Phase II trial of oral vinorelbine for the treatment of metastatic breast cancer in patients > or = 65 years of age: an NCCTG study.

BACKGROUND: A one-stage phase II trial was conducted to assess the tumor response rate and toxicity profile of single agent oral vinorelbine as first or second-line chemotherapy for women at least 65 years of age with metastatic breast cancer. PATIENTS AND METHODS: Twenty-five patients with metastatic breast cancer aged > or = 65 years of age were enrolled to receive oral vinorelbine on a weekly basis. The oral vinorelbine was given at 60 mg/m2 weekly for the first four doses and was increased to 70 mg/m2 for the subsequent administrations if there was no grade 4 neutropenia or no more than one episode of grade 3 neutropenia. Therapy was continued until progression or intolerable toxicity. RESULTS: Twenty-five patients were included and evaluable for analysis. One patient (4%) achieved a partial response (PR) that lasted for more than 13 months. Two additional patients remained stable for at least 6 months for a clinical benefit rate (PR + stable disease) of 12%. The 1-year survival rate was estimated to be 48% (95% CI 30% to 74.5%). Median time to progression was estimated to be 4.7 months (95% CI 2.0-5.5 months) and the 9-month disease progression-free rate was estimated to be 8% (95% CI 30.9% to 74.5%). The treatment was fairly well tolerated with grade 3 neutropenia in 12.5%, fatigue in 12.5% of the patients, and grade 2 neuromotor and neurosensory toxicities in 12.5% and 8.3%, respectively. CONCLUSION: Oral vinorelbine as a single agent at these dose and schedule in this population of women > or = 65 years is well tolerated but has a low level of objective efficacy for the treatment of metastatic breast cancer.

Docetaxel and capecitabine in patients with metastatic adenocarcinoma of the stomach and gastroesophageal junction: a phase II study from the North Central Cancer Treatment Group.

BACKGROUND: Previous studies suggest that the combination of docetaxel and capecitabine are worthy of further testing in patients with metastatic adenocarcinoma of the stomach and gastroesophageal junction. We therefore undertook this phase II study to test this combination in a multi-institutional, first-line clinical trial. PATIENTS AND METHODS: Forty-four eligible patients with histologic or cytologic confirmation of the above malignancy were recruited. The cohort had Eastern Cooperative Oncology Group performance scores of 0, 1 and 2 in 59%, 39% and 2% of patients, respectively. Median age was 57 years (range 32-77 years). Adequate organ function was a requirement for study entry. All patients were prescribed docetaxel 75 mg/m2 intravenously on day 1 and capecitabine 825 mg/m2 orally twice a day on days 1-14 of a 21-day cycle. RESULTS: The tumor response rate was 39% [95% confidence interval (CI) 23% to 55%]. There were two complete responses and the rest were partial. Median survival was 9.4 months (95% CI 6.3-10.7 months) and median time-to-tumor progression was 4.2 months (95% CI 3.6-5.6 months). There was one treatment-related death from a myocardial infarction and dysrhythmia. Commonly occurring grade 3 adverse events included neutropenia (11 patients), infection (five patients), constipation (three patients), thrombosis (three patients), dyspnea (three patients) and hand-foot syndrome (three patients). In addition, 24/45 patients developed grade 4 neutropenia. CONCLUSIONS: The regimen docetaxel and capecitabine shows activity in patients with metastatic adenocarcinoma of the stomach and gastroesophageal junction. This regimen merits further study.

Investigating four 'myths' surrounding dysphagia in patients with metastatic esophageal cancer. A multi-institutional study from the North Central Cancer Treatment Group.

