. Two patients were unable to complete the study due to deterioration in renal function (both receiving PAM), four due to progressive disease (two receiving ZA, two PAM), two patients chose to discontinue the study before completion (both receiving ZA). Four patients (5%) had SREs during the study, two receiving ZA, two receiving PAM. Quality of life and pain analysis shows no difference between week 0 and week 12 scores in either arm. Toxicity was predominantly grade 1 and 2, numerically there were more adverse effects in the ZA arm than PAM. Conclusion Switching patients with high risk BM from PAM to ZA leads to a reduction in sCTX levels but may be associated with more toxicity. Quality of life and pain scores were similar between the two treatments. While the literature suggests that a reduction in sCTX may correlate with reduced rate of SREs, given the lack of symptom improvement a switching strategy cannot be recommended. NCT01907880 Clinical trial information: NCT01907880.

Perceptions of vascular access for intravenous systemic therapy and risk factors for lymphedema in early-stage breast cancer— a patient survey

Background The choice of vascular access for systemic therapy administration in breast cancer remains an area of clinical equipoise, and patient preference is not consistently acknowledged. Using a patient survey, we evaluated the patient experience with vascular access during treatment for early-stage breast cancer and explored perceived risk factors for lymphedema. Methods Patients who had received systemic therapy for early-stage breast cancer were surveyed at 2 Canadian cancer centres. Results Responses were received from 187 patients (94%). The route of vascular access was peripheral intravenous line (IV) in 24%, a peripherally inserted central catheter (picc) in 42%, and a surgically inserted central catheter (port) in 34%. Anthracycline-based regimens were associated with a greater use of central vascular access devices (cvads- that is, a picc or port; 86/97, 89%). Trastuzumab use was associated with greater use of ports (49/64, 77%). Although few patients (7%) reported being involved in the decisions about vascular access, most were satisfied or very satisfied (88%) with their access type. Patient preference centred mainly on avoiding delays in the initiation of chemotherapy. Self-reported rates of complications (183 evaluable responses) were infiltration with peripheral IVs (9/44, 20%), local skin infections with piccs (7/77, 9%), and thrombosis with ports (4/62, 6%). Perceived risk factors for lymphedema included use of the surgical arm for blood draws (117/156, 75%) and blood pressure measurement (115/156, 74%). Conclusions Most patients reported being satisfied with the vascular access used for their treatment. Improved education and understanding about the evidence-based requirements for vascular access are needed. Perceived risk factors for lymphedema remain variable and are not evidence-based.

Hydroxyurea Did Not Enhance the Clinical Response to Vinblastine in Patients with Anthracycline-Resistant Metastatic Breast Cancer

Background Vinblastine is commonly used in metastatic breast cancer after anthracycline failure. The response rate to vinblastine is approximately 20%, with short duration of response. In vitro studies have shown that the addition of hydroxyurea resulted in increased accumulation of vinblastine in tumor cells and in loss of double minutes. We evaluated the combination of vinblastine and hydroxyurea in patients with anthracycline-resistant metastatic breast cancer. Patients and Methods Fourteen assessable patients with metastatic breast cancer were entered in the study. All patients had progressed on anthracyclines or progressed within 8 months of stopping anthracyclines. Patients received hydroxyurea (500 mg orally) every Monday, Wednesday and Friday starting one week before the first course of chemotherapy and continuing throughout treatment until disease progression. Vinblastine (6 mg/m2) was given intravenously every 21 days. Results The median number of courses for vinblastine was 3.5 (range, 1-6). Three patients had partial responses in soft tissue metastases (21%). Four patients had stable disease. Four patients had > grade 2 neutropenia, and 1 patient had grade 4 thrombocytopenia. There were 2 cases of grade 3 constipation, 2 of grade 3 nausea, and 1 each of grade 2 neuropathy and myalgia. There was no treatment-related mortality. Conclusions Low-dose hydroxyurea in combination with vinblastine has a 21% response rate in metastatic breast cancer after anthracycline failure. Toxicity was mild and generally reversible. At the adopted dose schedule of hydroxyurea, the antitumor activity of vinblastine in anthracycline-resistant metastatic breast cancer did not appear to be enhanced.