Albert M. Bernath

Low dose elective brain irradiation in small cell carcinoma of the lung

Abstract Elective brain irradiation (EBI) in a dosage of 3000 rad (midplane) in 2 weeks (nominal standard dose (NSD) = 1314 ret) has proven highly effective in preventing initial brain relapse in small cell lung carcinoma. However, the optimal radiation dose for EBI is unknown. 55 patients (31 with regional disease, 24 with extensive disease) without brain metastases were treated with a 4 drug chemotherapy program, (lomustine (CCNU), methotrexate, cyclophosphamide, vincristine) plus radiotherapy (R.T.), 3000 rad in 2 weeks to the primary chest lesion and were randomized to EBI or a control group. The EBI consisted of 2400 rad whole brain, midplane, in 8 fractions, 10 days (NSD = 1130 ret) given at the same time as the R. T. to the primary (3 weeks post-initial chemotherapy). Though all 54 evaluable patients received CCNU 50 Mg/M 2 q. 6 weeks, there were 5 initial brain relapses among 31 control patients (16%) vs none in the 23 EBI patients. The time at risk for recurrence was similar in the two groups, i.e. 31 weeks median in the EBI and 32 weeks in the no-EBI patients. Brain relapses occurred in 2/17 with limited disease and 3/14 with extensive disease. It appears that 2400 rad in 8 fractions is as effective for EBI as larger doses. Toxicity was limited to alopecia. Survival was not significantly affected by EBI, though there is a suggestion of improvement in the regional group.

Increased self-efficacy to quit and perceived control over withdrawal symptoms predict smoking cessation following nicotine dependence treatment

AIM To examine changes in nicotine withdrawal, nicotine craving, self-efficacy to quit smoking, and perceived control over withdrawal symptoms as predictors of smoking cessation following behavioral counseling and nicotine replacement therapy in a sample of smokers. DESIGN AND SETTING The data were ascertained from a randomized effectiveness trial comparing nicotine patch to nicotine lozenge. Predictors of smoking cessation were assessed at baseline and 5 weeks post-baseline, and 24-hour point prevalence abstinence, biochemically confirmed, was assessed at the end-of-treatment (week 15) and 6 months after a target quit date (week 27). PARTICIPANTS 642 treatment-seeking smokers randomized to 12 weeks of nicotine patch or nicotine lozenge. FINDINGS Participants who showed a greater increase in self-efficacy to quit smoking (OR=1.09, 95% CI: 1.02-1.16, p=.01) and perceived control over withdrawal symptoms (OR=1.02, 95% CI: 1.00-1.04, p=.05) were significantly more likely to have quit smoking at week 15. Participants who showed a greater increase in self-efficacy to quit smoking (OR=1.04, 95% CI: 1.01-1.06, p=.01) were significantly more likely to have quit smoking at week 27. Changes in withdrawal symptoms and craving were not related to week 15 or week 27 abstinence rates. CONCLUSIONS The results highlight two relatively under-studied potential psychological predictors of abstinence following treatment for nicotine dependence. Behavioral counseling interventions to promote smoking cessation should help smokers develop confidence in their ability to quit smoking and increase their sense of control over withdrawal symptoms to increase their chances for cessation.

Randomized Comparison of a Nicotine Inhaler and Bupropion for Smoking Cessation and Relapse Prevention

