Preclinical activity of CPI-0610, a novel small-molecule bromodomain and extra-terminal protein inhibitor in the therapy of multiple myeloma.

Inhibition of the bromodomain and extra-terminal (BET) proteins is a promising therapeutic strategy for various hematologic cancers. Previous studies suggest that BET inhibitors constrain tumor cell proliferation and survival mainly through the suppression of MYC transcription and activity. However, suppression of the transcription of additional genes also contributes to the antitumor activity of BET inhibitors but is less well understood. Here we examined the therapeutic potential of CPI-0610, a potent BET inhibitor currently undergoing phase I clinical testing, in multiple myeloma (MM). CPI-0610 displays potent cytotoxicity against MM cell lines and patient-derived MM cells through G1 cell cycle arrest and caspase-dependent apoptosis. CPI-0610-mediated BET inhibition overcomes the protective effects conferred by cytokines and bone marrow stromal cells. We also confirmed the in vivo efficacy of CPI-0610 in a MM xenograft mouse model. Our study found IKZF1 and IRF4 to be among the primary targets of CPI-0610, along with MYC. Given that immunomodulatory drugs (IMiDs) stabilize cereblon and facilitate Ikaros degradation in MM cells, we combined it with CPI-0610. Combination studies of CPI-0610 with IMiDs show in vitro synergism, in part due to concomitant suppression of IKZF1, IRF4 and MYC, providing a rationale for clinical testing of this drug combination in MM patients.

Phase III study of cyclophosphamide, doxorubicin, and fluorouracil (CAF) plus leucovorin versus CAF for metastatic breast cancer: Cancer and Leukemia Group B 9140.

PURPOSE: To determine whether biochemical modulation with LV (leucovorin) enhances the efficacy of CAF (cyclophosphamide, doxorubicin, and fluorouracil) against metastatic breast cancer. PATIENTS AND METHODS: Women with histologically confirmed stage IV breast cancer, Cancer and Leukemia Group B (CALGB) performance status 0 to 2, and no prior chemotherapy for metastatic disease were randomly assigned to receive CAF (cyclophosphamide 500 mg/m2 day 1, doxorubicin 40 mg/m2 day 1, and fluorouracil [FU] 200 mg/m2 intravenous bolus days 1 to 5) with or without LV (LV 200 mg/m2 over 30 minutes days 1 to 5 given 1 hour before FU). RESULTS: Two hundred forty-two patients were randomly assigned to treatment; 124 patients had visceral crisis and 40 patients had a CALGB performance status score of 2. The median follow-up was 6 years. The two study arms were similar with regard to serious adverse events; four patients died from treatment-related causes, two patients on each study arm. Predictive variables for time to treatment failure and survival were visceral disease and performance status. The overall response rate was 29% for CAF versus 28% for CAF plus LV. The median time to treatment failure (9 months) and median survival (1.7 years) did not differ by treatment arm. CONCLUSION: Modulation of CAF with LV improved neither response rates nor survival among women with metastatic breast cancer, compared with CAF alone. Multivariate analyses confirmed the prognostic importance of performance status and visceral crisis. However, the overall and complete response rates, response durations, time to treatment failure, and survival were the same in the two treatment arms.

Alemtuzumab in previously treated chronic lymphocytic leukemia patients who also had received fludarabine.

