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.

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.

Interleukin-1 genetic polymorphisms and their relationship to the cancer anorexia/weight loss syndrome in metastatic gastric and gastroesophageal junction adenocarcinoma.

Interleukin-1 (IL-1) beta is a putative mediator of the cancer anorexia/weight loss syndrome, and certain polymorphisms of its gene are thought to be associated with a greater risk of gastric cancer. Do these IL-1 beta genetic polymorphisms predispose patients with gastric and gastroesophageal cancer to the anorexia/weight loss syndrome? This study focused on 44 patients with metastatic gastric and gastroesophageal cancer. All underwent genotyping, completed serial quality-of-life questionnaires germane to appetite, and underwent meticulous serial follow-up. Patients with the IL-1 beta-31 C/T and T/T genotypes were more likely to describe a worse appetite at baseline than were those with the C/C genotype. In addition, patients with the IL-1 beta+3954 C/T and T/T genotypes showed greater improvements in their weight (P = 0.02) and in survival (hazard ratio, 0.3; P = 0.04) over time than did patients with the C/C genotype. These associations occurred independently of tumor response. These preliminary data suggest that certain interleukin-1 beta genetic polymorphisms may modulate the cancer anorexia/weight loss syndrome in patients with metastatic gastric and esophageal cancer. Confirmatory studies are warranted.

Results of a Phase I trial of concurrent chemotherapy and escalating doses of radiation for unresectable non-small-cell lung cancer.

PURPOSE: This trial was performed to determine the maximum tolerated dose (MTD) of radiation that can be administered with carboplatin and paclitaxel. METHODS AND MATERIALS: This trial included 15 patients with unresectable non-small-cell lung cancer. Paclitaxel (50 mg/m2) and carboplatin (area under the curve=2) were given weekly during radiation therapy (RT). The RT included 2 Gy daily to an initial dose of 70 Gy, and the dose was increased in 4 Gy increments until determining the MTD. The MTD was defined as the highest safely tolerated dose where at most 1 patient of 6 experienced dose-limiting toxicity (DLT) with the next higher dose having at least 2 of 6 patients experiencing DLT. Three-dimensional treatment planning techniques were used without prophylactic nodal RT. RESULTS: Two patients were not evaluable because they did not receive therapy according to the protocol. No DLTs occurred in the 3 patients who received 70 Gy, 1 DLT occurred in the 6 patients who received 74 Gy, and 2 DLTs occurred in the 4 patients who received 78 Gy. The DLTs included Grade 3 pneumonitis (n=2) and Grade 4 pneumonitis (n=1). There have been 3 deaths during follow-up ranging from 14 to 38 months (median, 28 months). CONCLUSIONS: The MTD of the RT was 74 Gy with weekly carboplatin and paclitaxel. The Phase II portion of this trial is currently under way. The goal is to improve local control and survival with higher doses of RT delivered with this combined modality approach.

The prevalence of weight concerns in a smoking abstinence clinical trial.

Recent research has demonstrated there is a high prevalence of weight concerns in smokers and that smokers with weight concerns may respond poorly to treatment for tobacco dependence. Most studies have focused only on females or have consisted of small samples. In this study of a 12-week randomized trial of nicotine inhaler, bupropion or both for smoking cessation, 50% of the 1012 female smokers and 26% of the 680 male smokers, at study entry, were weight concerned. In examining the impact of weight concerns on the 12-week point-prevalence smoking abstinence, 26% of non-weight-concerned smokers quit smoking compared to 22% of weight-concerned smokers (p=0.06). This study, which includes a large sample of both genders, provides further evidence that approximately half of females who are seeking smoking cessation treatment are weight concerned and that one quarter of male smokers are weight concerned. Additionally, being weight concerned may impact the short-term success rates of stopping smoking using pharmacotherapy.

Gemcitabine and ISIS-2503 for patients with locally advanced or metastatic pancreatic adenocarcinoma: a North Central Cancer Treatment Group phase II trial.

