Symptoms of endocrine treatment and outcome in the BIG 1-98 study.

There may be a relationship between the incidence of vasomotor and arthralgia/myalgia symptoms and treatment outcomes for postmenopausal breast cancer patients with endocrine-responsive disease who received adjuvant letrozole or tamoxifen. Data on patients randomized into the monotherapy arms of the BIG 1-98 clinical trial who did not have either vasomotor or arthralgia/myalgia/carpal tunnel (AMC) symptoms reported at baseline, started protocol treatment and were alive and disease-free at the 3-month landmark (n = 4,798) and at the 12-month landmark (n = 4,682) were used for this report. Cohorts of patients with vasomotor symptoms, AMC symptoms, neither, or both were defined at both 3 and 12 months from randomization. Landmark analyses were performed for disease-free survival (DFS) and for breast cancer free interval (BCFI), using regression analysis to estimate hazard ratios (HR) and 95 % confidence intervals (CI). Median follow-up was 7.0 years. Reporting of AMC symptoms was associated with better outcome for both the 3- and 12-month landmark analyses [e.g., 12-month landmark, HR (95 % CI) for DFS = 0.65 (0.49-0.87), and for BCFI = 0.70 (0.49-0.99)]. By contrast, reporting of vasomotor symptoms was less clearly associated with DFS [12-month DFS HR (95 % CI) = 0.82 (0.70-0.96)] and BCFI (12-month DFS HR (95 % CI) = 0.97 (0.80-1.18). Interaction tests indicated no effect of treatment group on associations between symptoms and outcomes. While reporting of AMC symptoms was clearly associated with better DFS and BCFI, the association between vasomotor symptoms and outcome was less clear, especially with respect to breast cancer-related events.

Patterns and risk factors for locoregional failures after mastectomy for breast cancer: an International Breast Cancer Study Group report.

BACKGROUND: Rates and risk factors of local, axillary and supraclavicular recurrences can guide patient selection and target for postmastectomy radiotherapy (PMRT). PATIENTS AND METHODS: Local, axillary and supraclavicular recurrences were evaluated in 8106 patients enrolled in 13 randomized trials. Patients received chemotherapy and/or endocrine therapy and mastectomy without radiotherapy. Median follow-up was 15.2 years. RESULTS: Ten-year cumulative incidence for chest wall recurrence of >15% was seen in patients aged <40 years (16.1%), with ≥4 positive nodes (16.5%) or 0-7 uninvolved nodes (15.1%); for supraclavicular failures >10%: ≥4 positive nodes (10.2%); for axillary failures of >5%: aged <40 years (5.1%), unknown primary tumor size (5.2%), 0-7 uninvolved nodes (5.2%). In patients with 1-3 positive nodes, 10-year cumulative incidence for chest wall recurrence of >15% were age <40, peritumoral vessel invasion or 0-7 uninvolved nodes. Age, number of positive nodes and number of uninvolved nodes were significant parameters for each locoregional relapse site. CONCLUSION: PMRT to the chest wall and supraclavicular fossa is supported in patients with ≥4 positive nodes. With 1-3 positive nodes, chest wall PMRT may be considered in patients aged <40 years, with 0-7 uninvolved nodes or with vascular invasion. The findings do not support PMRT to the dissected axilla.

Extracapsular tumor spread and the risk of local, axillary and supraclavicular recurrence in node-positive, premenopausal patients with breast cancer.