PURPOSE: This phase II pilot study determined the efficacy and safety of alemtuzumab (Campath-1H; Burroughs Wellcome, United Kingdom) in patients with chronic lymphocytic leukemia (CLL), all of whom had previously received fludarabine and other chemotherapy regimens. PATIENTS AND METHODS: Twenty-four patients were treated with intravenous alemtuzumab at six centers in the United States. The target dose of 30 mg over 2 hours, three times weekly, was administered for up to 16 weeks. Responses were evaluated by an independent panel of experts using 1996 National Cancer Institute-sponsored Working Group criteria. Safety assessments included analysis of lymphocyte subpopulations. Antimicrobial prophylaxis was not mandatory. RESULTS: Eight patients (33%) achieved a major response (all partial remissions), with a median time to response of 3.9 months (range, 1.6 to 5.3 months). The median duration of response was 15.4 months (range, 4.6 to >or= 38.0 months), the median time to disease progression was 19.6 months (range, 7.7 to >or= 42.0 months), and the median survival time was 35.8 months (range, 8.8 to >or= 47.1 months). Acute infusion-related events, mainly grades 1 and 2, were most common and most severe in the first week. Ten patients (eight nonresponders and two responders) experienced major infections on-study. Pneumocystis carinii pneumonia was reported in two patients on-study; neither had received prophylaxis. Median CD4+ and CD8+ counts decreased and then began to increase by the end of the study, with further recovery by 1-month follow-up. One of 53 samples obtained from 10 patients had a low titer of alemtuzumab antibodies. CONCLUSION: Alemtuzumab has significant activity in poor-prognosis, fludarabine-treated CLL patients. However, because of a relatively high incidence of opportunistic infections accompanying profound lymphopenia, future protocols should include mandatory prophylaxis.

Cyclophosphamide, doxorubicin, vincristine, prednisone, and etoposide (CHOPE) for advanced-stage Hodgkin's disease: CALGB 8856.

Successful treatment of advanced-stage Hodgkin's disease (HD) may critically depend on dose intensity. Because mechlorethamine, Oncovin, procarbazine, and prednisone (MOPP), and Adriamycin, bleomycin, vinblastine, and dacarbazine (ABVD) are not suitable for major dose escalation, we evaluated the activity and toxicity of combined cyclophosphamide, doxorubicin, vincristine, prednisone, and etoposide (CHOPE) in advanced HD, here used at conventional dose intensity, as a preparatory study prior to using this regimen at higher dose intensity. Ninety-two patients were treated with CHOPE (cyclophosphamide, 750 mg/m2, day 1; doxorubicin, 50 mg/m2, day 1; vincristine, 1.4 mg/m2, days 1 and 8; prednisone, 100 mg/day, days 1-5; and etoposide, 80 mg/m2, days 1, 2, and 3) every 21 days. All had advanced HD with no prior chemotherapy with 46% stage IV, 63% with B symptoms, and 57% with bulky disease (> 5 cm). Radiation and growth factor support were not permitted. Full-dose vincristine (not capped at maximum 2 mg/dose) was used in the first 33 patients. An initial cohort of 41 patients was treated with four cycles of CHOPE to evaluate safety and efficacy followed by four cycles of ABVD. A second cohort of 51 patients was treated with 6-8 cycles of CHOPE alone. Toxicity was generally acceptable and primarily hematologic, with neutrophils < 500 in 63% of cohort I and 90% of cohort II, and platelets < 25,000 in 7% of cohort I and 8% of cohort II. The long-term neurotoxicity of full-dose, high-intensity vincristine was acceptable and largely reversible. In cohort I, 92% of patients achieved a complete response (CR) or partial response (PR) with four cycles of CHOPE and 85% were in CR after four additional cycles of ABVD. In cohort II, 77% achieved a CR with 6-8 cycles of CHOPE alone. FFS was 76% in cohort I and 59% in cohort II, with a median follow-up of 8.2 and 5.7 years, respectively. CHOPE, at conventional dose intensity as used here, is an effective first-line regimen for the treatment of advanced-stage HD and may warrant evaluation using higher doses of cyclophosphamide and etoposide with granulocyte colony stimulating factor (G-CSF) support.

Phase I study of anti--epidermal growth factor receptor antibody cetuximab in combination with radiation therapy in patients with advanced head and neck cancer.