Eighty-five to 95% of esophageal cancer patients suffer dysphagia. Yet, few studies have focused on this symptom, and four 'myths' persist: (i) dysphagia cannot be measured; (ii) chemotherapy cannot palliate it; (iii) dysphagia predicts a poor prognosis; (iv) dysphagia is associated with a frustratingly insatiable appetite. Forty-four patients with metastatic esophageal cancer participated in this quality of life/translational component of a previously reported clinical trial. All were monitored for chemotherapy efficacy and toxicity and completed questionnaires on dysphagia and appetite at baseline and every 6 weeks. The appetite hormones, leptin and neuropeptide y, were also assessed. Forty-five per cent of patients could easily swallow solid foods; all others had varying dysphagia, thus enabling exploration of these four 'myths.' First, a single-item visual analog scale (Swallowing Scale), demonstrated excellent agreement with a previously validated questionnaire (81% at baseline), thus reminding us that dysphagia is measurable. Second, chemotherapy was associated with a trend towards improved dysphagia (P = 0.059). Third, dysphagia did not predict tumor response or survival. Fourth, dysphagia was not associated with appetite, leptin or neuropeptide y. This study helps to dispel these four 'myths' and underscores the need for further quality of life research on dysphagia.

Gemcitabine and oxaliplatin for metastatic pancreatic adenocarcinoma: a North Central Cancer Treatment Group phase II study.

BACKGROUND: This study was performed to determine the efficacy of gemcitabine and oxaliplatin in patients with advanced or metastatic pancreatic adenocarcinoma (ACA). PATIENTS AND METHODS: Pancreatic ACA patients with previously untreated advanced or metastatic disease were enrolled in a phase II study of gemcitabine and oxaliplatin. Oxaliplatin was given i.v. on day 1 and gemcitabine i.v. on days 1 and 8 of a 3-week cycle. The primary end point of the trial was 6-month survival. Secondary end points included response rate, overall survival, median time to progression and toxicity. RESULTS: A total of 47 patients were enrolled, 46 of whom were evaluable. Of those patients assessed for the primary end point 50% lived for > or =6 months. The median time to progression was 4.53 months. Five confirmed responses were seen with a median duration of response of 2.7 months. Overall, the treatment was well tolerated. However, one patient died as a result of treatment-related hemolytic uremic syndrome. CONCLUSIONS: Gemcitabine and oxaliplatin, at doses of 1000 mg/m(2) and 100 mg/m(2), respectively, showed moderate activity in patients with pancreatic ACA. Based on the results of this study further evaluation of this combination is warranted.

Gemcitabine and oxaliplatin for patients with advanced or metastatic pancreatic cancer: a North Central Cancer Treatment Group (NCCTG) phase I study.

BACKGROUND: The study was performed to determine the maximum tolerated dose (MTD) of gemcitabine and oxaliplatin in patients with advanced or metastatic pancreatic adenocarcinoma (ACA). PATIENTS AND METHODS: Pancreatic ACA patients, with previously untreated advanced or metastatic disease, were enrolled in a dose escalation study of gemcitabine and oxaliplatin. Oxaliplatin was given intravenously on day 1 and gemcitabine intravenously on days 1 and 8 of a 3-week cycle. Doses of both drugs were increased with sequential cohorts of patients until dose-limiting toxicity (DLT) was observed. RESULTS: A total of 18 patients were enrolled to three dose levels. DLT of neutropenia and a severe infection was noted at a dose of gemcitabine 1250 mg/m2 and oxaliplatin 130 mg/m2. Hematological toxicity and nausea and vomiting were the most common grade 3/4 toxicities. The MTD, gemcitabine 1000 mg/m2 and oxaliplatin 100 mg/m2, was well tolerated. Three confirmed responses were seen. CONCLUSIONS: The MTD of gemcitabine and oxaliplatin in patients with pancreatic ACA was determined. A phase II study of this combination is ongoing and will be reported separately at a later date.

Comparison of conventional dose and double dose carboplatin in patients receiving cyclophosphamide plus carboplatin for advanced ovarian carcinoma: a North Central Cancer Treatment Group Study.