BACKGROUND: Extracapsular tumor spread (ECS) has been identified as a possible risk factor for breast cancer recurrence, but controversy exists regarding its role in decision making for regional radiotherapy. This study evaluates ECS as a predictor of local, axillary, and supraclavicular recurrence. PATIENTS AND METHODS: International Breast Cancer Study Group Trial VI accrued 1475 eligible pre- and perimenopausal women with node-positive breast cancer who were randomly assigned to receive three to nine courses of classical combination chemotherapy with cyclophosphamide, methotrexate, and fluorouracil. ECS status was determined retrospectively in 933 patients based on review of pathology reports. Cumulative incidence and hazard ratios (HRs) were estimated using methods for competing risks analysis. Adjustment factors included treatment group and baseline patient and tumor characteristics. The median follow-up was 14 years. RESULTS: In univariable analysis, ECS was significantly associated with supraclavicular recurrence (HR = 1.96; 95% confidence interval 1.23-3.13; P = 0.005). HRs for local and axillary recurrence were 1.38 (P = 0.06) and 1.81 (P = 0.11), respectively. Following adjustment for number of lymph node metastases and other baseline prognostic factors, ECS was not significantly associated with any of the three recurrence types studied. CONCLUSIONS: Our results indicate that the decision for additional regional radiotherapy should not be based solely on the presence of ECS.

A quality-adjusted time without symptoms or toxicity (Q-TWiST) analysis of adjuvant radiation therapy and chemotherapy for resectable rectal cancer.

BACKGROUND: Combined radiation therapy and chemotherapy after surgery, compared with postsurgical radiation therapy alone, has been shown to improve disease-free survival and overall survival significantly among patients with poor-prognosis (i.e., advanced stage disease or metastasis to regional lymph nodes) resectable rectal cancer. However, the combined therapy is associated with more toxic effects, raising the question of whether the benefits of the treatment justify its quality-of-life costs for the individual patient. PURPOSE: To assess the trade-offs between improved survival and increased treatment toxicity, we reanalyzed data from a randomized clinical trial that compared the efficacy of combined adjuvant chemotherapy and radiation therapy with adjuvant radiation therapy alone in the treatment of patients with poor-prognosis resectable rectal cancer. METHODS: The data were from a North Central Cancer Treatment Group trial in which 204 patients with poor-prognosis rectal cancer were randomly assigned to receive either postoperative radiation therapy alone or radiation therapy plus fluorouracil-based chemotherapy. A quality-adjusted time without symptoms or toxicity (Q-TWiST) analysis was used to account for freedom from symptomatic disease and from early and late side effects of treatment. All reported P values are two-sided. RESULTS: As reported previously, the combined therapy reduced the risk of relapse by 34% (95% confidence interval [CI] = 12%-50%; P = .0016) and reduced the overall death rate by 29% (95% CI = 7%-45%; P = .025) in comparison with adjuvant radiation therapy alone. In the 5 years following assignment to treatment, patients who received the combined therapy had more time with toxicity (3.1 months; 95% CI = 2.0-4.1 months), shorter survival after relapse (3.6 months less; 95% CI = 0.9-6.3 months less), and more TWiST (6.1 months; 95% CI = 0.2-12.0 months) than patients who received adjuvant radiation therapy alone. Despite an increase in the amount of time that individuals spent with early and late toxic effects, the Q-TWiST analysis indicated that the combined therapy conferred significantly greater benefit for a wide range of patient preferences about living with the toxicity of treatment or the symptoms of overt disease. CONCLUSIONS AND IMPLICATIONS: Use of combined chemotherapy and radiation therapy as an adjuvant to surgery for patients with poor-prognosis resectable rectal cancer is justified, since the improved outcome in terms of delayed recurrence and increased survival balances the time spent with early and late toxic effects. The Q-TWiST method is an excellent way to compare treatment outcomes that include quality-of-life considerations.

Exposure to breast milk in infancy and adult breast cancer risk.

BACKGROUND: There is considerable interest in the possibility of an infectious etiology for human breast cancer. Although studies have shown that certain strains of mice transmit mammary tumor virus via breast milk, few epidemiologic studies have addressed this topic in humans. METHODS: We evaluated the relationship between having been breast-fed as an infant and breast cancer risk among 8299 women who participated in a population-based, case-control study of breast cancer in women aged 50 years or more. Case women were identified through cancer registries in three states (Massachusetts, New Hampshire, and Wisconsin); control women were identified through statewide driver's license lists (age <65 years) or Medicare lists (ages 65-79 years). Information on epidemiologic risk factors was obtained through telephone interview. We used multiple logistic regression to assess having been breast-fed and maternal history of breast cancer in relation to breast cancer occurrence both in premenopausal women (205 case women; 220 control women) and in postmenopausal women (3803 case women; 4071 control women). RESULTS: We found no evidence that having been breast-fed increased breast cancer risk in either premenopausal women (odds ratio [OR] = 0.65; 95% confidence interval [CI] = 0.41-1.04) or postmenopausal women (OR = 0.95; 95% CI = 0.85-1.07). In addition, breast cancer risk was not increased by having been breast-fed by a mother who later developed breast cancer. CONCLUSION: Our results do not support the hypothesis that a transmissible agent in breast milk increases breast cancer risk. Because premenopausal women were not well represented in our study population, our findings with regard to this group may not be generalizable and should be viewed with caution.