PURPOSE: Gemcitabine remains the standard therapy for metastatic pancreatic adenocarcinoma (ACA), but has limited activity. ISIS-2503 is an antisense compound directed against H-ras with preclinical activity against pancreatic ACA in tumor models. The combination of ISIS-2503 and gemcitabine has been evaluated in a prior phase I study. METHODS: Patients with metastatic or locally advanced pancreatic ACA not amenable to surgery or local radiation received gemcitabine 1,000 mg/m(2) intravenously over 30 minutes on days 1 and 8 and ISIS-2503 6 mg/kg/d as a continuous intravenous infusion over 14 days of an every-3-weeks cycle. Responses were monitored by radiologic imaging every 6 weeks. RESULTS: Forty-eight eligible patients were enrolled, 43 with metastatic disease. Median follow-up was 12.6 months (range, 2.2 to 16.8 months) for living patients. A median of four cycles of treatment was given (range, 1 to 18 cycles). All patients were assessable for response and toxicity. The 6-month survival percentage was 57.5% (95% CI, 44.9% to 73.5%) and the median survival was 6.6 months. The response rate was 10.4% (one complete response, four partial responses). Clinically significant toxicity was limited except for one fatal pulmonary embolism. CONCLUSION: This study shows a promising response rate to the combination of gemcitabine and ISIS-2503 in patients with pancreatic ACA. The observed 6-month survival rate in these patients met our protocol-defined criteria for success. This regimen is tolerable, but is of unclear benefit. Additional studies evaluating the role of gemcitabine and ISIS-2503 in the treatment of pancreatic ACA should be considered.

Efficacy and quality-of-life data are related in a phase II trial of oral chemotherapy in previously untreated patients with metastatic colorectal carcinoma.

PURPOSE: To evaluate quality of life (QOL) and tumor response after administration of an oral chemotherapy regimen in patients with previously untreated metastatic colorectal cancer. PATIENTS AND METHODS: Seventy-eight patients received a mean number of 5.8 cycles of therapy. QOL data were analyzed at baseline, after every two cycles of therapy, and at the time of treatment discontinuation. The Uniscale and the European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire C30 were both utilized. RESULTS: The confirmed response rate was 26% (95% confidence interval [CI], 17% to 37%). Median survival was 11.3 months (95% CI, 9.6 to 15.1 months). Global QOL scores were unchanged over the course of therapy by either tool. Only the physical function subscale score had worsened at the end of therapy. In an analysis of responding patients, significant and durable improvements in both global QOL measures as well as select subscale scores were observed. Diarrhea and physical function QOL scores had declined at the time of treatment discontinuation. Patients who did not respond to therapy had preserved QOL scores when they were evaluated after two cycles of therapy. CONCLUSION: This oral treatment strategy preserved QOL in treated patients. Global QOL measures as well as several QOL subscale scores significantly improved in patients with a documented response to therapy. The profile of improved QOL components indicated that patient well-being was related to tumor response in specific and perceivable ways. Nonresponding patients reported preserved QOL during the first two cycles of therapy. QOL analysis was feasible and informative in this moderately sized multicenter phase II trial.

Phase II Trial of Paclitaxel/Cisplatin Followed by Surgery and Adjuvant Radiation Therapy and 5-Fluorouracil/Leucovorin for Gastric Cancer (ECOG E7296).

BACKGROUND: Randomized trials have shown an increase in survival with perioperative chemotherapy as well as with postoperative chemoradiation. It was hypothesized that combining induction chemotherapy with postoperative chemoradiation would be well tolerated and improve pathologic complete response. METHODS: Patients with resectable cancers of the stomach/gastroesophageal junction were eligible. Neoadjuvant chemotherapy consisted of 3 cycles of paclitaxel and cisplatin. Adjuvant therapy consisted of 1 cycle of 5-fluorouracil (FU) and leucovorin (LV) followed by chemoradiation (45 Gy with concurrent 5-FU/LV). Chemoradiation was followed by 2 additional cycles of 5-FU/LV. Response to neoadjuvant therapy was based on pathology. RESULTS: From 1999 to 2002, 38 eligible patients were enrolled; 35 completed induction chemotherapy, and 29 went on to surgery. Sixteen patients did not develop metastatic progression, 10 developed metastatic disease, and 12 were unevaluable. There were no pathologic complete responses after induction therapy. Twenty-five of 38 patients suffered grade 3-4 toxicities during induction paclitaxel/cisplatin. Six of the 7 patients who received postoperative therapy suffered grade 3-4 toxicities. Only 3 of 38 (7.9%) eligible patients completed all assigned treatment. The median overall survival was 1.6 years, and the 2-year survival was 40%. CONCLUSIONS: This regimen of neoadjuvant paclitaxel/cisplatin followed by postoperative 5-FU/LV-based chemoradiation did not have a high enough response rate and proved to be too toxic for further development.