PURPOSE: To evaluate the safety, pharmacokinetics, and efficacy of a chimeric anti-epidermal growth factor receptor monoclonal antibody, cetuximab, in combination with radiation therapy (RT) in patients with advanced squamous cell carcinoma of the head and neck. PATIENTS AND METHODS: We treated 16 patients in five successive treatment schedules. A standard dose escalation procedure was used; three patients entered onto the study at each dose level of cetuximab received conventional RT (70 Gy, 2 Gy/d), and the final three patients received hyperfractionated RT (76.8 Gy, 1.2 Gy bid). Cetuximab was delivered as a loading dose of 100 to 500 mg/m(2), followed by weekly infusions of 100 to 250 mg/m(2) for 7 to 8 weeks. Circulating levels of cetuximab during therapy were determined using a biomolecular interaction analysis core instrument. Human antichimeric antibody response was evaluated with a double-antigen radiometric assay. The recommended phase II/III dose was defined as the optimal cetuximab dose level based on the pharmacologic parameters and adverse events. RESULTS: The most commonly reported adverse events were fever, asthenia, transaminase elevation, nausea, and skin toxicities (grade 1 to 2 in most patients). Skin toxicity outside of the RT field was not strictly dose-dependent; however, grade 2 or higher events were observed in patients treated with higher dose regimens. There was one grade 4 allergic reaction. Most acute adverse effects were associated with RT (xerostomia, mucositis, and local skin toxicity). No antibodies against cetuximab were detected. All patients achieved an objective response (13 complete and two partial remissions). CONCLUSION: Cetuximab can be safely administered with RT. The recommended dose for phase II/III studies is a loading dose of 400 to 500 mg/m(2) and a maintenance weekly dose of 250 mg/m(2).

Social support as a buffer to the psychological impact of stressful life events in women with breast cancer.

BACKGROUND: Three theoretical models by which social support may influence the impact of stressful life events on cancer patients' psychological state were tested: 1) the additive model, in which social support and stressful life events each directly influence cancer patients' adjustment, irrespective of the magnitude of the other; 2) the buffering hypothesis, in which stressful events occurring in the presence of social support should produce less distress than if they occur in its absence; and 3) both additive and buffering models. METHODS: One hundred seventy-nine patients who had Stage II breast cancer (median age, 56 yrs; 68% disease free), treated a mean of 6.8 years since entry to Cancer and Leukemia Group B (CALGB) 8541, were interviewed by telephone concerning their psychosocial adjustment. The following measures were used: Medical Outcome Study Social Support Survey (MOS-SSS), Life Experience Survey (LES) a measure of stressful life events within the past 12 months, European Organization for Research on the Treatment of Cancer (EORTC QLQ-C30) a measure of quality of life, Mental Health Inventory (MHI), and the Systems of Belief Inventory (SBI) a measure of spiritual and religious involvement. RESULTS: Hierarchical regression analyses revealed that less than excellent levels of social support (P < 0.01), greater negative impact of LES fateful life events (e.g., death of family member) (P < 0.05), personal illness or injury (P < 0.05), and all other negative life events in the past year (< 4; P < 0.01) were significant predictors of greater MHI psychological distress, in addition to being divorced or separated (P < 0.001), and more recently treated for cancer on CALGB 8541 (P < 0.05). The interaction of LES scores with MOS-SSS or SBI social support, used to test the buffering hypothesis, did not significantly improve the prediction of MHI psychological distress. CONCLUSIONS: The results supported the additive model, with both stressful life events and social support independently and significantly affecting patients' emotional state. However, the level of social support needed to be very high to reduce the likelihood of severe psychological distress.

Persistent symptoms among survivors of Hodgkin's disease: an explanatory model based on classical conditioning.

Persistent symptoms of nausea, distress, and vomiting triggered by reminders of cancer treatment were examined among 273 Hodgkin's disease survivors, 1 to 20 years posttreatment. Prevalence rates were high for distress and nausea but low for vomiting. Retrospective report of anticipatory symptoms during treatment was the strongest predictor of persistent symptoms, suggesting that treatment-induced symptoms are less likely to persist if conditioning does not occur initially. Time since treatment was also a significant predictor, with patients more recently treated more likely to experience persistent symptoms. Thus, an explanatory model based on classical conditioning theory successfully predicted presence of persistent symptoms. Symptoms also were associated with ongoing psychological distress, suggesting that quality of life is diminished among survivors with persistent symptoms. Recommendations for prevention and treatment of symptoms are discussed.