Quality-of-life-adjusted survival analysis of interferon alfa-2b adjuvant treatment of high-risk resected cutaneous melanoma: an Eastern Cooperative Oncology Group study.

PURPOSE: To evaluate the quality-of-life effects of adjuvant high-dose interferon alfa-2b (IFN alpha 2b) treatment of high-risk melanoma. PATIENTS AND METHODS: A quality-of-life-adjusted survival analysis (Quality-Adjusted Time Without Symptoms, and Toxicity [Q-TWiST]) was applied to the Eastern Cooperative Oncology Group Trial E1684, which compared high-dose IFN alpha 2b treatment for 1 year versus observation in 280 high-risk patients. IFN alpha 2b was administered at a dosage of 20 mU/m2 intravenously daily for 5 days per week for 4 weeks, and then three times weekly at 10 mU/m2 subcutaneously for 48 weeks. RESULTS: After 84 months of median follow-up time, the IFN alpha 2b group gained a mean of 8.9 months without disease relapse (P = .03) and 7.0 months of overall survival (P = .07) as compared with the observation group, but had severe treatment-related toxicity for 5.8 months, on average. The IFN alpha 2b group had more quality-of-life-adjusted time than the observation group regardless of the relative valuations placed on time with toxicity (Tox) and time with relapse (Rel). This gain was significant (P < .05) for patients who consider Tox to have a high relative value and Rel to have a low relative value. In contrast, for patients who value Tox about the same as Rel, the quality-adjusted gain for IFN alpha 2b was not statistically significant. An analysis stratified according to tumor burden indicated that the benefit of IFN alpha 2b was greatest in the node-positive strata. CONCLUSION: For patients with high-risk melanoma, the clinical benefits of high-dose IFN alpha 2b can offset the toxic effects. The optimal treatment for an individual patient depends on the patient's tumor burden and preferences regarding toxicity and disease relapse.

High-dose intravenous methotrexate for patients with nonleukemic leptomeningeal cancer: is intrathecal chemotherapy necessary?

PURPOSE: Standard treatments for neoplastic meningitis are only modestly effective and are associated with significant morbidity. Isolated reports suggest that concurrent systemic and intrathecal (i.t.) therapy may be more effective than i.t. therapy alone. We present our experience, which includes CSF and serum pharmacokinetic data, on the use of high-dose (HD) intravenous (i.v.) methotrexate (MTX) as the sole treatment for neoplastic meningitis. PATIENTS AND METHODS: Sixteen patients with solid-tumor neoplastic meningitis received one to four courses (mean, 2.3 courses) of HD (8 g/m2 over 4 hours) i.v. MTX and leucovorin rescue. Serum and CSF MTX concentrations were measured daily. Toxicity, response, and survival were retrospectively compared with a reference group of 15 patients treated with standard i.t. MTX during the same time interval. RESULTS: Peak methotrexate concentrations ranged from 3.7 to 55 micromol/L (mean, 17.1 micromol/L) in CSF and 178 to 1,700 micromol/L (mean, 779 micromol/L) in serum. Cytotoxic CSF and serum MTX concentrations were maintained much longer than with i.t. dosing. Toxicity was minimal. Cytologic clearing was seen in 81% of patients compared with 60% of patients treated intrathecally (P = .3). Median survival in the HD i.v. MTX group was 13.8 months versus 2.3 months in the i.t. MTX group (P = .003). CONCLUSION: HD i.v. MTX is easily administered and well tolerated. This regimen achieves prolonged cytotoxic serum MTX concentrations and CSF concentrations at least comparable to those achieved with standard i.t. therapy. Cytologic clearing and survival may be superior in patients treated with HD i.v. MTX. Prospective studies and a reconsideration of the use of i.t. chemotherapy for patients with neoplastic meningitis are warranted.