Tetracycline to prevent epidermal growth factor receptor inhibitor-induced skin rashes: results of a placebo-controlled trial from the North Central Cancer Treatment Group (N03CB).

BACKGROUND: Epidermal growth factor receptor (EGFR) inhibitors are effective cancer therapies, but they are reported to cause a rash in >50% of patients. In the current study, the authors examined the use of tetracycline for rash prevention. METHODS: This placebo-controlled, double-blinded trial enrolled patients who were starting cancer treatment with an EGFR inhibitor. Patients could not have had a rash at the time of enrollment. All patients were randomly assigned to receive either tetracycline at a dose of 500 mg orally twice a day for 28 days versus a placebo. Patients were monitored for rash (through monthly physician assessment and weekly patient-reported questionnaires), quality of life (using the SKINDEX-16, a skin-specific quality of life index), and adverse events. Monitoring occurred during the 4-week intervention and then for an additional 4 weeks. The primary objective of the current study was to compare the incidence of rash between the study arms, and the enrollment of 30 patients per arm provided a 90% probability of detecting a 40% difference in incidence with a P value of .05 (2-sided). RESULTS: A total of 61 evaluable patients were enrolled. The 2 treatment arms were well balanced with regard to baseline characteristics, dropout rates, and rates of discontinuation of the EGFR inhibitor. The incidence of rash was found to be comparable across treatment arms. Physicians reported that 16 patients treated with tetracycline (70%) and 22 patients treated with placebo (76%) developed a rash (P = .61). Tetracycline appears to have lessened the rash severity, although the high dropout rates invite caution when interpreting these findings. By Week 4, physician-reported grade 2 rash (using the National Cancer Institute's Common Terminology Criteria for Adverse Events [version 3.0]) occurred in 17% of tetracycline-treated patients (n = 4 patients) and in 55% of placebo-exposed patients (n = 16 patients) (P = .04). Patients treated with tetracycline reported better scores, as per the SKINDEX-16, on certain quality-of-life parameters such as skin burning or stinging, skin irritation, and being bothered by the persistence/recurrence of a skin condition. Adverse events were found to be comparable across treatment arms. CONCLUSIONS: In the current study, tetracycline was not found to prevent EGFR inhibitor-induced rashes and therefore cannot be clinically recommended for this purpose. However, preliminary observations of diminished rash severity and improved quality of life suggest this antibiotic merits further study.

Paclitaxel, carboplatin, 5-fluorouracil, and radiation for locally advanced esophageal cancer: phase II results of preliminary pharmacologic and molecular efforts to mitigate toxicity and predict outcomes: North Central Cancer Treatment Group (N0044).

PURPOSE: Locally advanced esophageal cancer is challenging to treat. This study tested a 3-drug, multimodality approach. Chemotherapy dose reductions, the addition of amifostine, and pharmacogenetics were tested in an effort to mitigate toxicity and predict outcomes. PATIENTS AND METHODS: This phase II trial tested chemotherapy (carboplatin area under the curve = 4 [lower dose than that from Meluch et al] on day 1 and 22, 5-fluorouracil 225 mg/m2 per day continuous infusion on days 1 to 42, and paclitaxel 200 mg/m2 on days 1 and 22) with concomitant radiation 4500 cG for locally advanced esophageal cancer. Esophagectomy was scheduled after radiation. Amifostine 500 mg subcutaneously before radiation was given to the first 19 patients. RESULTS: Among 54 eligible patients, the pathologic complete response rate was 35% (95% confidence interval [CI], 23%-49%). Median survival was 21.2 months (95% CI, 13.6-37.6 months), and median time to cancer recurrence/progression 19 months (95% CI, 11.4-44.6 months). Nearly all patients (94%) suffered at least one grade 3 or worse adverse event, including 3 treatment-related deaths. Amifostine was discontinued because of one of these deaths. There was no statistically significant difference in the rates of severe adverse events among patients who received amifostine and those who did not. Genotyping for polymorphisms of dihydropyrimidine dehydrogenase, cytochrome P3A4, and glutathione-S-transferase did not predict tumor response or severe adverse events. CONCLUSIONS: This 3-drug, multimodality approach yielded a pathologic complete response rate of 35%, but the severe adverse event rate was high. Utilizing amifostine to reduce toxicity or employing molecular approaches to predict outcomes did not show promise.