Between March 1992 and November 1994, 91 patients with stage III and IV ovarian carcinoma were enrolled in a randomized comparative study of cyclophosphamide 600 mg/m2 plus carboplatin 300 mg/m2 vs. cyclophosphamide 600 mg/m2 plus carboplatin 600 mg/m2, each regimen given monthly for six cycles. Patients on the intensive regimen also received 10 micrograms/kg of granulocyte macrophage colony stimulating factor (GM-CSF) (molgramostim) daily for 14 days following each chemotherapy treatment. The study was closed prematurely because of very poor case accrual following the preliminary announcement (in May 1993) that paclitaxel appeared superior to cyclophosphamide in the platinum-based treatment of ovarian cancer. More than 4 years after our last case entry, we analyzed the survival results for the 44 eligible patients who received the conventional dose of carboplatin and the 43 eligible patients receiving our intensified dose of carboplatin. More than 90% of the treated patients receiving the conventional dose regimen received at least 75% of the planned doses at each of the six treatment intervals, whereas the percentage of treated patients able to receive at least 75% of the assigned intensive dose regimen had declined from 95% in cycle 2 to 53% by cycle 6. Furthermore, although 32 patients received all six planned cycles of treatment in the conventional regimen group, only 15 received all six cycles of the intensified regimen. Patients receiving the intensive regimen had more fever, dermatitis, lethargy, musculoskeletal pain, and pulmonary complications than did the conventional dose patients. Median survival times for the two treatment groups were very similar (38.5 and 38.1 months, respectively, for the conventional and intensive regimens), and we saw no evidence that the distribution of survival times differed between the treatment regimens (p = 0.95).

A phase II study of sequential combination chemotherapy with cyclophosphamide, prednisone, and 2-chlorodeoxyadenosine in previously untreated patients with chronic lymphocytic leukemia.

In an earlier study of previously untreated patients with chronic lymphocytic leukemia (CLL), we used a concomitant combination of chlorambucil and 2-chlorodeoxyadenosine and reported overall (OR) and complete (CR) remission rates of 80% and 20%, respectively. After a median follow-up of 5 years, more than 80% of the responders have had a relapse. In the current phase II study of 27 previously untreated patients with CLL, we used a sequential combination of six cycles of intravenous cyclophosphamide (1 g/m2) plus oral prednisone (100 mg/m2 per day for 5 days) followed by two to six cycles of 2-chlorodeoxyadenosine (5 mg/m2 per day for 5 days). The OR and CR rates were 96% and 33%, respectively. After a median follow-up of 29 months, 35% of the responders have had a relapse. Progression-free survival was significantly better in CR patients than in those with partial remission. However, minimal residual disease was phenotypically detected in four of the nine CR patients. Despite the fact that the current OR and CR rates are superior to those seen in a historical cohort treated with a concomitant schedule, a longer follow-up period is needed to assess the durability of these remissions, and a controlled trial is necessary to estimate the impact on overall survival and toxicity.

A phase III study of radiation therapy plus carmustine with or without recombinant interferon-alpha in the treatment of patients with newly diagnosed high-grade glioma.

BACKGROUND: The current study was conducted to determine whether the addition of interferon-alpha (IFN-alpha) to treatment with radiation therapy and carmustine (BCNU) improves time to disease progression or overall survival in patients with high-grade glioma. METHODS: Patients with anaplastic astrocytoma, anaplastic oligoastrocytoma, glioblastoma multiforme, or gliosarcoma received radiation therapy plus BCNU as initial therapy. Subsequently, patients without tumor progression at the completion of radiation therapy were stratified by age, extent of surgery, tumor grade and histology, Eastern Cooperative Oncology Group performance status, and treating institution, and then were randomly assigned to receive either BCNU alone (200 mg/m(2) on Day 1) or BCNU (150 mg/m(2) on Day 3) plus IFN--alpha (12 million U/m(2) on Days 1-3, Weeks 1, 3, and 5) every 7 weeks for a maximum of 6 cycles. RESULTS: Of the 383 patients enrolled in the study, 275 eligible patients were randomized. There was no significant difference with regard to time to disease progression or overall survival between the two groups. Patients receiving IFN-alpha experienced more fever, chills, myalgias, and neurocortical symptoms including somnolence, confusion, and exacerbation of neurologic deficits. Cox multivariate regression models confirmed known favorable prognostic variables including younger age, Grade 3 tumor (according to World Health Organization criteria), and greater extent of surgery. Cox and classification and regression tree analysis models also demonstrated that a normal baseline Folstein mini-mental status examination (MMSE) score was associated with better prognosis. CONCLUSIONS: IFN-alpha does not appear to improve time to disease progression or overall survival in patients with high-grade glioma and appears to add significantly to toxicity. The baseline MMSE score may serve as an independent prognostic factor and warrants further investigation.