Phase I study of weekly outpatient paclitaxel and concurrent cranial irradiation in adults with astrocytomas.

PURPOSE: Astrocytomas are extremely resistant to currently available treatments. Cranial irradiation is a mainstay of frontline therapy, but tumor recurrence is nearly universal. Paclitaxel has shown antitumor efficacy against astrocytoma cell lines, and is a potent radiosensitizer. For these reasons, we conducted a phase I study of weekly paclitaxel and concurrent cranial irradiation in patients with newly diagnosed astrocytomas. PATIENTS AND METHODS: Patients with astrocytomas were eligible for this study following initial surgery if they had a Karnofsky performance score (KPS) > or = 60%; normal hematologic, liver, and renal function; and could give informed consent. Beginning on day 1 of treatment, patients received paclitaxel by 3-hour infusion once weekly for 6 weeks, concurrent with standard cranial irradiation. Pharmacokinetic studies were performed on 10 patients. RESULTS: Sixty patients were enrolled; 56 were fully assessable. Forty-eight had glioblastomas (GBMs), 10 anaplastic astrocytomas (AAs), and two astrocytomas. Age ranged from 21 to 81 years (median, 55); KPS ranged from 60 to 100 (median, 70). The paclitaxel dose was escalated from 20 mg/m2 to 275 mg/m2. No clinically significant anemia or thrombocytopenia occurred. Only one patient (175 mg/m2) became neutropenic. Sensory neuropathy was dose-limiting. The maximum tolerated dose (MTD) was 250 mg/m2. Paclitaxel pharmacokinetic profiles in study patients were identical to those of previously reported patients with other solid tumors. CONCLUSION: The MTD of paclitaxel administered weekly for 6 weeks by 3-hour infusion is 250 mg/m2. Since patients with brain tumors often have preexisting neurologic deficits, we suggest 225 mg/m2 as the optimum dose for phase II trials in this group of patients.

Quality-of-life-adjusted survival analysis of interferon alfa-2b treatment for advanced follicular lymphoma: an aid to clinical decision making.

PURPOSE: To evaluate the trade-off of toxicity versus improved clinical outcome with interferon alfa-2b (IFN) administered concomitantly with a doxorubicin-containing regimen for the treatment of advanced follicular lymphoma. PATIENTS AND METHODS: A quality-of-life-adjusted survival analysis (Quality-Adjusted Time Without Symptoms or Toxicity [Q-TWiST]) was applied to the Groupe d'Etude des Lymphomes Folliculaires (GELF) trial 86, which compared a regimen of cyclophosphamide, doxorubicin, teniposide, and prednisone (CHVP) versus CHVP plus IFN in 242 patients with confirmed follicular lymphoma. CHVP was administered monthly for 6 months then every other month for 12 months. The IFN dosage was 5 x 10(6) U three times weekly for 18 months. RESULTS: After a median follow-up duration of 72 months, the IFN group gained a mean of 12.3 months of progression-free survival (PFS) and 7.4 months of overall survival (OS), but also experienced additional time with grade 3 or worse toxicity compared with the CHVP group. Sensitivity analysis demonstrated that CHVP plus IFN provided a greater amount of quality-adjusted survival regardless of the relative quality-of-life valuations placed on time with toxicity due to CVHP alone, time with toxicity due to CHVP plus IFN, and time following disease progression. This gain was significant (P < .05) in all cases except for patients who consider time with toxicity to have a low relative value and time following disease progression to have a high relative value. CONCLUSION: In patients with advanced follicular lymphoma, the clinical benefits of concomitant IFN can significantly offset the associated grade 3 or worse toxic effects. The magnitude of this clinical benefit depends on an individual patient's relative quality-of-life valuations for time with toxicity and time following disease progression.