Phase III trial of gabapentin alone or in conjunction with an antidepressant in the management of hot flashes in women who have inadequate control with an antidepressant alone: NCCTG N03C5.

PURPOSE: Despite the utility of newer antidepressants for alleviating hot flashes, antidepressants do not work adequately enough in many patients. Gabapentin is a nonhormonal agent that also can reduce hot flashes. No data have been available to address whether the combination of both agents would more effectively alleviate hot flashes, compared with gabapentin alone, in patients with inadequate hot flash control with an antidepressant alone. PATIENTS AND METHODS: This was a randomized trial in which 118 patients with inadequate hot flash control on an antidepressant were randomly assigned to receive both an antidepressant and gabapentin versus being weaned off the antidepressant and receiving gabapentin alone. Patients were observed for 5 weeks (including a baseline week in which patients continued on their current antidepressant without gabapentin) during which time they completed validated daily hot flash diaries. RESULTS: Ninety-one patients provided complete data at the 5-week assessment. Regardless of whether or not the antidepressant was continued when gabapentin was started, there was an approximately 50% median reduction in hot flash frequencies (54%; 95% CI, 34% to 70% for combined treatment v 49%; 95% CI, 26% to 58% for gabapentin alone) and scores (56%; 95% CI, 26% to 71% for combined treatment v 60%; 95% CI, 33% to 73% for gabapentin alone). CONCLUSION: Gabapentin seems to decrease hot flashes by approximately 50% in women with inadequate hot flash control who were using an antidepressant. This study saw no significant additional hot flash reduction from continuation of the antidepressant.

Phase III comparison of depomedroxyprogesterone acetate to venlafaxine for managing hot flashes: North Central Cancer Treatment Group Trial N99C7.

PURPOSE: Vasomotor hot flashes are a common problem in menopausal women. Given concerns regarding estrogen and/or combined hormonal therapy, other treatment options are desired. Prior trials have confirmed that progestational agents and newer antidepressants effectively reduce hot flashes. This current trial compared a single intramuscular dose of medroxyprogesterone acetate (MPA), depot preparation, versus daily oral venlafaxine as treatment for hot flashes. METHODS: Women with bothersome hot flashes were entered onto this trial, were randomly assigned to treatment, and then had a baseline week where hot flash scores were recorded without treatment. They were then treated and observed for 6 weeks; daily diaries were used to measure hot flash frequencies and severities. There were 109 patients per each arm randomly assigned to receive MPA 400 mg intramuscularly for a single dose versus venlafaxine 37.5 mg per day for a week, then 75 mg per day. RESULTS: During the sixth week after random assignment, hot flash scores were reduced by 55% in the venlafaxine arm versus 79% in the MPA arm (P < .0001). In an intention-to-treat analysis, 46% of venlafaxine patients (50 of 109) compared with 74% of the MPA patients (81 of 109) had a decrease in hot flashes by more than 50% from baseline (P < .0001). Less toxicity was reported in the MPA arm. CONCLUSION: A single MPA dose seems to be well tolerated and more effectively reduces hot flashes than does venlafaxine.

Phase III study of two different dosing schedules of erythropoietin in anemic patients with cancer.

