Richard J. Gralla

Prospective Randomized Trial of Docetaxel Versus Best Supportive Care in Patients With Non–Small-Cell Lung Cancer Previously Treated With Platinum-Based Chemotherapy

PURPOSE To evaluate whether treatment with single-agent docetaxel would result in longer survival than would best supportive care in patients with non-small-cell lung cancer who had previously been treated with platinum-based chemotherapy. Secondary end points included assessment of response (docetaxel arm only), toxicity, and quality of life. PATIENTS AND METHODS Patients with performance statuses of 0 to 2 and stage IIIB/IV non-small-cell lung cancer with either measurable or evaluable lesions were eligible for entry onto the study if they had undergone one or more platinum-based chemotherapy regimens and if they had adequate hematology and biochemistry parameters. They were excluded if they had symptomatic brain metastases or if they had previously been treated with paclitaxel. Patients were stratified by performance status and best response to cisplatin chemotherapy and were then randomized to treatment with docetaxel 100 mg/m(2) (49 patients) or 75 mg/m(2) (55 patients) or best supportive care. Patients in both arms were assessed every 3 weeks. RESULTS One hundred four patients (103 of whom were eligible for entry onto the study) were well balanced for prognostic factors. Of 84 patients with measurable lesions, six (7. 1%) achieved partial responses (three patients at each dose level). Time to progression was longer for docetaxel patients than for best supportive care patients (10.6 v 6.7 weeks, respectively; P <.001), as was median survival (7.0 v 4.6 months; log-rank test, P =.047). The difference was more significant for docetaxel 75 mg/m(2) patients, compared with corresponding best supportive care patients (7.5 v 4.6 months; log-rank test, P =.010; 1-year survival, 37% v 11%; chi(2) test, P =.003). Febrile neutropenia occurred in 11 patients treated with docetaxel 100 mg/m(2), three of whom died, and in one patient treated with docetaxel 75 mg/m(2). Grade 3 or 4 nonhematologic toxicity, with the exception of diarrhea, occurred at a similar rate in both the docetaxel and best supportive care groups. CONCLUSION Treatment with docetaxel is associated with significant prolongation of survival, and at a dose of 75 mg/m(2), the benefits of docetaxel therapy outweigh the risks.

Topotecan versus cyclophosphamide, doxorubicin, and vincristine for the treatment of recurrent small-cell lung cancer.

PURPOSE Topotecan and cyclophosphamide, doxorubicin, and vincristine (CAV) were evaluated in a randomized, multicenter study of patients with small-cell lung cancer (SCLC) who had relapsed at least 60 days after completion of first-line therapy. PATIENTS AND METHODS Patients received either topotecan (1.5 mg/m2) as a 30-minute infusion daily for 5 days every 21 days (n = 107) or CAV (cyclophosphamide 1,000 mg/m2, doxorubicin 45 mg/m2, and vincristine 2 mg) infused on day 1 every 21 days (n = 104). Eligibility included the following: bidimensionally measurable disease, Eastern Cooperative Oncology Group performance status of less than or equal to 2, and adequate marrow, liver, and renal function. Response was confirmed by blinded independent radiologic review. RESULTS Response rate was 26 of 107 patients (24.3%) treated with topotecan and 19 of 104 patients (18.3%) treated with CAV (P = .285). Median times to progression were 13.3 weeks (topotecan) and 12.3 weeks (CAV) (P = .552). Median survival was 25.0 weeks for topotecan and 24.7 weeks for CAV (P = .795). The proportion of patients who experienced symptom improvement was greater in the topotecan group than in the CAV group for four of eight symptoms evaluated, including dyspnea, anorexia, hoarseness, and fatigue, as well as interference with daily activity (P< or =.043). Grade 4 neutropenia occurred in 37.8% of topotecan courses versus 51.4% of CAV courses (P<.001). Grade 4 thrombocytopenia and grade 3/4 anemia occurred more frequently with topotecan, occurring in 9.8% and 17.7% of topotecan courses versus 1.4% and 7.2% of CAV courses, respectively (P<.001 for both). Nonhematologic toxicities were generally grade 1 to 2 for both regimens. CONCLUSION Topotecan was at least as effective as CAV in the treatment of patients with recurrent SCLC and resulted in improved control of several symptoms.