Quality-adjusted survival after treatment for acute myeloid leukemia in childhood: A Q-TWiST analysis of the Pediatric Oncology Group Study 8821.

PURPOSE: To describe quality-of-life considerations in post-remission therapies for children with acute myelogenous leukemia. PATIENTS AND METHODS: A quality-adjusted survival analysis, using the quality-adjusted time without symptoms or toxicity (Q-TWiST) method, was applied to Pediatric Oncology Group Trial 8821, which compared randomized assignment with intensive consolidation chemotherapy (CC) or autologous bone marrow transplantation (ABMT). Nonrandomized assignment to allogeneic bone marrow transplantation (allo BMT) on the basis of availability of a matched related donor was also evaluated. A 25-patient cohort provided data for modeling chronic graft-versus-host disease. The Q-TWiST analysis was performed based on the intent-to-treat principle. RESULTS: As previously reported, the 3-year event-free survival was not significantly different between the randomized arms (CC v ABMT). At a median follow-up of 5 years (of the censoring distribution), the CC group had less time in toxicity (TOX) and more time without symptoms or toxicity (TWiST), relapse-free time, and alive time than patients assigned to ABMT (none of these were statistically significant). Compared with the CC group, allo BMT patients spent more time in TOX (P <.001), more time in TWiST (P =.06), and had more relapse-free time (P =.03) and time alive (P =.07). Allo BMT was superior to ABMT with greater time in TWiST (P =.02), relapse-free time (P =.01), and time alive P =.002). CONCLUSION: The Q-TWiST analysis is a powerful decision aid in choosing among alternative therapies. Prospective information on patient preferences will facilitate future trials evaluating treatment outcomes. Refinements in the Q-TWiST method could be included to further enhance the power of this patient care decision-making tool.

Phase II trial of weekly paclitaxel and concurrent radiation therapy for locally advanced non-small cell lung cancer.

We conducted a prospective Phase II study to determine the response rate, toxicity, and 2-year survival rate of concurrent weekly paclitaxel and radiation therapy (RT) for locally advanced unresectable non-small cell lung cancer. The weekly paclitaxel regimen was designed to optimize the radiosensitizing properties of paclitaxel. Thirty-three patients with unresectable stage IIIA and IIIB non-small cell lung cancer from six institutions were entered into the study between March 1994 and February 1995. Weekly i.v. paclitaxel (60 mg/m2; 3-h infusion) plus concurrent chest RT (60 Gy over 6 weeks) was delivered for 6 weeks. Twenty-nine patients were evaluable for response. Three patients achieved a complete response (10%), and 22 patients (76%) achieved a partial response, for an overall response rate of 86% (95% confidence interval, 68-96%). One patient progressed during the therapy, and three patients had stable disease. Esophagitis was the principal toxicity. Grade 3 or 4 esophagitis occurred in 11 patients (37%). One patient died of pneumonia after completion of therapy. Additional grade > or =3 toxicities included pneumonitis (12%) and neutropenia (6%). One patient had a grade 3 hypersensitivity reaction. The median overall survival duration for all 33 patients who entered the study was 20 months, and 1-, 2-, and 3-year overall survival rates were 60.6%, 33.3%, and 18.2%, respectively. The median progression-free survival duration for all 33 patients was 10.7 months, and 1-, 2-, and 3-year progression-free survival rates were 39.4%, 12.1%, and 6.1%, respectively. Weekly paclitaxel plus concurrent RT is a well-tolerated outpatient regimen. The survival outcome from this regimen is encouraging and seems to be at least equivalent to that of other chemotherapy/radiation trials. These findings warrant further clinical evaluation of weekly paclitaxel/RT in Phase II trials in the neoadjuvant setting and in combination with other cytotoxic agents.

A randomized controlled trial comparing intrathecal sustained-release cytarabine (DepoCyt) to intrathecal methotrexate in patients with neoplastic meningitis from solid tumors.