Phase II study of infusional chemotherapy with doxorubicin, vincristine and etoposide plus cyclophosphamide and prednisone (I-CHOPE) in resistant diffuse aggressive non-Hodgkin's lymphoma: CALGB 9255. Cancer and Leukemia Group B.

BACKGROUND: Patients with resistant diffuse aggressive non-Hodgkin's lymphoma (DA-NHL) have a poor prognosis. Studies have suggested infusional therapy may be beneficial. PATIENTS AND METHODS: This trial used an infusional regimen called I-CHOPE in resistant patients who had previously received only bolus CHOPE or CHOP regimen. Resistance was defined as: a) primary refractory disease, b) progression on therapy, c) partial response, d) complete remission lasting less than one year. Eligibility criteria included a diagnosis of DA-NHL (IWF E-H), no prior irradiation and adequate organ function. RESULTS: Thirty-seven patients were entered and twenty-nine were eligible. Reasons for ineligibility were incorrect histology (5) and other (3). The median age was 57 years (range 29-81) with 21 males. The performance status scores were: 0 (12 patients); 1 (9 patients); 2 (8 patients). Prior therapy consisted of standard CHOP (26 patients), bolus CHOPE (2 patients), high dose CHOP (1 patient). Therapy consisted of a 120 hour continuous intravenous infusion of doxorubicin 10 mg/m2/day, vincristine 0.28 mg/m2/day (maximum 0.4 mg/day), and etoposide 48 mg/m2/day. Cyclophosphamide 750 mg/m2 was given as an i.v. bolus day 6 and prednisone was given at 100 mg/day p.o. on days 1-5. G-CSF was allowed for myelosuppression. The overall response rate was 48% (CR 17%; PR 31%). Freedom from progression was 24% at six months and 8% at one year. Survival was 69% at six months and 40% at one year. In an exploratory analysis a prior CR or PR predicted response to I-CHOPE. Twelve of sixteen patients who had a CR/PR on previous therapy responded while two of thirteen who had no prior response, responded to I-CHOPE (P = 0.003). The toxicity was tolerable with grade 3-4 hematologic toxicity being leucopenia 94% and thrombocytopenia 41%. The grade 3-4 non-hematologic toxicities were infection in 28%, phlebitis in 11%, and stomatitis in 15%. CONCLUSIONS: I-CHOPE can induce responses in this group of patients with a poor prognosis, but most were seen in those who had previously had a response to bolus chemotherapy.

Lack of effect of a low-fat, high-fiber diet on the recurrence of colorectal adenomas. Polyp Prevention Trial Study Group.

BACKGROUND: We tested the hypothesis that dietary intervention can inhibit the development of recurrent colorectal adenomas, which are precursors of most large-bowel cancers. METHODS: We randomly assigned 2079 men and women who were 35 years of age or older and who had had one or more histologically confirmed colorectal adenomas removed within six months before randomization to one of two groups: an intervention group given intensive counseling and assigned to follow a diet that was low in fat (20 percent of total calories) and high in fiber (18 g of dietary fiber per 1000 kcal) and fruits and vegetables (3.5 servings per 1000 kcal), and a control group given a standard brochure on healthy eating and assigned to follow their usual diet. Subjects entered the study after undergoing complete colonoscopy and removal of adenomatous polyps; they remained in the study for approximately four years, undergoing colonoscopy one and four years after randomization. RESULTS: A total of 1905 of the randomized subjects (91.6 percent) completed the study. Of the 958 subjects in the intervention group and the 947 in the control group who completed the study, 39.7 percent and 39.5 percent, respectively, had at least one recurrent adenoma; the unadjusted risk ratio was 1.00 (95 percent confidence interval, 0.90 to 1.12). Among subjects with recurrent adenomas, the mean (+/-SE) number of such lesions was 1.85+/-0.08 in the intervention group and 1.84+/-0.07 in the control group. The rate of recurrence of large adenomas (with a maximal diameter of at least 1 cm) and advanced adenomas (defined as lesions that had a maximal diameter of at least 1 cm or at least 25 percent villous elements or evidence of high-grade dysplasia, including carcinoma) did not differ significantly between the two groups. CONCLUSIONS: Adopting a diet that is low in fat and high in fiber, fruits, and vegetables does not influence the risk of recurrence of colorectal adenomas.

