Donald B. Wender

Phase II Trial of Irinotecan in Patients With Metastatic Colorectal Carcinoma

PURPOSE To evaluate the objective tumor response rate and toxicities of patients with metastatic colorectal carcinoma treated with irinotecan hydrochloride (CPT-11). PATIENTS AND METHODS A total of 121 patients with advanced colorectal carcinoma--90 with prior fluorouracil (5-FU) exposure and 31 chemotherapeutically naive patients--were enrolled between May 1993 and June 1994. Patients were treated with CPT-11 at 125 mg/m2 intravenously weekly for 4 weeks followed by a 2-week rest. RESULTS Among 90 patients with prior 5-FU chemotherapy, 12 partial responses were observed (response rate, 13.3%; 95% confidence interval [CI], 7.1% to 22.1%). Among 31 chemotherapy-naive patients, eight had partial responses (response rate, 25.8%; 95% CI, 11.9% to 44.6%). The median response duration as measured from time of initial treatment for the two groups was 7.7 months and 7.6 months, respectively. The major adverse reactions were gastrointestinal and hematologic. The incidence of grade 3 or 4 diarrhea was 36.4%, while the overall incidence of grade 3 or 4 leukopenia was 21.5% of patients. Only four of 121 patients (3.3%) developed neutropenic fever (grade 4 neutropenia with > or = grade 2 fever). The incidence of grade 4 leukopenia was higher in patients with prior pelvic radiotherapy (chi2 test P = .04), while the incidence of grade 3 or 4 diarrhea demonstrated no association with previous pelvic irradiation. CONCLUSION According to the study design, CPT-11 showed promising activity in chemotherapy-naive patients with advanced colorectal carcinoma and modest activity in patients with prior 5-FU exposure. The toxicity with this schedule appears manageable with appropriate dose modification for individual patient tolerance and an intensive loperamide regimen for the management of diarrhea. Care should be taken when treating patients with prior pelvic radiotherapy because of the increased risk of neutropenia.

Intravenous Calcium and Magnesium for Oxaliplatin-Induced Sensory Neurotoxicity in Adjuvant Colon Cancer: NCCTG N04C7

PURPOSE Cumulative sensory neurotoxicity (sNT) is the dose-limiting toxicity of oxaliplatin, which commonly leads to early discontinuation of oxaliplatin-based therapy in the palliative and adjuvant settings. In a nonrandomized, retrospective study, intravenous (IV) calcium/magnesium (Ca/Mg) was associated with reduced oxaliplatin-induced sNT. METHODS Patients with colon cancer undergoing adjuvant therapy with infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX) were randomly assigned to Ca/Mg (1g calcium gluconate plus 1g magnesium sulfate pre- and post-oxaliplatin) or placebo, in a double-blinded manner. The primary end point was the percentage of patients with grade 2 or greater sNT at any time during or after oxaliplatin-based therapy by National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE; version 3) criteria. An oxaliplatin-specific sNT scale and patient questionnaires were also used to assess sNT. After 104 of 300 planned patients were enrolled, the study was closed. This was due to preliminary reports from another trial that suggested that Ca/Mg decreased treatment efficacy; these data were subsequently found to be incorrect. RESULTS Overall, 102 patients were available for analysis. Ca/Mg decreased the incidence of chronic, cumulative, grade 2 or greater sNT, as measured by NCI CTCAE (P = .038) and also by the oxaliplatin-specific sNT scale (P = .018). In addition, acute muscle spasms associated with oxaliplatin were significantly reduced (P = .01) No effect on acute, cold-induced sNT was found. No substantial differences in adverse effects were noted between Ca/Mg and placebo. CONCLUSION Despite early termination and decreased statistical power, this study supports IV Ca/Mg as an effective neuroprotectant against oxaliplatin-induced cumulative sNT in adjuvant colon cancer.

Phase III placebo-controlled trial of capsaicin cream in the management of surgical neuropathic pain in cancer patients.

PURPOSE A minority of cancer survivors develops long-term postsurgical neuropathic pain. Based on evidence that capsaicin, the pungent ingredient in hot chili peppers, might be useful for treating neuropathic pain, we developed the present clinical trial. PATIENTS AND METHODS Ninety-nine assessable patients with postsurgical neuropathic pain were entered onto this study. After stratification, patients were to receive 8 weeks of a 0.075% capsaicin cream followed by 8 weeks of an identical-appearing placebo cream, or vice versa. A capsaicin/placebo cream was to be applied to the painful site four times daily. Treatment evaluation was performed by patient-completed weekly questionnaires. RESULTS During the first 8-week study period, the capsaicin-cream arm was associated with substantially more skin burning, skin redness, and coughing (P < .0001 for each). Nonetheless, treatment was stopped for patient refusal or toxicity just as often while patients were receiving the placebo as compared with the capsaicin. The capsaicin cream arm had substantially more pain relief (P = .01) after the first 8 weeks, with an average pain reduction of 53% versus 17%. On completion of the 16-week study period, patients were asked which treatment period was most beneficial. Of the responding patients, 60% chose the capsaicin arm, 18% chose the placebo arm, and 22% chose neither (P = .001). CONCLUSION A topical capsaicin cream decreases postsurgical neuropathic pain and, despite some toxicities, is preferred by patients over a placebo by a three-to-one margin among those expressing a preference.