Phase III evaluation of octreotide versus chemotherapy with 5-fluorouracil or 5-fluorouracil plus leucovorin in advanced exocrine pancreatic cancer: a North Central Cancer Treatment Group study.

There continues to be a need for new systemic approaches for the treatment of advanced pancreatic cancer. The purpose of this study was to compare the antitumor activity of the somatostatin analogue octreotide to 5-fluorouracil chemotherapy in a Phase III setting. Eighty-four patients with an Eastern Cooperative Oncology Group performance status of 0 or 1 and limited tumor volume were randomized to receive octreotide 200 microg three times daily or 5-fluorouracil with or without leucovorin. After the first 12 patients had been randomized to octreotide, we increased the dose in the remaining patients to 500 microg three times daily. This change was based on early reports in other studies, suggesting that our original dose may not have been effective and that higher doses of octreotide were well tolerated. A planned interim analysis performed after 84 patients were enrolled demonstrated inferior time to progression and survival for the patients randomized to octreotide. Further accrual to the octreotide arm of this protocol was therefore terminated. Octreotide in doses of 200-500 microg three times daily does not delay progression or extend survival in patients with advanced pancreatic cancer compared with treatment with 5-fluorouracil with or without leucovorin.

Sucralfate in the prevention of treatment-induced diarrhea in patients receiving pelvic radiation therapy: A North Central Cancer Treatment Group phase III double-blind placebo-controlled trial.

PURPOSE: Randomized studies have suggested that sucralfate is effective in mitigating diarrhea during pelvic radiation therapy (RT). This North Central Cancer Treatment Group study was undertaken to confirm the antidiarrheal effect of sucralfate. Several other measures of bowel function were also assessed. PATIENTS AND METHODS: Patients receiving pelvic RT to a minimum of 45 Gy at 1.7 to 2.1 Gy/d were eligible for the study. Patients were assigned randomly, in double-blind fashion, to receive sucralfate (1.5 g orally every 6 hours) or an identical looking placebo during pelvic RT. RESULTS: One hundred twenty-three patients were randomly assigned and found assessable. Overall, there was no significant difference in patient characteristics between those receiving sucralfate and those receiving placebo. Moderate or worse diarrhea was observed in 53% of patients receiving sucralfate versus 41% of those receiving placebo. Compared with patients receiving placebo, more sucralfate-treated patients reported fecal incontinence (16% v 34%, respectively; P =. 04) and need for protective clothing (8% v 23%, respectively; P =. 04). The incidence and severity of nausea were worse among those taking sucralfate (P =.03). Analysis of patient-reported symptoms 10 to 12 months after RT showed a nonsignificant trend toward more problems in patients taking sucralfate than in those taking placebo (average, 2.3 v 1.9 problems, respectively; P =.34). CONCLUSION: Sucralfate did not decrease pelvic RT-related bowel toxicity by any of the end points measured and seems to have aggravated some gastrointestinal symptoms.

Significance of neuron-specific enolase levels before and during therapy for small cell lung cancer.