Phase I studies of anti-epidermal growth factor receptor chimeric antibody C225 alone and in combination with cisplatin.

PURPOSE: The epidermal growth factor (EGF) receptor is frequently overexpressed in epithelial tumors. C225 is a human-to-murine chimeric monoclonal antibody that binds to the receptor and inhibits growth of cancer cells expressing the receptor. We evaluated the pharmacokinetics and toxicity of C225 in patients with advanced tumors overexpressing EGF receptors. PATIENTS AND METHODS: We treated 52 patients in three successive phase I clinical trials of C225 as a single dose (n = 13), weekly multiple dose (n = 17), and weekly multiple dose with cisplatin (n = 22). C225 dose levels were 5, 20, 50, and 100 mg/m(2). In the study combining C225 with cisplatin, limited to patients with either head and neck or non-small-cell lung cancer, C225 was further escalated to 200 and 400 mg/m(2). Cisplatin was given at a dose of 60 mg/m(2) once every 4 weeks, and treatment was continued for up to 12 weeks if no disease progression occurred. RESULTS: C225 displayed nonlinear pharmacokinetics, with antibody doses in the range of 200 to 400 mg/m(2) being associated with complete saturation of systemic clearance. C225 clearance did not change with repeated administration or with coadministration of cisplatin. Antibodies against C225 were detected in only one patient, and C225-associated toxicity was minimal. Patients experiencing disease stabilization were seen in all studies. In the study combining C225 and cisplatin, nine (69%) of 13 patients treated with antibody doses >/= 50 mg/m(2) completed 12 weeks of therapy, and two partial responses were observed. CONCLUSION: C225 has dose-dependent pharmacokinetics, and doses that achieve saturation of systemic clearance are well tolerated. C225 given in combination with cisplatin has biologic activity at pharmacologically relevant doses.

Rural breast cancer treatment: evidence from the Reaching Communities for Cancer Care (REACH) project.

BACKGROUND: Research shows that rural populations are more likely than their urban counterparts to be diagnosed with late-stage cancer, but less is known about appropriateness of cancer treatment in rural locations after diagnosis. The objective of this analysis was to assess the degree to which rural breast cancer treatment was received in concordance with national recommendations. METHODS: Data came from 251 stage I and II breast cancer patients residing in rural North Carolina. State-of-the-art care was defined using the National Cancer Institute's (NCI) physician data query (PDQ) database, and cases were categorized into appropriate primary and/or adjuvant treatment. Chi-square and Fishers' exact tests were used to assess changes in appropriate treatment over time (1991-1996) and between stage. Multiple logistic regression was used to determine whether any patient or disease characteristics were associated with receipt of appropriate treatment. RESULTS: Most (81-90%) of the breast cancer cases received the appropriate primary therapy (mastectomy or lumpectomy followed by radiation therapy); of these, the majority received a mastectomy (66-72%). Fewer women received adjuvant therapy as recommended (27-61%), although significantly more stage II than stage I cases did so (p < or = 0.05). Regression showed that stage and estrogen-receptor (ER) status were associated with appropriate therapy. CONCLUSIONS: The findings suggest that there exist deviations from NCI established treatment recommendations among rural breast cancer patients. More research is needed to develop better methods for dissemination of state-of-the-art cancer information to rural physicians and patients, and to understand how treatment decisions are made.