A placebo-controlled double blind trial of etanercept for the cancer anorexia/weight loss syndrome : Results from N00C1 from the north central cancer treatment group

Tumor necrosis factor‐α (TNF‐α) is a putative mediator of the cancer anorexia/weight loss syndrome. The current study was designed to determine whether etanercept (a dimeric fusion protein consisting of the extracellular ligand‐binding portion of the human 75‐kilodalton TNF receptor linked to the Fc portion of human immunoglobulin [Ig] G1) could palliate this syndrome.

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 II study of high-dose somatostatin analogue in patients either previously treated or untreated who have extensive-stage small cell lung cancer

The authors conducted a phase II study of somatostatin analogue in 18 patients with extensive stage small cell lung cancer (four with previous treatment, 14 without previous treatment). Patients received 2,000 mg subcutaneously thrice daily. They were required to have an Eastern Cooperative Oncology Group performance score of 0-2 and acceptable pretreatment biochemical parameters. No patient responded to treatment. The median time to progression was 44 days. The median survival was 106 days. Toxicity related to treatment consisted of mild diarrhea and anorexia. Somatostatin analogue is not active as a single agent in the treatment of extensive-stage small cell lung cancer.

Topotecan and Paclitaxel in Previously Treated Patients with Relapsed Small Cell Lung Cancer: Phase II Trial of the North Central Cancer Treatment Group

Small cell lung cancer (SCLC) is one of the most aggressive and lethal cancers in humans. It constitutes approximately 15 to 25% of all cases of primary lung cancers.1 Initial response rates of 70 to 90% for both limited and extensive stages of SCLC may be achieved using standard combination cytotoxic chemotherapy agents. The 5-year survival for limited-state SCLC is 15 to 25%, but patients with extensivestage SCLC rarely survive 5 years. Even among patients who achieve a complete response, there is a high rate of relapse.2 Until recently, there has been no well-established treatment available for patients with recurrent SCLC.3 Topotecan is a camptothecin analogue that stabilizes the covalent adduct between topoisomerase I and DNA. In S-phase cells, these topo I-DNA adducts are converted into double-strand breaks that seem to be responsible for cytotoxicity.4 Several phase II5–8 trials as well as a phase III trial3 have demonstrated antitumor efficacy, manageable toxicities, and acceptable safety profile of topotecan in both chemo-naive and previously treated patients with SCLC. Patients in the topotecan group derived significant palliative benefits in general symptoms (e.g., anorexia, fatigue, interference with daily activities, and pulmonary symptoms) over CAV chemotherapy in a randomized trial.3 Although topotecan is currently approved for second-line therapy in SCLC at a starting dose of 1.5 mg/m by a daily 30-minute intravenous infusion for 5 consecutive days of a 21-day cycle, advanced age, extensive pretreatment, prior platinum therapy, prior radiotherapy, and renal impairment are potential risk factors for increased myelosuppression during topotecan therapy. Several studies suggest that the 1.0and 1.25-mg/m doses of topotecan may be appropriate for patients with such high-risk factors.9–11 Paclitaxel is a chemotherapeutic agent that promotes the assembly and stabilization of microtubules. Such binding causes cells to form abundant arrays of disorganized and dysfunctional microtubules, leading to apoptosis. Although there is documented single-agent activity of paclitaxel in phase II studies among chemo-naive patients with SCLC with extensive disease,12,13 response duration is short, which suggests that paclitaxel is not sufficient as a single agent. It is also widely accepted that combinations of cytotoxic drugs produce higher response rates and survival rates in patients with SCLC compared with single-agent therapy. The combination of topotecan and paclitaxel is rational as they have non-overlapping mechanisms of action and are both active agents in SCLC, as discussed previously. Moreover, there is demonstrable in vitro synergy of this combination in SCLC cell lines,14,15 although there are insufficient data on sequence-specific synergy. Phase II trials of the combination of topotecan and paclitaxel that have been reported used a 5-day topotecan schedule as first-line treatment in patients with extensive SCLC.16–19 A randomized phase II study evaluating four treatment combinations17 showed that paclitaxel (230 mg/m on day 1) plus topotecan (1 mg/m on days 1-5) produced excessive toxicity, with toxic deaths occurring in 25% of patients. Objective response rate was 54% with a median survival of 13.8 months. The toxicities were ameliorated in the treatment arm using an attenuated paclitaxel dose of 175 mg/m, with treatment-related death occurring in 3% of patients. Objective response rate in this arm was 69% with a median survival of 9.9 months and 1-year survival of 40%, similar to standard etoposide plus cisplatin chemotherapy. Another phase II trial in patients with chemo-naive extensive SCLC used topotecan 1 mg/m (first three patients received 1.25 mg/m) daily for 5 days and paclitaxel (135 mg/m) on day 5 via a 24-hour infusion every 4 weeks.16 Despite prophylactic G-CSF administration, this combination was associated with a high incidence of myelosuppression *Mayo Clinic and Mayo Foundation, Rochester, Minnesota, †Illinois Oncology Research Association CCOP, Peoria, Illinois; ‡Cedar Rapids Oncology Project CCOP, Cedar Rapids, Iowa; §Carle Cancer Center CCOP, Urbana, Illinois; Missouri Valley Cancer Consortium, Omaha, Nebraska; ¶Duluth CCOP, Duluth, Minnesota; **Wichita Community Clinical Oncology Program, Wichita, Kansas; ††Siouxland HematologyOncology Associates, Sioux City, Iowa. Address correspondence to: Grace K. Dy, MD, Mayo Clinic, 200 First Street, SW, Rochester, MN 55905. E-mail: Dy.Grace@mayo.edu Copyright