The level of serum neuron-specific enolase (NSE) has been implicated as a prognostic factor for patients with small cell lung cancer (SCLC). A prospective evaluation was undertaken to assess the prognostic significance of pretreatment NSE and treatment-induced minimum NSE values in patients with SCLC. Patients from two Phase III North Central Cancer Treatment Group trials [one for patients with extensive stage SCLC and one for patients with limited stage SCLC] were asked to enter this laboratory correlational trial. Both trials included treatment with four to six cycles of etoposide and cisplatin, and 121 patients (71 extensive stage SCLC and 50 limited stage SCLC) were entered into the present study of NSE. Pretreatment NSE values and treatment-induced minimum NSE values were independent predictors of time to progression and survival in multivariate analysis. Hazard rate modeling allowed the formulation of specific relationships of NSE to time to progression and survival. Pretreatment NSE levels inversely correlated with time to progression and survival in these patients with SCLC. Pretreatment NSE accounted for 28% of the variance in survival. Both pretreatment NSE and treatment-induced minimum NSE were independent prognostic predictors of time to progression and survival.

A phase II study of paclitaxel plus carboplatin as first-line chemotherapy for women with metastatic breast carcinoma.

BACKGROUND: This Phase II multicenter study evaluated the efficacy and toxicity of paclitaxel (200 mg/m(2) by 3-hour infusion) with carboplatin (area under the curve 6 mg/mL per minute) administered every 3 weeks as first-line therapy for women with metastatic breast carcinoma. METHODS: Eligible patients had measurable metastatic disease and an Eastern Cooperative Oncology Group performance status of 0-2. Prior adjuvant chemotherapy, including anthracycline-based therapy, was allowed, as was prior hormonal therapy as part of either adjuvant treatment or treatment for metastasis. Prior therapy with taxanes or platinum was not allowed. RESULTS: A total of 53 patients were enrolled in this study, with 50 patients evaluable for response and toxicity. The overall response rate was 62% (95% confidence interval ¿CI, 48-75%); 16% of patients had complete responses and 46% had partial responses. The median time to progression was 7.3 months (95% CI, 5.9-12.9), and the 12-month survival estimate was 72% (95% CI, 61-86%). Therapy was generally well tolerated. Grade 3-4 neutropenia was the predominant toxicity, observed in 82% of patients, but there were no episodes of febrile neutropenia or sepsis. Hematopoietic growth factors were not routinely necessary. Grade 3 peripheral neuropathy occurred in 16% of patients. CONCLUSIONS: Paclitaxel (200 mg/m(2)) with carboplatin (area under the curve 6 mg/mL per minute) demonstrated substantial efficacy in patients with metastatic breast carcinoma, and the 12-month survival rate of 72% was encouraging. This therapy represents a viable option for patients with metastatic disease.

Venlafaxine in management of hot flashes in survivors of breast cancer: a randomised controlled trial.

BACKGROUND: Hot flashes can be troublesome, especially when hormonal therapy is contraindicated. Preliminary data have suggested that newer antidepressants, such as venlafaxine, can diminish hot flashes. We undertook a double-blind, placebo-controlled, randomised trial to assess the efficacy of venlafaxine in women with a history of breast cancer or reluctance to take hormonal treatment because of fear of breast cancer. METHODS: Participants were assigned placebo (n=56) or venlafaxine 37.5 mg daily (n=56), 75 mg daily (n=55), or 150 mg daily (n=54). After a baseline assessment week, patients took the study medication for 4 weeks. All venlafaxine treatment started at 37.5 mg daily and gradually increased in the 75 mg and 150 mg groups. Patients completed daily hot-flash questionnaire diaries. The primary endpoint was average daily hot-flash activity (number of flashes and a score combining number and severity). Analyses were based on the women who provided data throughout the baseline and study weeks. FINDINGS: 191 patients had evaluable data for the whole study period (50 placebo, 49 venlafaxine 37.5 mg, 43 venlafaxine 75 mg, 49 venlafaxine 150 mg). After week 4 of treatment, median hot flash scores were reduced from baseline by 27% (95% CI 11-34), 37% (26-54), 61% (50-68), and 61% (48-75) in the four groups. Frequencies of some side-effects (mouth dryness, decreased appetite, nausea, and constipation) were significantly higher in the venlafaxine 75 mg and 150 mg groups than in the placebo group. INTERPRETATION: Venlafaxine is an effective non-hormonal treatment for hot flashes, though the efficacy must be balanced against the drug's side-effects. Confirmation of the results of this 4-week study awaits the completion of three ongoing randomised studies to assess the effects of other related antidepressants for the treatment of hot flashes.

