Oral clonidine in postmenopausal patients with breast cancer experiencing tamoxifen-induced hot flashes: a University of Rochester Cancer Center Community Clinical Oncology Program study.

BACKGROUND: Hot flashes are the most frequently reported side effect of tamoxifen treatment. Although hormones are an effective treatment, their safety is questionable in women with breast cancer. It is therefore important to evaluate nonhormonal treatments for hot flashes. OBJECTIVE: To evaluate the effectiveness of oral clonidine for control of hot flashes associated with tamoxifen therapy in postmenopausal women with breast cancer. DESIGN: Randomized, double-blind, placebo-controlled clinical trial. SETTING: University of Rochester Cancer Center Community Clinical Oncology Program. PATIENTS: 194 postmenopausal women with breast cancer who were receiving adjuvant tamoxifen therapy. INTERVENTION: Oral clonidine hydrochloride, 0.1 mg/d, or placebo for 8 weeks. MEASUREMENTS: In a daily diary, patients recorded number, duration, and severity of hot flashes and overall quality-of-life score (on a 10-point scale) during a 1-week baseline period and during the 4th, 8th, and 12th weeks of the study. RESULTS: Patients in the placebo and treatment groups were similar in age, duration of tamoxifen use, reported frequency and duration of hot flashes at baseline, and dropout rates. One hundred forty-nine patients completed 12 weeks of follow-up. The mean decrease in hot flash frequency was greater in the clonidine group than in the placebo group after 4 weeks of treatment (37% compared with 20% [95% CI for difference, 7% to 27%]) and 8 weeks of treatment (38% compared with 24% [CI for difference, 3% to 27%]). Patients receiving clonidine were more likely than patients receiving placebo to report difficulty sleeping (41% compared with 21%; P = 0.02). A significant difference was seen in the mean change in quality-of-life scores (0.3 points in the clonidine group compared with -0.2 points in the placebo group; P = 0.02) at 8 weeks, although the median difference was 0 in both groups. CONCLUSION: Oral clonidine, 0.1 mg/d, is effective against tamoxifen-induced hot flashes in postmenopausal women with breast cancer.

Group psychotherapy for recently diagnosed breast cancer patients: a multicenter feasibility study.

As many as 80% of breast cancer patients report significant distress during initial treatment, yet there is little in the way of systematic psychotherapeutic interventions for women coping with the stress of a recent diagnosis of breast cancer. The literature on psychotherapeutic treatment of cancer patients provides uniform evidence for an improvement in mood, coping and adjustment as a result of group therapy. The present study examined the feasibility of implementing a manualized treatment, supportive-expressive group psychotherapy, in busy oncology practices across the US. This intervention was applied to women with primary breast cancer in a manner which tests not only the efficacy of the approach but also its accessibility to group therapists not previously experienced in its use. One hundred and eleven breast cancer patients within 1 year of diagnosis were recruited from ten geographically diverse sites of the National Cancer Institute's Community Clinical Oncology Program (CCOP) and two academic medical centers. Two therapists from each site were trained in supportive-expressive group psychotherapy. Training consisted of participation in a workshop, reading a treatment manual, and viewing explanatory videotapes. Each patient participated in a supportive-expressive group that met for 12 weekly sessions lasting 90 min. Assessment of mood disturbance was made at entry, 3, 6, and 12 months. Results indicated a significant 40% decrease in the Total Mood Disturbance (TMD) scores of the Profile of Mood States (POMS) (ANOVA F [2,174]=3.98, p<0.05). The total symptom score of the Hospital Anxiety and Depression Scale (HADS) was likewise significantly reduced over the 6-month period (F [2, 174]=5.2, p<0.01). Similarly, the total score of the Impact of Event Scale (IES) was significantly reduced (F [2,174]=4.0, p<0.05). There was substantial uniformity of treatment effect across sites. Outcome was independent of stage of disease (I vs. II). We conclude that this treatment program can be effectively implemented in a community setting and results in reduced distress among breast cancer patients.

