Maha Hussain

Design and End Points of Clinical Trials for Patients With Progressive Prostate Cancer and Castrate Levels of Testosterone: Recommendations of the Prostate Cancer Clinical Trials Working Group

PURPOSEnTo update eligibility and outcome measures in trials that evaluate systemic treatment for patients with progressive prostate cancer and castrate levels of testosterone.nnnMETHODSnA committee of investigators experienced in conducting trials for prostate cancer defined new consensus criteria by reviewing previous criteria, Response Evaluation Criteria in Solid Tumors (RECIST), and emerging trial data.nnnRESULTSnThe Prostate Cancer Clinical Trials Working Group (PCWG2) recommends a two-objective paradigm: (1) controlling, relieving, or eliminating disease manifestations that are present when treatment is initiated and (2) preventing or delaying disease manifestations expected to occur. Prostate cancers progressing despite castrate levels of testosterone are considered castration resistant and not hormone refractory. Eligibility is defined using standard disease assessments to authenticate disease progression, prior treatment, distinct clinical subtypes, and predictive models. Outcomes are reported independently for prostate-specific antigen (PSA), imaging, and clinical measures, avoiding grouped categorizations such as complete or partial response. In most trials, early changes in PSA and/or pain are not acted on without other evidence of disease progression, and treatment should be continued for at least 12 weeks to ensure adequate drug exposure. Bone scans are reported as new lesions or no new lesions, changes in soft-tissue disease assessed by RECIST, and pain using validated scales. Defining eligibility for prevent/delay end points requires attention to estimated event frequency and/or random assignment to a control group.nnnCONCLUSIONnPCWG2 recommends increasing emphasis on time-to-event end points (ie, failure to progress) as decision aids in proceeding from phase II to phase III trials. Recommendations will evolve as data are generated on the utility of intermediate end points to predict clinical benefit.

Absolute Prostate-Specific Antigen Value After Androgen Deprivation Is a Strong Independent Predictor of Survival in New Metastatic Prostate Cancer: Data From Southwest Oncology Group Trial 9346 (INT-0162)

PURPOSEnTo establish whether absolute prostate-specific antigen (PSA) value after androgen deprivation (AD) is prognostic in metastatic (D2) prostate cancer (PCa).nnnPATIENTS AND METHODSnD2 PCa patients with baseline PSA of at least 5 ng/mL received 7 months induction AD. Patients achieving PSA of 4.0 ng/mL or less on months 6 and 7 are randomly assigned to continuous versus intermittent AD on month 8. Eligibility for this analysis required a prestudy PSA with at least two subsequent PSAs and that patients be registered at least 1 year before analysis date. Survival was defined as time to death after 7 months of AD. Associations were evaluated by proportional hazards regression models.nnnRESULTSnOne thousand one hundred thirty four of 1,345 eligible patients achieved a PSA of 4 ng/mL or less. At end of induction, 965 patients maintained PSA of 4 or less and 604 had a PSA of 0.2 ng/mL or less. After controlling for prognostic factors, patients with a PSA of 4 or less to more than 0.2 ng/mL had less than one third the risk of death (ROD) as those with a PSA of more than 4 ng/mL (P < .001). Patients with PSA of 0.2 ng/mL or less had less than one fifth the ROD as patients with a PSA of more than 4 ng/mL (P < .001) and had significantly better survival than those with PSA of more than 0.2 to 4 ng/mL or less (P < .001). Median survival was 13 months for patients with a PSA of more than 4 ng/mL, 44 months for patients with PSA of more than 0.2 to 4 ng/mL or less, and 75 months for patients with PSA of 0.2 ng/mL or less.nnnCONCLUSIONnA PSA of 4 ng/mL or less after 7 months of AD is a strong predictor of survival. This data should be used to tailor future trial design for D2 prostate cancer.

Trastuzumab, Paclitaxel, Carboplatin, and Gemcitabine in Advanced Human Epidermal Growth Factor Receptor-2/neu–Positive Urothelial Carcinoma: Results of a Multicenter Phase II National Cancer Institute Trial