Antiemetic Efficacy of High-Dose Metoclopramide: Randomized Trials with Placebo and Prochlorperazine in Patients with Chemotherapy-Induced Nausea and Vomiting

In a study of the effectiveness of high intravenous doses of metoclopramide as an antiemetic, 41 patients with advanced cancer who were being treated with cisplatin were entered into two double-blind trials. In the first trial patients were randomly assigned to receive either metoclopramide or placebo, and in the second trial they received either metoclopramide or prochlorperazine. Patients given metoclopramide had significantly fewer episodes of emesis than patients given placebo (medians, 1.0 vs. 10.5; P = 0.001) or prochlorperazine (medians, 1.5 vs. 12.0; P = 0.005). Metoclopramide was superior to placebo and to prochlorperazine in reducing the volume of emesis (P = 0.001 and P = 0.022, respectively) and was more effective than placebo in shortening the duration of nausea (P = 0.042) and vomiting (P = 0.028). Side effects from metoclopramide were minor, with mild sedation frequently observed; one patient had a brief extrapyramidal reaction. We conclude that metoclopramide in high intravenous doses has greater antiemetic activity than placebo or prochlorperazine in patients receiving cisplatin chemotherapy.

Recommendations for the Use of Antiemetics: Evidence-Based, Clinical Practice Guidelines

THE GOAL OF ANTIEMETIC therapy is to prevent nausea and vomiting completely. This goal is achieved for many patients receiving chemotherapy or radiation therapy, and is based on clinical and basic research that has steadily improved the control of emesis over the last 20 years. As therapy has become more effective, it has also become safer, with few side effects associated with the most commonly used regimens. These regimens are convenient for patients to receive and for health care professionals to administer. However, despite improvements, a significant number of patients still experience emesis, and efforts to reduce this side effect of treatment must continue. As antiemetic usage has grown, the classes of agents available for antiemetic treatment, the number of agents, and the indications for antiemetics have all increased as well. The prevention of delayed emesis and anticipatory emesis is equal in importance to the need to prevent acute chemotherapyand radiation-induced emesis. Additionally, managing special and difficult emetic problems and selecting the proper antiemetic approach necessitate identification of the patient’s emetic risk. Although the neuropharmacologic basis of emesis is still incompletely understood, the selection of an appropriate antiemetic regimen is possible and can have an impact on several aspects of clinical care. Goals related to the complete control of emesis, ie, no vomiting, include providing care that is convenient for the patient, treatment that reduces hospitalization and time in the ambulatory setting, and therapy that enhances the patient’s quality of life. Additionally, practitioners need to be mindful of reducing costs of treatment while achieving these goals. 1-3

The Oral Neurokinin-1 Antagonist Aprepitant for the Prevention of Chemotherapy-Induced Nausea and Vomiting: A Multinational, Randomized, Double-Blind, Placebo-Controlled Trial in Patients Receiving High-Dose Cisplatin—The Aprepitant Protocol 052 Study Group

PURPOSE In early clinical trials with patients receiving highly emetogenic chemotherapy, the neurokinin antagonist aprepitant significantly enhanced the efficacy of a standard antiemetic regimen consisting of a type-three 5-hydroxytryptamine antagonist and a corticosteroid. This multicenter, randomized, double-blind, placebo-controlled phase III study was performed to establish definitively the superiority of the aprepitant regimen versus standard therapy in the prevention of chemotherapy-induced nausea and vomiting (CINV). PATIENTS AND METHODS Patients receiving cisplatin > or = 70 mg/m2 for the first time were given either standard therapy (ondansetron and dexamethasone on day 1; dexamethasone on days 2 to 4) or an aprepitant regimen (aprepitant plus ondansetron and dexamethasone on day 1; aprepitant and dexamethasone on days 2 to 3; dexamethasone on day 4). Patients recorded nausea and vomiting episodes in a diary. The primary end point was complete response (no emesis and no rescue therapy) on days 1 to 5 postcisplatin, analyzed by a modified intent-to-treat approach. Treatment comparisons were made using logistic regression models. Tolerability was assessed by reported adverse events and physical and laboratory assessments. RESULTS The percentage of patients with complete response on days 1 to 5 was significantly higher in the aprepitant group (72.7% [n = 260] v 52.3% in the standard therapy group [n = 260]), as were the percentages on day 1, and especially on days 2 to 5 (P <.001 for all three comparisons). CONCLUSION Compared with standard dual therapy, addition of aprepitant was generally well tolerated and provided consistently superior protection against CINV in patients receiving highly emetogenic cisplatin-based chemotherapy.