Further evaluation of intensified and increased total dose of cyclophosphamide for the treatment of primary breast cancer: findings from National Surgical Adjuvant Breast and Bowel Project B-25.

PURPOSE: In 1989, the National Surgical Adjuvant Breast and Bowel Project initiated the B-22 trial to determine whether intensifying or intensifying and increasing the total dose of cyclophosphamide in a doxorubicin-cyclophosphamide combination would benefit women with primary breast cancer and positive axillary nodes. B-25 was initiated to determine whether further intensifying and increasing the cyclophosphamide dose would yield more favorable results. PATIENTS AND METHODS: Patients (n = 2,548) were randomly assigned to three groups. The dose and intensity of doxorubicin were similar in all groups. Group 1 received four courses, ie, double the dose and intensity of cyclophosphamide given in the B-22 standard therapy group; group 2 received the same dose of cyclophosphamide as in group 1, administered in two courses (intensified); group 3 received double the dose of cyclophosphamide (intensified and increased) given in group 1. All patients received recombinant human granulocyte colony-stimulating factor. Life-table estimates were used to determine disease-free survival (DFS) and overall survival. RESULTS: No significant difference was observed in DFS (P =.20), distant DFS (P =.31), or survival (P =.76) among the three groups. At 5 years, the DFS in groups 1 and 2 (61% v 64%, respectively; P =. 29) was similar to but slightly lower than that in group 3 (61% v 66%, respectively; P = 08). Survival in group 1 was concordant with that in groups 2 (78% v 77%, respectively; P =.71) and 3 (78% v 79%, respectively; P =.86). Grade 4 toxicity was 20%, 34%, and 49% in groups 1, 2, and 3, respectively. Severe infection and septic episodes increased in group 3. The decrease in the amount and intensity of cyclophosphamide and delays in therapy were greatest in courses 3 and 4 in group 3. The incidence of acute myeloid leukemia increased in all groups. CONCLUSION: Because intensifying and increasing cyclophosphamide two or four times that given in standard clinical practice did not substantively improve outcome, such therapy should be reserved for the clinical trial setting.

'Neo-FAC' (5-fluorouracil, doxorubicin, and cyclophosphamide) for poor-prognosis stage IV breast cancer: a Southwest Oncology Group Phase II Study.

The authors report a phase II pilot investigation in the Southwest Oncology Group examining a combination of 5-fluorouracil, doxorubicin, and cyclophosphamide (FAC) incorporating modulated 5-FU in patients with poor-prognosis stage IV breast cancer. Patients with poor-prognosis stage IV breast cancer were treated with this "neo-FAC" as front-line therapy. The regimen consisted of 5-fluorouracil by continuous ambulatory infusion pump at 200 mg/m2/day for 42 days, repeated at 56-day intervals; doxorubicin at 20 mg/m2/week intravenously to a maximum cumulative total dose (including adjuvant therapy, if any) of 500 mg/m2; cyclophosphamide 60 mg/m2/day taken orally; methotrexate 15 mg/m2/week intravenously beginning 1 week after termination of doxorubicin; and oral prednisone decreasing from 60 mg/day on a tapering schedule for a total of 7 weeks of treatment. Treatment was continued until progression, unacceptable toxicity, or patient refusal. Twenty-four patients were accrued to this study. Of these, two were ineligible, and the remaining 22 were evaluable for response. Ten patients experienced grade 3 toxicity, and six had grade 4. There were no treatment-associated deaths. Best responses were a complete response in one patient (5%) and partial responses in 6, for an overall response rate of 32% (7/22 evaluable patients). Overall survival in five pilot studies in the Southwest Oncology Group in this poor-prognosis population are relatively superimposable. The present regimen, with its relatively poor outcome and the expense and inconvenience of administering chemotherapy by ambulatory infusion pump, will not be pursued further.

Infusional paclitaxel and weekly vinorelbine chemotherapy with concurrent filgrastim for metastatic breast cancer: high complete response rate in a phase I-II study of doxorubicin-treated patients.