Rural physicians' understanding of the state-of-the-art in breast, colon and rectum cancer treatment.

OBJECTIVES: This study measured the impact of an educational intervention aimed at heightening rural physicians' awareness of state-of-the-art breast and colorectal cancer therapies. METHODS: Pre- and post-intervention mailed surveys were administered to all primary-care physicians and referring physicians in the seven-county intervention region in North Carolina (NC) and a comparison region in South Carolina (SC). RESULTS: The survey revealed few significant changes in physicians' perspectives that could be attributed to the intervention. Physicians erroneously stated that lumpectomy without follow-up radiation was acceptable for treating breast cancer (55%), failed to indicate that adjuvant therapy was an accepted practice for treating Stage I breast cancer (67%), failed to acknowledge chemotherapy as experimental for Dukes' B colon cancer patients (70%), and failed to recognize a combination of surgery, chemotherapy, and radiation as a standard treatment for rectal cancer (25%). CONCLUSIONS: The low levels of awareness of National Cancer Institute guidelines were reflected in low breast-sparing surgery rates for women living in the intervention region. Stronger consensus on appropriate cancer treatments is needed throughout the medical community in order to reduce undesired variation in rural, community-based cancer care.

Colon cancer treatment in rural North and South Carolina.

The purpose of this study was to determine the degree to which colon cancer treatment in rural North and South Carolina in 1991 and 1996 conformed to national treatment recommendations. Data came from medical records of colon cancer patients residing in rural North and South Carolina. The National Cancer Institute's Physician Data Query (PDQ) database was used to define state-of-the-art care and to categorize receipt of primary and/or adjuvant treatment. Changes in treatment over time, location, and stage and bivariate relationships between treatment and selected covariates were assessed with chi-square and Fisher's exact tests. Regression was used to control for possible interactions between patient and/or disease characteristics and treatment. The majority of colon cancer cases received primary therapy as suggested by the PDQ which was not significantly related to other factors examined. There was variation in provision of adjuvant therapy. Stage III patients received adjuvant therapy significantly more often than did stage II patients (p

Dose-response trial of megestrol acetate in advanced breast cancer: cancer and leukemia group B phase III study 8741.

PURPOSE: To investigate whether dose escalation of megestrol acetate (MA) improves response rate and survival in comparison with standard doses of MA. PATIENTS AND METHODS: Three hundred sixty-eight patients with metastatic breast cancer, positive and/or unknown estrogen and progesterone receptors, zero or one prior trial of hormonal therapy, and no prior chemotherapy for metastatic disease were prospectively randomized into three groups. The groups of patients received either MA 160 mg/d (one tablet per day), MA 800 mg/d (five tablets per day), or MA 1,600 mg/d (10 tablets per day). RESULTS: Patient characteristics were well balanced in the three treatment groups. Three hundred sixty-six patients received treatment and were included in the analyses. The response rates were 23%, 27%, and 27% for the 160-mg, 800-mg, and 1,600-mg arms, respectively. Response duration correlated inversely with dose. Median durations of response were 17 months, 14 months, and 8 months for the 160-mg, 800-mg, and 1,600-mg arms, respectively. No significant differences in the treatment arms were noted for time to disease progression or for survival; survival medians were 28 months (low dose), 24 months (mid dose) and 29 months (high dose). The most frequent and troublesome toxicity, weight gain, was dose-related, with approximately 20% of patients on the two higher-dose arms reporting weight gain of more than 20% of their prestudy weight, compared with only 2% in the 160-mg dose arm. CONCLUSION: With a median follow-up of 8 years, these results demonstrate no advantage for dose escalation of MA in the treatment of metastatic breast cancer.

High-dose paclitaxel plus G-CSF for malignant mesothelioma: CALGB phase II study 9234.