PURPOSEnWe investigated the safety and efficacy (response rates, time to disease progression, survival) of trastuzumab, carboplatin, gemcitabine, and paclitaxel in advanced urothelial carcinoma patients and prospectively evaluated human epidermal growth factor receptor-2 (Her-2/neu) overexpression rates.nnnPATIENTS AND METHODSnAdvanced urothelial carcinoma patients were screened for Her-2/neu overexpression. Eligibility for therapy required human epidermal growth factor receptor-2 (Her-2/neu) overexpression by immunohistochemistry (IHC), gene amplification and/or elevated serum Her-2/neu, no prior chemotherapy for metastasis, and adequate organ function including a normal cardiac function. Treatment consisted of trastuzumab (T) 4 mg/kg loading dose followed by 2 mg/kg on days 1, 8, and 15; paclitaxel (P) 200 mg/m2 on day 1; carboplatin (C; area under the curve, 5) on day 1; and gemcitabine (G) 800 mg/m2 on days 1 and 8. The primary end point was cardiac toxicity.nnnRESULTSnFifty-seven (52.3%) of 109 registered patients were Her-2/neu positive, and 48.6% were positive by IHC. Her-2/neu-positive patients had more metastatic sites and visceral metastasis than did Her-2/neu negative patients. Forty-four of 57 Her-2/neu-positive patients were treated with TPCG. The median number of cycles was six (range, 1 to 12 cycles). The most common grade 3/4 toxicity was myelosuppression. Grade 3 sensory neuropathy occurred in 14% of patients, and 22.7% experienced grade 1 to 3 cardiac toxicity (grade 3, n = 2: one left ventricular dysfunction, one tachycardia). There were three [corrected] therapy-related deaths. Thirty-one (70%) of 44 patients responded (five complete and 26 partial), and 25 (57%) of 44 were confirmed responses. Median time to progression and survival were 9.3 and 14.1 months, respectively.nnnCONCLUSIONnWe prospectively characterized Her-2/neu status in advanced urothelial carcinoma patients. TPCG is feasible; cardiac toxicity rates were higher than projected, but the majority were grade two or lower. Determining the true contribution of trastuzumab requires a randomized trial.

Sphincter-Sparing Treatment for Distal Rectal Adenocarcinoma

Background: Studies suggest that the anal sphincter can be preserved in some patients with distal rectal adenocarcinoma (DRA), but this has not been validated in any prospective multi-institutional trial.Methods: To test the hypothesis that the anal sphincter can be preserved in some patients with DRA, the Cancer and Leukemia Group B and collaborators reviewed 177 patients who had T1/T2 adenocarcinomas ≤ 4xa0cm in diameter, which encompassed ≤ 40% of bowel wall circumference, and were ≤ 10xa0cm from the dentate line. Of the 177 patients, 59 patients who were eligible for the study had T1 adenocarcinomas and received no further treatment; 51 eligible T2 patients received external beam irradiation (5400 cGY/30 fractions 5 days/week) and 5-fluorouracil (500xa0mg/m2 IV d1–3, d29–31) after local excision.Results: At 48 months median follow-up, 6-year survival and failure-free survival rates of the eligible patients are 85% and 78% respectively. Three patients died of unrelated disease. Two patients were treated for second primary colorectal tumors; both remain disease free (NED). Another eight patients died of disease, four with distant recurrence only. One T1 patient is alive with distant disease. Two T1 and seven T2 patients experienced isolated local recurrences; all underwent salvage abdominoperineal resection (APR). After APR, one T1 and four of seven T2 patients were NED at the time of last visit (2–7 years). One T1 patient died of local and distant disease. Three of seven T2 patients died with distant disease.Conclusions: We conclude that sphincter preservation can be achieved with excellent cancer control without initial sacrifice of anal function in most patients. After local recurrence, salvage resection appears effective, but longer follow-up time of local and distant disease-free survival is advised before extrapolation to patients with T3 primaries.

Phase II evaluation of oral estramustine and oral etoposide in hormone-refractory adenocarcinoma of the prostate.

PURPOSEnEstramustine and etoposide (VP-16) have been demonstrated to inhibit the growth of prostate cancer cells in experimental models. This led us to evaluate the effectiveness of this combination in the treatment of patients with metastatic prostate carcinoma refractory to hormone therapy.nnnPATIENTS AND METHODSnEstramustine 15 mg/kg/d and VP-16 50 mg/m2/d, were administered orally in divided doses for 21 days. Patients were then taken off therapy for 7 days and the cycle then repeated. Therapy continued until evidence of disease progression.nnnRESULTSnForty-two patients have been enrolled onto this trial with a minimum of 40 weeks follow-up. Of 18 patients with measurable soft tissue disease, three demonstrated a complete response (CR) and six a partial response (PR) for longer than 2 months. Of these 18 patients, pretreatment prostate-specific antigen (PSA) levels decreased by at least 75% in five men (28%) and by at least 50% in nine (50%). The median survival duration has not been reached in those patients who demonstrated a response either by soft tissue or PSA criteria. Of 24 patients with disease limited to bone, six (25%) demonstrated improvement and nine (38%) demonstrated stability in their bone scans. Five men (21%) demonstrated a decrease of at least 75% in pretreatment PSA levels and 14 (58%) demonstrated at least a 50% decrease; the median survival duration has not been reached in these patients. Pretreatment performance status is an important predictor of survival.nnnCONCLUSIONnWe conclude that the combination of estramustine and VP-16 is an active oral regimen in hormone-refractory prostate cancer.