Phase III comparison of twice-daily split-course irradiation versus once-daily irradiation for patients with limited stage small-cell lung carcinoma.

PURPOSE: Because small-cell lung cancer is a rapidly proliferating tumor, it was hypothesized that it may be more responsive to thoracic irradiation (TI) given twice-daily than once-daily. This hypothesis was tested in a phase III trial. PATIENTS AND METHODS: Patients with limited-stage small-cell lung cancer were entered onto a phase III trial, and all patients initially received three cycles of etoposide (130 mg/m(2) x 3) and cisplatin (30 mg/m(2) x 3). Subsequently, patients who did not have progression to a distant site (other than brain) were randomized to twice-daily thoracic irradiation (TDTI) versus once-daily thoracic irradiation (ODTI) given concomitantly with two additional cycles of etoposide (100 mg/m(2) x 3) and cisplatin (30 mg/m(2) x 3). The irradiation doses were TDTI, 48 Gy in 32 fractions, with a 2.5-week break after the initial 24 Gy, and ODTI, 50.4 Gy in 28 fractions. After thoracic irradiation, the patients received a sixth cycle of etoposide/cisplatin, followed by prophylactic cranial irradiation (30 Gy/15 fractions) if they had a complete response. RESULTS: Of 311 assessable patients enrolled in the trial, 262 underwent randomization to TDTI or ODTI. There were no differences between the two treatments with respect to local-only progression rates, overall progression rates, or overall survival. The patients who received TDTI had greater esophagitis (> or = grade 3) than those who received ODTI (12.3% v 5.3%; P =.05). Although patients received thoracic irradiation encompassing the postchemotherapy volumes, only seven of 90 local failures were out of the portal of irradiation. CONCLUSION: When TI is delayed until the fourth cycle of chemotherapy, TDTI does not result in improvement in local control or survival compared with ODTI.

Randomized comparison of megestrol acetate versus dexamethasone versus fluoxymesterone for the treatment of cancer anorexia/cachexia.

PURPOSE: Previous double-blind, placebo-controlled, randomized clinical trials have demonstrated that both corticosteroids and progestational agents do partially alleviate cancer anorexia/cachexia. Pilot information suggested that an anabolic corticosteroid might also improve appetite in patients with cancer anorexia/cachexia. The current trial was developed to compare and contrast a progestational agent, a corticosteroid, and an anabolic corticosteroid for the treatment of cancer anorexia/cachexia. PATIENTS AND METHODS: Patients suffering from cancer anorexia/cachexia were randomized to receive either dexamethasone 0. 75 mg qid, megestrol acetate 800 mg orally every day, or fluoxymesterone 10 mg orally bid. Patients were observed at monthly intervals to evaluate weight changes and drug toxicity. Patients also completed questionnaires at baseline and at monthly intervals to evaluate appetite and drug toxicities. RESULTS: Fluoxymesterone resulted in significantly less appetite enhancement and did not have a favorable toxicity profile. Megestrol acetate and dexamethasone caused a similar degree of appetite enhancement and similar changes in nonfluid weight status, with nonsignificant trends favoring megestrol acetate for both of these parameters. Dexamethasone was observed to have more corticosteroid-type toxicity and a higher rate of drug discontinuation because of toxicity and/or patient refusal than megestrol acetate (36% v 25%; P =.03). Megestrol acetate had a higher rate of deep venous thrombosis than dexamethasone (5% v 1%; P =.06). CONCLUSION: Whereas fluoxymesterone clearly seems to be an inferior choice for treating cancer anorexia/cachexia, megestrol acetate and dexamethasone have similar appetite stimulating efficacy but differing toxicity profiles.

Evaluation of tamoxifen plus letrozole with assessment of pharmacokinetic interaction in postmenopausal women with metastatic breast cancer.