BACKGROUND: New agents with activity in mesothelioma are sorely needed. The Cancer and Leukemia Group B (CALGB) therefore performed a phase II study of high-dose paclitaxel in patients with malignant mesothelioma who had no prior chemotherapy. PATIENTS AND METHODS: Thirty-five patients accrued to this multi-institutional phase II study of paclitaxel given as a 24-hour infusion at 250 mg/m2 every three weeks plus filgrastim (G-CSF) 300 mcg subcutaneously days 3-18. RESULTS: There were three (9%) regressions of evaluable disease. The median survival was five months (95% confidence interval (95% CI): 1.9-9.6 months), the one-year survival rate was 14% and the two-year survival rate was 6%. Toxicity was tolerable with one death from pneumonia (without neutropenia) on day 18 and a 23% rate of grade 4 granulocytopenia. CONCLUSIONS: The level of activity seen with paclitaxel is similar to that seen in other CALGB trials of the single agents carboplatin, trimetrexate and 5-azacytidine. Future studies of of paclitaxel (at lower doses) in combination with synergistic agents could be considered.

Survival advantage of adjuvant chemotherapy in high-risk node-negative breast cancer: ten-year analysis--an intergroup study.

PURPOSE: Preliminary analysis showed that adjuvant chemotherapy is effective in improving disease-free survival (DFS) among high-risk breast cancer patients. This report updates the analysis of the high-risk group and reports the results of the low-risk group. METHODS: Patients who had undergone a modified radical mastectomy or a total mastectomy with low-axillary sampling, with negative axillary nodes and either an estrogen receptor-negative (ER-) tumor of any size or an estrogen receptor-positive (ER+) tumor that measured > or = 3 cm (high-risk) were randomized to receive six cycles of cyclophosphamide, methotrexate, fluorouracil, and prednisone (CMFP) or no further treatment. Patients with ER+ tumors less than 3 cm (low-risk) were monitored without therapy. RESULTS: DFS and overall survival (OS) at 10 years were 73% and 81%, respectively, among patients who received chemotherapy, as compared with 58% and 71% in the observation group (P=.0006 for DFS and P=.02 for OS). Chemotherapy was beneficial for patients with large tumors, both ER+ and ER-, showing a 10-year DFS of 70% versus 51 % (P=.0009) and OS of 75% versus 65% (P=.06). Ten-year survival was 77% among low-risk patients, 85% among premenopausal patients, and 73% in the postmenopausal group. CONCLUSION: The observed 37% reduction in risk of recurrence and 34% reduction in mortality risk at 10 years, associated with a 15.4% absolute benefit in disease-free state and 10.1% in survival, reaffirm the role of adjuvant chemohormonal therapy in the management of high-risk node-negative breast cancer. Tumor size remains a significant prognostic factor associated with recurrence and survival in the low-risk group.

Phase II study of suramin plus aminoglutethimide in two cohorts of patients with androgen-independent prostate cancer: simultaneous antiandrogen withdrawal and prior antiandrogen withdrawal.