PURPOSE: We investigated 96-hour paclitaxel infusion combined with weekly (days eight and 15) vinorelbine as salvage therapy for metastatic breast cancer in anthracycline-exposed patients. All patients received scheduled support with granulocyte colony-stimulating factor (G-CSF; filgrastim). Tumor response, toxicity, time to progression (TTP), and survival were assessed. PATIENTS AND METHODS: This single-center nonrandomized trial enrolled 32 patients. Anthracycline exposure and subsequent progression were common to all patients. Paclitaxel and vinorelbine were escalated over three dosing levels, stratified by liver function. RESULTS: Seven patients (22%) achieved a complete response and nine patients achieved a partial response for an overall response rate of 50%. The median TTP was 6.1 months, and median survival time was 14.1 months. Dose-limiting toxicity was neutropenia, with dose delay or reduction in seven of 32 patients. Febrile neutropenia requiring hospitalization was uncommon (three of 32 patients; 9%). There were no treatment-related deaths. Grade 3/4 thrombocytopenia occurred in two patients (6%), and 13 patients (41%) required RBC transfusions for anemia. Grade 3 nausea and vomiting was seen in one patient, who was found to be Addisonian. Despite potentially overlapping neurologic toxicities of the two agents, only two patients (6%) were removed from the study because of progressive peripheral neuropathy. CONCLUSION: Administration of 96-hour paclitaxel infusion and subsequent weekly vinorelbine with G-CSF support is well tolerated. The response rate, TTP, and survival data are encouraging for therapy given to anthracycline pretreated patients with metastatic breast cancer. If these results can be verified in multi-institution trials, this or a similar combination of drugs would merit investigation as first-line therapy in this patient population.

Initial control of chemotherapy-induced nausea and vomiting in patient quality of life.

The side effects commonly experienced by patients receiving chemotherapy for the treatment of cancer can challenge many aspects of daily life. Nausea and vomiting, the most common side effects reported by patients, affect the ability to continue with usual life activities and, thus have a pronounced impact on quality of life. This paper reviews studies of the impact of nausea and emesis on quality of life, and highlights the importance of prevention of these side effects by presenting new data on how persistent uncontrolled nausea and vomiting can be. The Morrow Assessment of Nausea and Emesis (MANE) was used to collect information on symptoms experienced by consecutive patients starting chemotherapy between September 1987 and December 1995 at any of 18 geographically diverse member sites of the University of Rochester Cancer Center Community Clinical Oncology Program. Data from 1,413 patients were collected after each of four successive chemotherapy treatments. Reported incidences of posttreatment nausea and posttreatment vomiting after the first treatment were 59.4% and 28.6%, respectively. Occurrence of nausea/vomiting at the first treatment was a strong predictor of nausea/vomiting at later treatments. Of the 839 patients reporting initial nausea, 763 (90.9%) reported nausea at at least one subsequent treatment, and approximately 59% reported nausea after all three subsequent treatments. Fewer than half (45.6%) of the patients who had no nausea at the first treatment developed it later. The majority (72.0%) of patients reporting vomiting at the first treatment also reported subsequent vomiting, 30.7% of whom experienced emesis at all remaining treatments. Conversely, 76.2% of patients who were emesis-free at the first treatment remained so for all later treatments. These findings show a continuing need for further progress in controlling nausea and vomiting, and demonstrate the importance of aggressive nausea/vomiting control at the first treatment. In addition, more emphasis on controlling chemotherapy-induced nausea after its initial occurrence is necessary.

Progress in reducing anticipatory nausea and vomiting: a study of community practice.