The goals of this clinical trial involving postmenopausal women with metastatic breast cancer were to: (a) examine the effects of letrozole on tamoxifen (TAM) pharmacokinetics; (b) examine estrogen suppression in patients receiving TAM plus letrozole; and (c) evaluate tolerability, toxicity, objective response, and time to progression for the combination. Postmenopausal women with measurable or evaluable metastatic breast cancer received TAM (20 mg daily) for 6 weeks, and then letrozole (2.5 mg daily) was added. To examine for any effect of letrozole on the levels of TAM and two metabolites [N-desmethyl-TAM and 4-hydroxy-TAM], serum samples were obtained at 6, 12, 18, and 24 weeks. To examine for aromatase inhibition, serum samples were obtained before treatment and at 6, 12, 18, and 24 weeks for estradiol, estrone (E1) E1 sulfate, and sex hormone-binding globulin. A total of 34 patients were entered on this trial, and 23 patients were still on study at week 24, 18 of whom had blood samples available at both week 6 and week 24. The 95% confidence interval for the mean difference between levels at week 24 and levels at week 6 was -34 to 15 ng/ml for TAM, -35 to 45 ng/ml for N-desmethyl-TAM, and -1 to 2 for 4-hydroxy-TAM. For estradiol, a significant decrease (median, 88.5%; range, 73.7-95.2%) was identified after 6 weeks of letrozole, which was maintained for an additional 12 weeks. Similar significant reductions were identified for E1. E1 sulfate levels increased after 6 weeks of TAM alone but then decreased significantly after the addition of letrozole. Sex hormone-binding globulin levels were significantly elevated after 6 weeks of TAM alone and remained elevated after the addition of letrozole. Six of the 34 patients (17.6%) achieved an objective response (95% confidence interval, 6.8-34.5%), with a median time to disease progression of 7.6 months. There was no indication of a systematic decrease in TAM, N-desmethyl-TAM, or 4-hydroxy-TAM after the additional of letrozole. Estrogen suppression induced by letrozole was substantial despite the concomitant administration of TAM. The antitumor effect of TAM plus letrozole was less than expected.

A randomized trial of tamoxifen alone or combined with octreotide in the treatment of women with metastatic breast carcinoma.

BACKGROUND: Tamoxifen (TAM) is generally considered the hormonal agent of choice for postmenopausal women with hormone receptor positive breast carcinoma. The somatostatin analogues, including octreotide, have demonstrated inhibition of breast carcinoma cell lines and multiple endocrinologic actions, including reduction of insulin-like growth factor I (IGF-I), a potent mitogen for breast carcinoma cells. In an attempt to improve the efficacy of TAM, this randomized trial was performed. METHODS: One hundred thirty-five eligible postmenopausal women with metastatic breast carcinoma were randomized to TAM (10 mg twice daily) alone or combined with octreotide 150 microg (administered subcutaneously thrice daily). The two groups were well balanced, except the TAM group had higher proportions of patients with visceral disease (50% vs. 37%) and a disease free interval longer than 5 years (47% vs. 34%). A cohort of 18 patients was evaluated for the impact of treatment on serum IGF-I, free IGF-I, IGF binding protein 3 levels, and total IGF binding capacity. RESULTS: The median time to progression was estimated to be 14.2 months with TAM and 10.3 months with TAM plus octreotide. The distribution of progression free survival times revealed no significant difference (P = 0.26), and the progression hazard ratio (TAM/TAM + octreotide) was 0.81 (95% confidence interval [CI], 0.56-1.17). The distribution of survival times revealed no significant difference (P = 0.92), and the death hazard ratio was 0.98 (95% CI, 0.62-1.55). When the 106 patients with measurable or evaluable disease were considered, the objective response rate was 49% with TAM alone and 43% with TAM plus octreotide (P = 0.70). Patients who received TAM plus octreotide had higher incidences of nausea, diarrhea, and steatorrhea. The percentage of decline in serum IGF-I, from pretreatment levels to those following 3-6 weeks of treatment, was significantly greater (P < 0.01) with TAM plus octreotide than with TAM alone. CONCLUSIONS: There is no indication that the combination of TAM plus octreotide as administered in this study is substantially more efficacious than TAM alone in the treatment of postmenopausal women with metastatic breast carcinoma. The limited cohort included in IGF-I studies suggests that TAM plus octreotide produces a significantly greater reduction in serum IGF-I levels.