OBJECTIVE To compare the combination of a nicotine inhaler and bupropion to either treatment alone for initiating smoking abstinence and relapse prevention. METHODS Smokers were randomized to receive a nicotine inhaler, bupropion, or both for 3 months. At 3 months, smoking-abstinent study participants were randomized to their initial medications or placebo. Participants who were smoking at 3 months were randomized to an alternative treatment regimen or placebo. This study was conducted from July 2001 to January 2003. RESULTS A total of 1700 smokers were randomized to treatment (phase 1) for 3 months. Among the 941 study participants eligible for randomization to the phase 2 trial, 837 continued in the study. For the phase 2 trial, 405 smoking-abstinent participants were randomized to relapse prevention for 9 additional months, and 432 smokers were randomized to re-treatment for an additional 3 months. At the end of the initial 3 months of treatment (phase 1), 82 (14%) of 566, 145 (26%) of 567, and 194 (34%) of 567 study participants receiving a nicotine inhaler, bupropion, or both, respectively, were abstinent from smoking. Of the 405 smoking-abstinent participants at the end of 3 months, the bupropion group had more smokers than the placebo group (mean No. of smokers, 1.5 vs 1.1; P < .001), and the nicotine inhaler group had higher smoking abstinence rates at 12 months than the placebo group. Those receiving combination therapy had reduced rates of relapse to smoking for the first 3 months of relapse prevention, but this difference disappeared after the initial 3 months. Of the 432 study participants who were smoking at the end of 3 months and who received an alternative treatment regimen, the 223 smokers initially assigned to a nicotine inhaler were more likely to stop smoking at 6 months if they were re-treated with bupropion instead of placebo (8 [7%] of 111 vs 0 [0%] of 112; P = .003), and the 209 smokers initially treated with bupropion and re-treated with a nicotine inhaler did not have significantly higher smoking abstinence rates (6 [6%] of 104 vs 3 [3%] of 105; P = -.50). CONCLUSION Combined therapy with a nicotine inhaler and bupropion increased smoking abstinence rates. Continuation of the initial combination therapy does not appear to prevent relapse to smoking. Timing of re-treatment and alternative approaches to relapse prevention should be further examined.

Phase III Evaluation of 4 Doses of Megestrol Acetate as Therapy for Patients with Cancer Anorexia and/or Cachexia

Several randomized, placebo-controlled clinical trials have demonstrated that megestrol acetate therapy can result in appetite stimulation and nonfluid weight gain in patients with cancer anorexia/cachexia. The present trial was designed to compare megestrol acetate doses ranging from 160 to 1,280 mg/day. day. This trial randomly assigned 342 evaluable patients with cancer anorexia/cachexia to receive oral megestrol acetate at doses of 160, 480, 800 and 1,280 mg/day. Patients were evaluated monthly by history, examination and patient-completed questionnaires, as well as by serum albumin levels. The data demonstrate a positive dose-response effect for megestrol acetate on appetite stimulation (p = 0.02). there was a trend for more nonfluid weight gain with higher drug doses. Megestrol acetate was well tolerated in this group of patients with advanced malignant disease. The positive dose-response effect observed for megestrol acetate on appetite stimulation supports both the prestudy hypothesis and findings in the literature. The optimal dose in this study seemed to be 800 mg/day; no further benefit was derived from using the higher dose. Nonetheless, it may be reasonable to start with lower initial doses in routine clinical practice, taking into account dosage form, availability and cost of therapy.

A North Central Cancer Treatment Group Phase II Trial of Topotecan in Relapsed Gliomas

Current systemic treatment options for patientswith relapsed gliomas are limited. Thetopoisomerase I inhibitor topotecan has demonstrated broadantitumor activity in both preclinicalstudies as well as a number of phase I and II trials in humans.Studies in primates have shown goodcerebrospinal fluid levels of topotecan following systemicadministration. We therefore performed this phase II trial in patients who developed evidence of progressive glioma after definitive radiation therapy. Patients were treated with 1.5mg/m2 intravenously daily for 5 consecutive days repeatedevery three weeks. For patients who had received priornitrosourea-containing chemotherapy, thestarting dose was 1.25 mg/m2. Thirty-three patients wereentered on this study. All patients wereeligible and evaluable for both response and toxicity. Sevenpatients experienced grade 4 leukopeniawith 2 of these patients dying of infection-relatedcomplications. Six of these seven patients werenot taking anticonvulsants during treatment. Nine patientsdeveloped grade 3-4 thrombocytopenia,seven of whom were not taking anticonvulsants. Nonhematologicside effects were infrequent andmanageable. One patient experienced a partial response to thistreatment for an overall response rateof 3% (95% binomial confidence interval 0.3%-20.4%). The median time to progression was 14.9weeks and median survival 19.9 weeks. Topotecan at this dose andschedule showed no substantial activity in relapsed gliomas.