Guideline update for MASCC and ESMO in the prevention of chemotherapy- and radiotherapy-induced nausea and vomiting: results of the Perugia consensus conference

Despite the relevant progress achieved in the last 20 years,vomiting and, especially, nausea, continue to be two of themost distressing side-effects of cancer chemotherapy. In the late1990s several professional organizations publishedrecommendations on the optimal antiemetic prophylaxis inpatients submitted to chemotherapy and radiotherapy.Subsequently, due to the emergence of new findings and newantiemetic agents since the first recommendations from 1997,representatives from several oncology societies met in Perugia,Italy, in 2004 and updated the antiemetic guidelines. On 20–21June 2009 the European Society of Medical Oncology (ESMO)and the Multinational Association of Supportive Care inCancer (MASCC) organized the third Consensus Conferenceon antiemetics in Perugia. The results of this Conference arereported in this paper.The methodology for the guideline process was based ona literature review through 1 June 2009 using MEDLINE(National Library of Medicine, Bethesda, MD, USA) and otherdatabases, with evaluation of the evidence by an expert panelcomposed of 23 oncology professionals in clinical medicine,medical oncology, radiation oncology, surgical oncology,oncology nursing, statistics, pharmacy, pharmacology, medicalpolicy and decision making. With the participating expertscoming from 10 different countries, on five continents, webelieve that this is the most representative and evidence-basedguideline process that has yet been performed.The panel comprised 10 committees dealing with majortopics in this field (e.g. acute or delayed nausea and vomitinginduced by highly emetogenic chemotherapy). Althoughprevention of acute and delayed nausea and vomiting inducedby highly and moderately emetogenic chemotherapy (HEC andMEC) had specific committees, these worked finally together, as

Efficacy and Tolerability of Aprepitant for the Prevention of Chemotherapy-Induced Nausea and Vomiting in Patients With Breast Cancer After Moderately Emetogenic Chemotherapy

PURPOSE This is the first study in which the NK(1)-receptor antagonist, aprepitant (APR), was evaluated for the prevention of chemotherapy-induced nausea and vomiting (CINV) with moderately emetogenic chemotherapy. PATIENTS AND METHODS Eligible breast cancer patients were naive to emetogenic chemotherapy and treated with cyclophosphamide +/- doxorubicin or epirubicin. Patients were randomly assigned to either an aprepitant regimen (day 1, APR 125 mg, ondansetron (OND) 8 mg, and dexamethasone 12 mg before chemotherapy and OND 8 mg 8 hours later; days 2 through 3, APR 80 qd) [DOSAGE ERROR CORRECTED] or a control regimen (day 1, OND 8 mg and dexamethasone 20 mg before chemotherapy and OND 8 mg 8 hours later; days 2 through 3, OND 8 mg bid). Data on nausea, vomiting, and use of rescue medication were collected with a self-report diary. The primary efficacy end point was the proportion of patients with complete response, defined as no vomiting and no use of rescue therapy, during 120 hours after initiation of chemotherapy in cycle 1. The secondary end point was the proportion of patients with an average item score higher than 6 of 7 on the Functional Living Index-Emesis questionnaire. RESULTS Of 866 patients randomized, 857 patients (99%) were assessable. Overall complete response was greater with the aprepitant regimen than with the control regimen (50.8% v 42.5%; P = .015). More patients in the aprepitant group reported minimal or no impact of CINV on daily life (63.5% v 55.6%; P = .019). Both treatments were generally well tolerated. CONCLUSION The aprepitant regimen was more effective than the control regimen for prevention of CINV in patients receiving both an anthracycline and cyclophosphamide.