Standard treatment for neoplastic meningitis requires frequent intrathecal (IT) injections of chemotherapy and is only modestly effective. DepoCyt is a sustained-release formulation of cytarabine that maintains cytotoxic concentrations of the drug in the cerebrospinal fluid (CSF) for more than 14 days after a single 50-mg injection. We conducted a randomized, controlled trial of DepoCyt versus methotrexate in patients with solid tumor neoplastic meningitis. Sixty-one patients with histologically proven cancer and positive CSF cytologies were randomized to receive IT DepoCyt (31 patients) or IT methotrexate (30 patients). Patients received up to six 50-mg doses of DepoCyt or up to sixteen 10-mg doses of methotrexate over 3 months. Treatment arms were well balanced with respect to demographic and disease-related characteristics. Responses occurred in 26% of DepoCyt-treated and 20% of methotrexate-treated patients (P = 0.76). Median survival was 105 days in the DepoCyt arm and 78 days in the methotrexate arm (log-rank P = 0.15). The DepoCyt group experienced a greater median time to neurological progression (58 versus 30 days; log-rank P = 0.007) and longer neoplastic meningitis-specific survival (log-rank P = 0.074; median meningitis-specific survival, 343 versus 98 days). Factors predictive of longer progression-free survival included absence of visible central nervous system disease on neuroimaging studies (P<0.001), longer pretreatment duration of CSF disease (P<0.001), history of intraparenchymal tumor (P<0.001), and treatment with DepoCyt (P = 0.002). The frequency and grade of adverse events were comparable between treatment arms. In patients with solid tumor neoplastic meningitis, DepoCyt produced a response rate comparable to that of methotrexate and significantly increased the time to neurological progression while offering the benefit of a less demanding dose schedule.

gp120-directed antibody-dependent cellular cytotoxicity as a major determinant of the rate of decline in CD4 percentage in HIV-1 disease.

OBJECTIVE: To determine the relationship between the rate of CD4 percentage decline and two factors postulated to be associated with CD4 cell destruction: circulating HIV-1 viral load and gp120-directed antibody-dependent cellular cytotoxicity (ADCC). DESIGN: Four women and 16 men had serial determinations of CD4 percentage gp120-directed ADCC activity [using the cell-mediated cytotoxicity (CMC) assay] natural killer (NK) cell number, spontaneous NK lytic function, and plasma HIV-1 RNA. METHODS: The rate of decline in CD4 percentage was modeled as a function of gp120-directed ADCC activity and circulating HIV-1 RNA using Pearson correlation and multiple regression analyses. RESULTS: All individuals had at least four CMC assays performed and two HIV-1 RNA polymerase chain reaction measurements over a median follow-up of 27 months. Although the rate of CD4 percentage decline was associated with either CMC activity (r = -0.53, P = 0.02) or circulating HIV-1 RNA (r = -0.42, P = 0.07), it was strongly correlated with an interaction between CMC and HIV-1 RNA (r = -0.76, P < 0.0001). Mean CMC activity was associated with both mean percentage of circulating NK cells and mean spontaneous NK cell lysis. CONCLUSIONS: The ability of cells from HIV-infected individuals to mediate gp120-directed ADCC, together with a sufficient circulating viral load, define conditions under which rapid CD4 cell destruction may occur. This relationship between viral load and an HIV-1-specific immune response lends important insights into the central causes of immunodeficiency in AIDS and suggests additional avenues for therapeutic intervention.

Evaluation of effectiveness: Q-TWiST. The International Breast Cancer Study Group.

The effectiveness of cancer treatments is often expressed in terms of disease-free survival or overall survival relative risk reduction or odds ratios, and the quality of life effects are often assessed separately from survival. Such end points and summary measures may be inadequate, however, for comparing two treatments in terms of their palliative effects because there is a trade-off between treatment toxicity and increased disease-free interval. Furthermore, this trade-off may depend on individual patient preferences and prognostic situations. The goal of this paper is to describe a method for evaluating the effectiveness of cancer treatments in terms of palliation by simultaneously considering both quality and quantity of time following treatment so that therapeutic choice may be determined according to patient preferences on quality of life and prognostic situation. The method we present is an extension of the Quality-adjusted Time Without Symptoms and Toxicity (Q-TWiST) method for comparing treatment effectiveness in clinical trials of adjuvant therapies. We illustrate an application using data from the International Breast Cancer Study Group Trial V which compares two chemotherapy schedules with different toxicities.