Management of prostate cancer progression after failure of initial hormonal therapy is controversial. Recently, the activity of the simple discontinuation of antiandrogen therapy has been established by several groups, as well as the enhanced activity when combined with adrenal suppression (i.e., aminoglutethimide and hydrocortisone). Furthermore, suramin has generated considerable interest following reports of response rates ranging from 17 to 70%. More recently, suramin response rates of 18 and 22% have been reported when the potential confounding variables of flutamide withdrawal and hydrocortisone were prospectively controlled. On the basis of the activity of combining aminoglutethimide with flutamide withdrawal, we designed a protocol in which suramin was combined with aminoglutethimide in two cohorts of patients (those with simultaneous antiandrogen withdrawal compared to those who had previously discontinued antiandrogen therapy). Eighty-one evaluable patients were enrolled in this study between June 1992 and November 1994. Patients were a priori divided into two cohorts, those receiving prior antiandrogen withdrawal (n = 56) and those receiving simultaneous antiandrogen withdrawal (n = 25) at the time the patients were enrolled into the trial. For the group that discontinued antiandrogen prior to enrolling in therapy, the partial response rate (> 50% decline in PSA for > 4 weeks) was 14.2%, whereas the partial response was 44% for those patients who discontinued their antiandrogen at the time of starting suramin and aminoglutethimide. The median time to progression was 3.9 months in patients failing prior antiandrogen withdrawal and 5.5 months in those patients having concomitant antiandrogen withdrawal (P = 0.36 for the overall difference). The progression-free survival estimate at 1 year for patients having prior antiandrogen withdrawal was 19.8% [95% confidence interval (CI), 11-32.9%]. For those patients who experienced antiandrogen withdrawal simultaneous with the treatment, the progression-free survival estimates at 1 and 2 years were 27.1 (95% CI, 13.2-47.6%) and 4.5% (95% CI, 0.8-21.6%). The median survival time for those patients having prior antiandrogen withdrawal was 14.2 months, whereas the median survival was 21.9 months for those having concomitant antiandrogen withdrawal (P = 0.029 for the overall difference). In conclusion, the partial response rate of 44% for those who had concomitant flutamide withdrawal with adrenal suppression was consistent with that of other reports using a similar maneuver. Although this study was not randomized and thus we should not over-interpret the results, flutamide withdrawal plus adrenal suppression appears to have greater activity than flutamide withdrawal alone. Furthermore, these data suggest that suramin adds little to the response rate observed for other adrenal suppressive agents in the presence of antiandrogen withdrawal. This interpretation is in agreement with those studies controlling for adrenal suppression and flutamide withdrawal prior to suramin administration, which noted modest activity of short duration. Given that antiandrogen withdrawal is now accepted as an active maneuver for a subset of patients progressing after maximum androgen blockade, we propose that future trials attempting to maximize response rates incorporate this maneuver whenever possible into prospectively designed regimens.

Comparison of psychosocial adaptation of advanced stage Hodgkin's disease and acute leukemia survivors. Cancer and Leukemia Group B.

BACKGROUND: The purpose of this study was to compare the long-term psychosocial adaptation of Hodgkin's disease and adult acute leukemia survivors. PATIENTS AND METHODS: Two hundred seventy-three Hodgkin's disease (HD) and 206 adult acute leukemia (AL) survivors were interviewed by telephone concerning their psychosocial adjustment and problems they attributed to having been treated for cancer, using identical research procedures and a common set of instruments. The following measures were used: Psychosocial Adjustment to Illness Scale (PAIS); Brief Symptom Inventory (BSI); current Conditioned Nausea and Vomiting triggered by treatment-related stimuli (CNVI); Indices of Employment, Insurance and Sexual Problems Attributed to Cancer; Negative Socioeconomic Impact of Cancer Index (NSI). All participants had been treated on one of nine Hodgkin's disease or 13 acute leukemia Cancer and Leukemia Group B (CALGB) clinical trials from 1966-1988, and had been off treatment for one year or more (mean years: HD = 5.9; AL = 5.6). RESULTS: HD survivors' risk of having a high distress score on the BSI was almost twice that found for AL survivors (odds ratio = 1.90), with 21% of HD vs. 14% of AL survivors (P < 0.05) having scores that were 1.5 standard deviations above the norm, suggestive of a possible psychiatric disorder. HD survivors reported greater fatigue (POMS Fatigue, P = 0.01; Vigor Subscales, P = 0.001), greater conditioned nausea (CNVI, P < 0.05), greater impact of cancer on their family life (PAIS Domestic Environment, P = 0.004) and poorer sexual functioning (PAIS Sexual Relationships, P = 0.0001), than AL survivors. CONCLUSIONS: Treatment-related issues may have placed HD survivors at a greater risk for problems in long-term adaptation than AL survivors.