Chemotherapy-related nausea and vomiting (NV) in 300 consecutive patients treated in community practices prior to the availability of 5-HT3 antiemetics (9/87 to 1/91) were compared with NV in a second sample of 300 patients treated after their commercial introduction (9/93 to 2/95). Eighty-six percent of the later patients received 5-HT3 antiemetics, and significantly fewer (43.3%) reported one or more episodes of posttreatment vomiting during their first four cycles of chemotherapy compared with those in the previous sample (55.0%: P < .01). Identical numbers of both groups (79.3%) reported at least one episode of posttreatment nausea. A significant increase in the average duration of both posttreatment nausea (from 28.1 h to 37.2 h; P = 0.001) and posttreatment vomiting (from 10.9 h-16.5 h, P = .02) was found; no significant differences were seen in the reported severity of either symptom. The proportion of patients experiencing at least one episode of anticipatory nausea (31.0% vs 32.0%) or anticipatory vomiting (7.7% vs 6.3%) did not differ significantly (P > 0.5) between groups, nor were there significant differences in the duration or severity of anticipatory symptoms (P > 0.4 for all comparisons). The reduction in the frequency of posttreatment vomiting supports research findings of efficacy. Findings of an increase in duration of posttreatment nausea and emesis and no change in the frequency of posttreatment nausea or in anticipatory symptoms show a continuing need for progress in control of posttreatment emesis and emphasize the need for further research on the control of chemotherapy-induced nausea.

Improving breast self-examination compliance: a Southwest Oncology Group randomized trial of three interventions.

BACKGROUND: Only 20-40% of U.S. women conduct breast self-examination (BSE). This Southwest Oncology Group experimental study compared the impact of three interventions on BSE compliance. METHODS: Subjects were randomly assigned to one of three arms: (1) physician message; (2) physician message and BSE class; or (3) physician message, BSE class, and reinforcement (phone and postcard). Compliance (frequency and accuracy) was measured by interview at intake and at 6 months and by phone contact at 1 year. Logistic and multiple regression were employed. RESULTS: This analysis included 2,233 subjects from six institutions. At 1 year the percentages of women doing BSE were 59, 62, and 78% for Arms 1-3, respectively; gains over intake frequency (27% average) were significant within each arm (P < or = 0.0001). At both 6 months and 1 year the differences between Arm 1 and Arm 2 average accuracy scores and the differences between Arm 2 and Arm 3 in the percentage of women doing BSE were significant (P < or = 0.0001). Findings within institutions were consistent with the overall findings. CONCLUSIONS: The addition of a BSE class increased accuracy over physician message alone; physician message, BSE class, and reinforcement gave the highest percentage of women doing BSE.

Efficacy of prednisone in refractory multiple myeloma and measurement of glucocorticoid receptors. A Southwest Oncology Group study.

BACKGROUND: Prednisone is an active drug in the treatment of multiple myeloma. The optimal dose, frequency, and role of glucocorticoid receptors (GR) in response to prednisone is unknown. PURPOSE: The purposes of this study were (1) to estimate the response rate of alternate-day high dose prednisone in patients with relapsing and refractory multiple myeloma; (2) to measure the rate of GR levels; and (3) to correlate the response of prednisone with GR status. PATIENTS AND METHODS: Between 8/86 and 1/90, 127 patients were entered onto the study with 121 evaluable for response. The number of GR sites/cell was determined on mononuclear cells isolated from pretreatment bone marrow aspirates using a one point GR binding assay. Patients received prednisone 100 mg po qod x 2 weeks, followed by 50 mg po qod x 10 weeks. RESULTS: The overall response rate was 10% (95% CI: 5-15%) with a median survival of 11.8 months. The GR sites/cell ranged from 0-53,212 with a mean of 8,371 sites/cells. Stratification of GR sites into 0-2,500, 2,501-6,000 and > 6,000 sites/cells was associated with a response rate of 6%, 27% and 4% respectively (p = 0.009). The median survival of patients in these categories was 8.1, 14.9 and 10.6 months respectively. This was not significant by the logrank test (p = 0.11). Although myeloma patients with intermediate levels of GR sites/cell initially responded more favorably to prednisone, their long-term survival was not significantly improved. CONCLUSIONS: Alternate-day high-dose prednisone was well tolerated and may provide palliative benefit for a subset of patients with relapsing and refractory multiple myeloma. The survival of patients on this study was comparable to that reported with other but more toxic doses of glucocorticoids.

A phase II evaluation of ifosfamide and mesna in unresectable diffuse malignant mesothelioma. A Southwest Oncology Group study.