Correlates of smoking cessation self-efficacy in a community sample of smokers

While numerous studies show that higher levels of smoking cessation self-efficacy predicts motivation to quit smoking and successful smoking cessation, few studies have evaluated factors related to smoking cessation self-efficacy that could be targets of behavioral interventions to promote greater confidence to quit smoking. This study, using a large community sample of smokers enrolled in a smoking cessation treatment program, evaluated potential associations between self-efficacy to quit smoking and demographic (e.g., age, race), smoking-related (e.g., rate, cessation history, past use of treatments), and psychosocial (e.g., stress, cue reactivity, self-medication smoking) variables. The results indicated that Hispanic-American smokers, relative to smokers of other racial/ethnic groups, report significantly lower self-efficacy to quit smoking when facing internal stimuli (e.g., feeling depressed), as do smokers who report that they have little confidence to control abstinence-induced symptoms (F(9,576)=6.9, p<.001). The results also indicated that smokers who reported that they have little confidence to control abstinence-induced symptoms and report high smoking urge reactivity to situations that illicit positive affect (e.g., at a bar, with coffee, at a party) report lower self-efficacy to quit smoking when facing external stimuli (e.g., during a celebration; F[7,600]=9.05, p<.05). These findings can be used to refine behavioral smoking cessation interventions to increase self-efficacy to quit smoking.

Subcutaneous interleukin-4 (IL-4) for relapsed and resistant non-Hodgkin lymphoma : A phase II trial in the North Central Cancer Treatment Group, NCCTG 91-78-51

Interleukin-4 (IL-4), a pleiotropic cytokine, has in vitro activity against non-Hodgkin lymphoma (NHL). This phase II study was conducted to learn the efficacy and toxicity of IL-4 in patients with NHL. Patients with relapsed or refractory indolent or aggressive NHL were eligible to receive 2.5 or 5.0 mcg/kg of subcutaneous IL-4 for 28 days of a 42-day cycle. Patients with response and acceptable toxicity after two cycles were eligible to continue treatment for six cycles. The target overall response rate (ORR) was 20%. Forty-one patients were enrolled and assessable for toxicity; two were ineligible after histology review. The ORR was 13% (5/39) with one complete and four partial responses. All responders were treated with 5.0 mcg/kg; the median time to progression was 84 days, the median duration of response for responders was 8.3 months. The most common toxicities of any grade in all patients were edema (66%), malaise (56%), and elevated liver function tests (56%). Grade 3 and 4 toxicities were more common at 5.0 mcg/kg, leading to a reduction in the starting dose. Although the study observed anti-tumor activity with IL-4, the ORR goal of the study was not achieved. Agents that target the IL-4 receptor can potentially benefit patients with NHL; however, alternative schedules using IL-4 in shorter duration and in combination with other agents would be required to overcome toxicities observed in this study.

Phase II evaluation of continuous-infusion 5-fluorouracil, leucovorin, mitomycin-C, and oral dipyridamole in advanced measurable pancreatic cancer: a North Central Cancer Treatment Group Trial.

At present there remains a need for more effective systemic therapy in advanced pancreatic cancer. Some studies have suggested that infusional chemotherapy schedules and biomodulation of 5-fluorouracil (5-FU) may improve the therapeutic outcome in advanced colon cancer. One such regimen that uses continuous infusion 5-FU, weekly leucovorin, daily dipyridamole, and intermittent mitomycin-C has activity in both colon and unresectable pancreatic carcinoma. The intent of this trial was to test the effectiveness of this four-drug regimen in advanced pancreatic cancer. Patients received 5-FU 200 mg/m2 daily by continuous infusion, leucovorin 30 mg/m2 IV weekly, mitomycin-C 10 mg/m2 day 1, and dipyridamole 75 mg orally four times daily for 5 weeks. After a 1-week break, treatment cycles were repeated every 6 weeks. Eligibility included biopsy-proven advanced measurable pancreatic cancer, Eastern Cooperative Oncology Group performance status 0 and 2, and no prior systemic chemotherapy. Of 46 evaluable patients, 9 partial responses and 1 complete tumor response were seen, for an overall response rate of 22% (95% confidence interval 11–36%). The median survival in the group of 50 patients registered to this trial was 4.6 months, with a range of 0.33 to 40.2 months. Toxicity was manageable, with the most common toxicities (≥grade III National Cancer Institute Common Toxicity Criteria) being anorexia (13%), stomatitis (17%), and hand–foot syndrome (13%). Of note, little severe hematologic toxicity and no significant headaches were reported. Although some patients did respond, the therapeutic results are not encouraging enough to take this regimen to phase III testing.