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.

Phase II trial of topotecan for the treatment of mesothelioma.

The North Central Cancer Treatment Group designed a phase II trial to assess the efficacy and toxicity of topotecan in patients with unresectable malignant pleural mesothelioma. Twenty-two previously untreated patients with unresectable pleural mesothelioma and good performance status (Eastern Cooperative Oncology Group performance status 0, 1, or 2) were enrolled on this trial from October 1993 through July 1994. Nineteen men and three women, median age 66 years (range, 44-78 years), were treated with topotecan 1.5 mg/m2 intravenously over 30 minutes daily for 5 days at 3-week intervals until toxicity, progression of disease, or a patient decided to discontinue treatment. There were seven patients with measurable disease and 15 with evaluable disease; all were assessable for response and toxicity. A total of 113 cycles of treatment were given, for a median of three cycles (range, 1-26 cycles). Myelosuppression was the most frequent toxicity. Eighteen of 21 patients (86%) experienced grade 3 or 4 neutropenia during the initial treatment cycle. The median neutrophil nadir was 0.5 x 10(3)/microl (range, 0.1-1.6 x 10(3)/microl), and the median platelet nadir was 127 x 10(3)/microl (range, 18-460 x 10(3)/microl). Other toxicities more than grade 2 included malaise (two patients), and anorexia, infection, fever, pulmonary, and cardiac in one patient each. There were no objective responses, and 18 patients had stable disease for a median of 74 days. The median survival for all patients was 230 days, with 23% alive at 1 year. Topotecan as administered in this trial is reasonably well tolerated; however, the response rate was insufficient to warrant additional study in pleural mesothelioma.

Phase II trial of nitrogen mustard, vincristine, and procarbazine in patients with recurrent glioma: North Central Cancer Treatment Group results.

PURPOSE: Previous investigators have reported responses in 52% of patients treated with mechlorethamine (nitrogen mustard), vincristine, and procarbazine (MOP) for recurrent glioma. To confirm these promising results, we conducted a phase II prospective study. PATIENTS AND METHODS: Sixty-three patients with histologic confirmation of recurrent glioma were treated with the MOP regimen. Patients with or without prior chemotherapy received nitrogen mustard 3 mg/m2 or 6 mg/m2, respectively, intravenously on days 1 and 8 plus vincristine 2 mg/m2 intravenously on days 1 and 8, and procarbazine 100 mg/m2 orally on days 1 to 14. Cycles were repeated every 28 days. RESULTS: Of 61 patients assessable for response, eight responded (13%), with one complete response (CR). Responses were as follows: low-grade gliomas, 19%; anaplastic astrocytomas, 11%; anaplastic oligodendrogliomas or oligoastrocytomas, 25%; and glioblastomas, 4.3%. The most common toxicity was myelosuppression with leukocyte nadirs less than 1,000/microL in 23% and platelet nadirs less than 25,000/microL in 13% of patients. Two patients died of infection in the setting of neutropenia. Nonhematologic toxicity included neurosensory changes in 21% of patients (severe in 3%) and severe dermatologic reactions in 8%. In multivariate analysis, Eastern Cooperative Oncology group (ECOG) performance status (PS) was the best predictor for response to chemotherapy (P=.01) and time to progression (P=.008), while PS and grade were the most important predictors of survival (P=.002 and .05, respectively). CONCLUSION: This study did not confirm the high response rate previously reported in recurrent gliomas. Patients with recurrent anaplastic oligodendrogliomas or oligoastrocytomas and recurrent low-grade gliomas had the highest response rates (25% and 19%, respectively). In multivariate analysis, ECOG PS was the best predictor of response, while PS and tumor grade were the most important predictors of survival.