BACKGROUND: Malignant mesothelioma is a highly treatment-resistant neoplasm. This study represents an attempt to define an effective form of systemic therapy. METHODS: Twenty-six patients with unresectable diffuse malignant mesothelioma were enrolled in Southwest Oncology Group (SWOG) study 8731 and treated with ifosfamide, 2 g/m2 intravenously for 4 days, and mesna 2 g/m2 intravenously for 5 days, every 3 weeks. Patients were either previously untreated with chemotherapy or had at most one prior systemic treatment. RESULTS: Two patients, or 8% (95% confidence interval, 1-25%), achieved partial response, with response durations of 4 and 6 months. One additional patient met criteria for tumor size reduction but not duration criteria. Thirteen (50%) patients had stable disease of 4 months' median duration (range, 1-13 months). The median survival of the entire group was 6.5 months. The dose-limiting toxicity was granulocytopenia (11 patients, < or = 250/microliters). CONCLUSIONS: Ifosfamide/mesna has modest activity in malignant mesothelioma. It could be tested using alternate dosage schedules and in combination with other agents in treating this highly resistant neoplasm.

Combination chemotherapy of intermediate-grade and high-grade non-Hodgkin's lymphoma with MACOP-B: a Southwest Oncology Group study.

One hundred nine assessable patients with measurable stage II, III, or IV intermediate- or high-grade lymphoma were treated with methotrexate with leucovorin, doxorubicin, cyclophosphamide, vincristine, prednisone, and bleomycin (MACOP-B) by members of the Southwest Oncology Group (SWOG) between November 1985 and June 1986 to confirm the activity of the program as initially described by Klimo and Connors and to test the safety of using third-generation regimens in a cooperative group. The median age was 53.5 years, and stage II was seen in 30% of patients and diffuse large-cell histology in 63%. Complete remission (CR) was achieved in 50% of all patients and partial remission (PR) in 33%. Response rates did not differ by histology. Median follow-up is 46 months with 51% of patients alive at 3 years and 63% of CR patients free of disease at 3 years. Severe (grade 3) or worse hematologic toxicity was seen in 51% of all treated individuals, and 29% had severe mucositis. We failed to confirm the high response rates as originally reported. Whether MACOP-B is superior to other treatment regimens requires the prospective trial currently being conducted by the SWOG.

Second-line treatment of advanced measurable ovarian cancer with iproplatin: a Southwest Oncology Group study.

105 patients with advanced ovarian cancer previously treated with cisplatin or carboplatin were entered into a study of iproplatin as second-line therapy. Patients were either clinically resistant to cisplatin or carboplatin, or had relapsed after complete response to these agents. Patients were treated intravenously at an initial dosage of 270 mg/m2 with dosage adjustments to 340, 200 or 135 based on observed toxicity. Of 101 eligible patients, 7 responses (3 complete, 4 partial; 12%) were observed in 60 patients resistant to cisplatin. 2 partial responses (11%) occurred in 18 patients resistant to carboplatin. 2 complete and 3 partial responses were observed in 19 patients (26%) previously treated with but not resistant to cisplatin. Response durations were 2-20 months. Toxicities of iproplatin included thrombocytopenia in 93% of patients, leukopenia in 76% of patients, anaemia in 68% of patients, and diarrhoea in 40% of patients. Thus iproplatin shares cross-resistance with cisplatin and carboplatin in the treatment of ovarian cancer and is not recommended as an effective second-line agent for platinum-resistant ovarian cancer.

A phase II evaluation of cisplatin in unresectable diffuse malignant mesothelioma: a Southwest Oncology Group Study.

Cisplatin was given intravenously to 35 evaluable patients with unresectable malignant mesothelioma on Southwest Oncology Group (SWOG) Study 8418. Five patients (14.3%) achieved partial response with median response duration of six months (range 2-12 months); eleven patients (31.4%) had stable disease of median duration of 5.5. months (range 2-21 months). Median survival for all patients was 7.5 months, 9 months for responders. Toxicity was as expected except that 12 patients (34.2%) discontinued cisplatin because of side effects. Cisplatin has moderate activity in mesothelioma and further studies with platinum analogues should be pursued.