Nicotine patch vs. nicotine lozenge for smoking cessation: An effectiveness trial coordinated by the Community Clinical Oncology Program

BACKGROUND Nicotine replacement therapies are efficacious for treating nicotine dependence. However, limited data exist on benefits of different NRTs and predictors of treatment outcome. This study compared the effectiveness of transdermal nicotine vs. nicotine lozenge for smoking cessation and identified predictors of treatment response. METHODS A randomized, open-label effectiveness trial was conducted at 12 medical sites participating in the National Cancer Institutes Community Clinical Oncology Program. The sample consisted of 642 treatment-seeking smokers randomized to 12 weeks of transdermal nicotine or nicotine lozenge. RESULTS Smoker characteristics were assessed at baseline, and 24-h point prevalence abstinence confirmed with breath carbon monoxide (CO) was evaluated at end of treatment (EOT) and at a 6-month follow-up. There was a trend for higher quit rates for transdermal nicotine vs. nicotine lozenge at EOT (24.3% vs. 18.7%, p=.10) and 6 months (15.6% vs. 10.9%, p=.10). A logistic regression model of EOT quit rates showed smokers who preferred transdermal nicotine, were not reactive to smoking cues, and did not use nicotine to alleviate distress or stimulate cognitive function had higher quit rates on transdermal nicotine. A logistic regression model of 6-month quit rates showed smokers who preferred transdermal nicotine had higher quit rates on transdermal nicotine, and smokers who used nicotine to alleviate distress or stimulate cognitive processes had lower quit rates on nicotine lozenge. CONCLUSIONS Transdermal nicotine may be more effective than nicotine lozenge for smokers who prefer transdermal nicotine and do not smoke to alleviate emotional distress or stimulate cognitive function.

N0332 phase 2 trial of weekly irinotecan hydrochloride and docetaxel in refractory metastatic breast cancer: a North Central Cancer Treatment Group (NCCTG) Trial

BACKGROUND Because of the single-agent activity of irinotecan hydrochloride, combination of irinotecan and docetaxel treatment against metastatic breast cancer (MBC) should be evaluated. PATIENTS AND METHODS Single-stage phase 2 study of irinotecan and docetaxel to evaluate tumor response, toxicity, time to progression, and overall survival was carried out. Regimen of docetaxel (25 mg/m(2)) and irinotecan (70 mg/m(2)) was administered on days 1 and 8 of each 3-week cycle. Patients had histologically confirmed breast adenocarcinoma and metastatic cancer measurable with RECIST. RESULTS Of 70 patients enrolled, 64 were assessable. Prior treatment with an anthracycline and a taxane was required. Eighteen (28%) patients [95% confidence interval (CI) 15% to 31%] had tumor response, plus four patients had stable disease (less than 30% decrease in sum of longest diameter and less than 20% increase) for >6 months. The clinical benefit rate was 34% overall. Median duration of tumor response was 6.7 months (95% CI 4.2-37.7 months); median follow-up was 18.6 months (range 8.5-37.7 months). The most common severe adverse events included fatigue [n = 16 (25%)] and neutropenia [n = 13 (20%)]. CONCLUSIONS Weekly dosing of combination of irinotecan and docetaxel is active against MBC. However, the response rate to our regimen was not significantly better than single-agent docetaxel. Other schedules of irinotecan plus docetaxel should be considered for future studies.