Measuring patient-centered outcomes in neurologic disease. Extending the Q-TWiST method.

BACKGROUND: Current clinical research and outcomes assessment on multiple sclerosis rely on an approach to disability measurement that is heavily influenced by ambulation. Not only is this strategy often insensitive to the clinical changes affected by pharmacotherapeutic or rehabilitative interventions but it also disregards the symptoms that patients seem to consider most enervating. We propose a new method for evaluating clinical interventions in terms of their impact on the symptoms of multiple sclerosis, side effects, parameters of exacerbation, and disease progression, while considering the patient's perspective. METHODS: The extended Q-TWiST method yields an estimation of treatment trade-offs in terms of Quality-adjusted Time Without Symptoms and Toxicities (Q-TWiST). An illustration of this method is presented by using a hypothetical clinical trial of two treatments. The trade-offs between the two treatments are highlighted to facilitate treatment decision making by using individual patient importance weights. CONCLUSION: We discuss applications to other clinical research and other chronic diseases.

The role of paclitaxel in the treatment of primary and metastatic brain tumors.

The rationale for the use of paclitaxel to treat brain tumors includes impressive activity in a wide array of chemotherapy-resistant solid tumors, in vitro and in vivo evidence of cytotoxicity against primary brain tumors, and a paucity of effective alternative agents. A review of published studies evaluating paclitaxel alone or in combination with other chemotherapeutic agents suggests that paclitaxel alone is not highly active against newly diagnosed or recurrent glioblastoma multiforme. However, additional prospective trials are warranted to evaluate the efficacy of paclitaxel plus conventional cranial irradiation or stereotactic radiosurgery. Single-agent paclitaxel appears to be active against gliomas with an oligodendroglial component and may prove useful both as a component of initial therapy and for recurrent disease. Activity against anaplastic gliomas and brain metastases also should be explored. With radiation, a weekly paclitaxel administration schedule is particularly appealing from pharmacologic, safety, and dose-intensity perspectives. In addition, the dose of paclitaxel must be increased in patients who are concurrently receiving medications that induce the P-450 drug metabolizing system. Primary and metastatic brain tumors constitute a very difficult problem in oncology. Future investigations should be directed at evaluating paclitaxel-based chemotherapy regimens in selected brain tumor types, combining paclitaxel with stereotactic radiosurgery, and determining the importance of other proposed mechanisms of action of paclitaxel (eg, inhibition of angiogenesis and tumor invasion).

A randomized, blinded, placebo-controlled trial of divalproex sodium prophylaxis in adults with newly diagnosed brain tumors.

BACKGROUND: Seizures occur after the diagnosis of brain tumors in up to 40% of patients. Prophylactic anticonvulsants are widely advocated despite a lack of convincing evidence of their efficacy in preventing first seizures. We conducted a randomized, double-blind, placebo-controlled study comparing the incidence of first seizures in divalproex sodium- and placebo-treated patients with newly diagnosed brain tumors. PATIENTS AND METHODS: Patients who had not previously had a seizure were randomized within 14 days of diagnosis of their brain tumor to receive either divalproex sodium or placebo. All patients had at least one supratentorial brain lesion, a Karnofsky Performance Score (KPS) > or = 50%, and no previous anticonvulsant use or other brain disease. Compliance and adequacy of dosing were assessed by pill counts and monthly blood levels. RESULTS: Seventy-four of 75 consecutive eligible patients were entered in this study. Median follow-up was 7 months. The drug and placebo groups did not differ significantly in age, sex, KPS, primary tumor type, number or location of brain lesions, frequency of brain surgery, or pretreatment EEG. Thirteen of 37 patients (35%) receiving divalproex sodium and 9 of 37 patients (24%) on placebo had seizures. The odds ratio for a seizure in the divalproex sodium arm relative to the placebo arm was 1.7 (95% CI 0.6 to 4.6; p = 0.3). The hypothesis that anticonvulsant prophylaxis provides a reduction in the frequency of first seizure as small as 30% was rejected (p = 0.05). CONCLUSIONS: Anticonvulsant prophylaxis with divalproex sodium is not indicated for patients with brain tumors who have not had seizures.