Preoperative chemotherapy for stage IIIa (N2) lung cancer: The Sloan-Kettering experience with 136 patients

From 1984 to 1991, 136 patients with histologically confirmed non-small cell lung cancer and stage IIIa (N2) disease received two to three cycles of MVP (mitomycin + vindesine or vinblastine + high-dose cisplatin) chemotherapy. All patients had clinical N2 disease, defined as bulky mediastinal lymph node metastases or multiple levels of lymph node involvement in the ipsilateral mediastinum or subcarinal space on chest roentgenograms, computed tomographic scans, or mediastinoscopy. The overall major response rate to chemotherapy was 77% (105/136). Thirteen patients had a complete response and 92 patients had a partial but major response (> 50%). The overall complete resection rate was 65% (89/136) with a complete resection rate of 78% (82/105) in patients with a major response to chemotherapy. There was no histologic evidence of tumor in the resected specimens of 19 patients. The overall survival was 28% at 3 years and 17% at 5 years (median, 19 months). For patients who had complete resection, the median survival was 27 months and the 3-year and 5-year survivals were 41% and 26%, respectively. There were seven treatment-related deaths, five of which were postoperative deaths. To date, 33 patients, all of whom had complete resection, have had no recurrence after treatment. These results demonstrate that (1) preoperative chemotherapy with MVP produces high response rates in stage IIIa (N2) disease, (2) high complete resection rates occur after response to chemotherapy, and (3) survival is longest in patients who have a complete resection after major response to chemotherapy.

REDUCTION OF CISPLATIN-INDUCED EMESIS BY A SELECTIVE NEUROKININ-1-RECEPTOR ANTAGONIST

BACKGROUND The localization of substance P in brain-stem regions associated with vomiting, and the results of studies in ferrets, led us to postulate that a neurokinin-1-receptor antagonist would be an antiemetic in patients receiving anticancer chemotherapy. METHODS In a multicenter, double-blind, placebo-controlled trial involving 159 patients who had not previously received cisplatin, we evaluated the prevention of acute emesis (occurring within 24 hours) and delayed emesis (on days 2 to 5) after a single dose of cisplatin therapy (70 mg or more per square meter of body-surface area). Before receiving cisplatin, all the patients received granisetron (10 microg per kilogram of body weight intravenously) and dexamethasone (20 mg orally). The patients were randomly assigned to one of three treatments in addition to granisetron and dexamethasone: 400 mg of an oral trisubstituted morpholine acetal (also known as L-754,030) before cisplatin and 300 mg on days 2 to 5 (group 1), 400 mg of L-754,030 before cisplatin and placebo on days 2 to 5 (group 2), or placebo before cisplatin and placebo on days 2 to 5 (group 3). Additional medication was available at any time to treat occurrences of vomiting or nausea. RESULTS In the acute-emesis phase, 93 percent of the patients in groups 1 and 2 combined and 67 percent of those in group 3 had no vomiting (P<0.001). In the delayed-emesis phase, 82 percent of the patients in group 1, 78 percent of those in group 2, and 33 percent of those in group 3 had no vomiting (P<0.001 for the comparison between group 1 or 2 and group 3). The median nausea score in the delayed-emesis phase was significantly lower in group 1 than in group 3 (P=0.003). No serious adverse events were attributed to L-754,030. CONCLUSIONS The neurokinin-1-receptor antagonist L-754,030 prevents delayed emesis after treatment with cisplatin. Moreover, combining L-754,030 with granisetron plus dexamethasone improves the prevention of acute emesis.

Cisplatin and vindesine combination chemotherapy for advanced carcinoma of the lung: A randomized trial investigating two dosage schedules

Eighty-five patients with advanced squamous carcinoma or adenocarcinoma of the lung were randomly assigned to receive vindesine with either high dose (120 mg/m2 of body surface area) or low dose (60 mg/m2) cisplatin. All patients had measurable disease and had not previously received chemotherapy. The response rate was similar with both treatments (43% complete and partial remission rate), but the high dose cisplatin regimen was superior to the low dose in median duration of response (12 versus 5.5 months; p = 0.05) and in median survival for responding patients (21.7 versus 10 months; p = 0.02). Myelosuppression was generally not a treatment problem; peripheral neuropathy and moderate azotemia were the major dose-limiting toxicities. With improved survival and response rates over those reported for conventional regimens, this combination of new agents supports the approach of new drug investigation in patients with lung cancer and the importance of the incorporation of active new agents into initial chemotherapy regimens.