PURPOSE: To compare maintenance epoetin alfa administered once every 3 weeks with continued weekly epoetin alfa for patients with cancer-associated anemia. PATIENTS AND METHODS: Eligible patients were randomly assigned at enrollment to receive three weekly doses of epoetin alfa 40,000 U subcutaneously (SC), followed by either standard weekly epoetin alfa (40K arm) or 120,000 U of epoetin alfa (120K arm) SC every 3 weeks for 18 additional weeks. RESULTS: Three hundred sixty-five patients were enrolled. One hundred eighty-three patients were assigned to the 40K arm, and 182 were assigned to the 120K arm. There was no difference in the proportion of patients requiring transfusions during the study (23% in 40K arm and 18% in 120K arm, P = .22) or specifically during the maintenance phase (13% in 40K arm v 15% in 120K arm, P = .58). Patients randomly assigned to the 40K arm were more likely to have a > or = 2 or > or = 3 g/dL hemoglobin (Hb) increment, were more likely to have a drug dose held because of high Hb, and had higher mean end-of-study Hb levels. Toxicities, including thromboembolism, and overall survival were similar. Patients in the 40K arm had a higher global quality of life (QOL) at baseline for unclear reasons, whereas patients in the 120K arm had a greater global QOL improvement during the study, so end-of-study QOL was equivalent. CONCLUSION: After three weekly doses of epoetin alfa 40,000 U, a dose of 120,000 U can be administered safely once every 3 weeks without increasing transfusion needs or sacrificing QOL. The Hb increment is somewhat greater with continued weekly epoetin alfa. Lack of blinding as a result of different treatment schedules may have confounded results.

Gemcitabine, 5-fluorouracil, and leucovorin in advanced biliary tract and gallbladder carcinoma: a North Central Cancer Treatment Group phase II trial.

BACKGROUND: Gemcitabine has broad activity in a variety of solid tumors including biliary tract carcinomas. The authors evaluated 6-month survival, response, and toxicity associated with a combination of gemcitabine, 5-fluorouracil (5-FU), and leucovorin (LV) in patients with unresectable or metastatic biliary tract or gallbladder adenocarcinoma (ACA). METHODS: A 4-week course included 1000 mg/m2 gemcitabine by intravenous infusion over 30 minutes on Days 1, 8, and 15, 25 mg/m2 LV by intravenous push, and 600 mg/m2 5-FU by intravenous push after LV. RESULTS: Forty-two patients were enrolled in 6 months, 35 of whom had metastatic disease. Patients with biliary tract ACA included 24 with hepatic disease (19 patients had intrahepatic disease and 5 patients had extrahepatic disease) and 4 with disease in the ampulla of Vater. All patients were evaluable and received a median of 4 courses of treatment (range, 1-21 courses). Commonly occurring severe toxicity (NCI CTC Grade 3 or worse) included: dyspnea (four patients), nausea (four patients), fatigue (seven patients), thrombocytopenia (six patients), emesis (four patients), and diarrhea (four patients). Five partial responses (9.5%) occurred, 3 of which were sustained for > or = 8 weeks. No treatment-related deaths occurred. Thirty-two patients had disease progression and 38 died after a median follow-up of 20 months (range, 1.4-24 months). The median time to disease progression was 4.6 months (95% confidence interval [95% CI], 2.4-6.6%). The median survival period was 9.7 months (95% CI, 7-12%). CONCLUSIONS: This combination regimen was manageable in patients with advanced biliary tract and gallbladder ACA. Of 42 patients, 24 (57%) survived > or = 6 months, satisfying the primary end point of the trial. The length of survival suggested that gemcitabine, 5-FU, and LV had benefit equivalent to gemcitabine alone.

Comparison of nicotine patch alone versus nicotine nasal spray alone versus a combination for treating smokers: a minimal intervention, randomized multicenter trial in a nonspecialized setting.

This multicenter, randomized, open-label clinical trial was conducted to determine whether the combined use of nicotine patch therapy and a nicotine nasal spray would improve smoking abstinence rates compared to either treatment alone, without behavioral counseling. Data were collected at 15 regional cancer control oncology centers within the North Central Cancer Treatment Group. Of the 1384 smokers randomized to the study, 20% were abstinent from smoking at 6 weeks and 8% were abstinent at 6 months. At 6 weeks, the 7-day point prevalence smoking abstinence rate for the patch alone (21.1%) was superior to the spray (13.6%) but was significantly lower than the rate for combination therapy (27.1%). At 6 months, the 7-day point prevalence abstinence rates were not significantly different among the three groups. Combination nicotine nasal spray and nicotine patches were delivered safely in a nonspecialized outpatient clinical setting and enhanced short-term smoking abstinence rates, but these rates were not sustained at 6 months.