Combined-modality therapy for advanced non-small cell lung cancer: paclitaxel and thoracic irradiation.

Despite advances in the modalities used to treat non-small cell lung cancer (NSCLC), the frequency of locoregional and distant relapses necessitates further enhancement of the therapeutic program. Paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) has demonstrated clinical efficacy against NSCLC and in vitro studies support its role as a radiation potentiator at concentrations achievable in vivo. Thus, a phase I study of weekly paclitaxel and daily concurrent thoracic radiation was conducted in patients with advanced NSCLC to determine (1) the maximum tolerated dose of paclitaxel administered on an outpatient basis for 6 consecutive weeks with daily radiation and (2) the toxicities of the paclitaxel/radiation combination. Paclitaxel was administered as a 3-hour infusion, repeated weekly for 6 weeks with the usual premedication regimen for hypersensitivity prophylaxis. The starting dose of paclitaxel was 10 mg/m2/wk, which was increased by 10 mg/m2 in successive cohorts of three new patients, as tolerated. Radiation therapy was delivered as 40 Gy in 20 fractions to the original volume with a boost of 20 Gy in 10 fractions to the primary tumor. Doses were escalated from 10 to 70 mg/m2/wk. Of the 23 patients evaluable for response, one had stage II NSCLC, four had stage IIIA, 17 had stage IIIB, and one had stage IV. Severe esophagitis (grade 4) occurred in two of the three patients treated at 70 mg/m2 and was dose limiting. One patient discontinued therapy due to hypersensitivity, two developed grade 3 neutropenia, and one developed radiation pneumonitis. With a median follow-up of 7 months, 15 of the 23 patients remain alive. Four had a complete response and 13 had a partial response, for an overall response rate of 74% (95% confidence interval, 52% to 90%). The schedule of weekly paclitaxel and daily thoracic radiation appears active in NSCLC and can be delivered safely in the outpatient setting. The principal dose-limiting toxicity is esophagitis, and the maximum tolerated dose of paclitaxel for this schedule is 60 mg/m2/wk. A phase II trial of weekly paclitaxel 60 mg/m2 and radiation has been initiated in patients with NSCLC.

Efficacy, safety, and risk-benefit analysis of adjuvant interferon alfa-2b in melanoma.

A recently completed Eastern Cooperative Oncology Group trial, E1684, has shown that adjuvant therapy with high-dose recombinant interferon alfa-2b (rIFN-alpha 2b) has a significant impact on relapse-free and overall survival in melanoma patients at high risk of recurrence. Adjuvant rIFN-alpha 2b increased the median overall survival to 3.82 years in the treatment group compared with 2.78 years with observation and yielded a 5-year survival rate of 46% versus 37% with observation. This is the first adjuvant therapy to significantly extend survival in this patient population (P = .0023, one-sided). The response to therapy was greatest among those patients with clinical evidence of nodal metastasis. The toxicity associated with this regimen was substantial but tolerable. Approximately 78% of patients treated with rIFN-alpha 2b experienced grade 3 or greater toxicity, and dose modifications were required for 37% and 36% of patients in the induction or maintenance phase, respectively. Quality-of-life-adjusted survival analysis has shown that, despite the toxicity associated with rIFN-alpha 2b therapy, the quality-of-life-adjusted time gained with rIFN-alpha 2b therapy outweighs the reduced quality of life associated with treatment toxicity and relapse. These data support the use of high-dose rIFN-alpha 2b as adjuvant therapy in melanoma patients at high risk of recurrence.