Randomized clinical trial of a family intervention for prostate cancer patients and their spouses

Few intervention studies have been conducted to help couples manage the effects of prostate cancer and maintain their quality of life. The objective of this study was to determine whether a family‐based intervention could improve appraisal variables (appraisal of illness or caregiving, uncertainty, hopelessness), coping resources (coping strategies, self‐efficacy, communication), symptom distress, and quality of life in men with prostate cancer and their spouses.

Activity of second-line chemotherapy in docetaxel-refractory hormone-refractory prostate cancer patients : randomized phase 2 study of ixabepilone or mitoxantrone and prednisone.

This randomized, noncomparative, multicenter, clinical trial evaluated ixabepilone or mitoxantrone/prednisone (MP) as second‐line chemotherapy for taxane‐refractory, hormone‐refractory, prostate cancer (HRPC).

Ixabepilone (Epothilone B Analogue BMS-247550) Is Active in Chemotherapy-Naive Patients With Hormone-Refractory Prostate Cancer: A Southwest Oncology Group Trial S0111

PURPOSEnThe epothilones are a new class of tubulin-polymerizing agents with activity in taxane-sensitive and resistant tumor models. We evaluated ixabepilone (BMS-247550) in patients with metastatic hormone-refractory prostate cancer (HRPC).nnnMETHODSnEligible patients had chemotherapy-naive metastatic HRPC, a Zubrod performance status of 0 to 2, and adequate organ function. All patients received BMS-247550 at 40 mg/m2 over 3 hours every 3 weeks. The primary end point was proportion of patients achieving a prostate-specific antigen (PSA) response.nnnRESULTSnForty-eight patients with metastatic HRPC were registered. Forty-two patients were eligible, with a median age of 73 years and a median PSA level of 111 ng/mL; 78% had bone-only or bone and soft tissue metastases, and 88% had objective radiologic disease progression at registration. Grade 3 and 4 adverse events (AEs) occurred in 16 and three patients, respectively. All grade 4 toxicities were neutropenia or leukopenia. The most frequent grade 3 AEs were neuropathy (eight patients), hematologic toxicity (seven patients), flu-like symptoms, and infection (five patients each). There were no grade 3/4 thrombocytopenia or grade 5 AEs. There were 14 confirmed PSA responses (33%; 95% CI, 20% to 50%); 72% of PSA responders had declines greater than 80%, and two patients achieved an undetectable PSA. The estimated median progression-free survival is 6 months (95% CI, 4 to 8 months), and the median survival is 18 months (95% CI, 13 to 24 months).nnnCONCLUSIONnIxabepilone has demonstrated activity in patients with chemotherapy-naive metastatic HRPC. Major toxicities were neutropenia and neuropathy. Further testing to define its activity relative to standard therapy is warranted.

Living With Prostate Cancer: Patients' and Spouses' Psychosocial Status and Quality of Life

PURPOSEnDespite the high prevalence of prostate cancer, little information is available on the quality of life of men and their spouses during the phases of illness. This study assessed patients and spouses quality of life, appraisal of illness, resources, symptoms, and risk for distress across three phases of prostate cancer: newly diagnosed, biochemical recurrence, and advanced.nnnPATIENTS AND METHODSnThe sample consisted of 263 patient/spouse dyads. A stress-appraisal conceptual model guided the selection of variables which were then assessed with established instruments. Study variables were examined for phase effects (differences in dyads across three phases), role effects (patients v spouses), and phase-by-role interactions (differences within dyads across phases) using analysis of variance (ANOVA).nnnRESULTSnMore phase effects than role effects were found, indicating that the psychosocial experiences of patients and their spouses were similar, but differed from dyads in other phases. Dyads in the advanced phase were at highest risk for distress. These patients had the lowest physical quality of life, and their spouses had the lowest emotional quality of life of all participants. Dyads in the biochemical recurrence and advanced phases had more negative appraisals of illness and caregiving, greater uncertainty, and more hopelessness compared with dyads in the newly diagnosed phase. Spouses, in contrast to patients, had less confidence in their ability to manage the illness and perceived less support across all phases of illness.nnnCONCLUSIONnPhase-specific programs of care are needed to assist both men with prostate cancer and their spouses to manage the effects of illness.

Couples' experiences with prostate cancer: focus group research.

PURPOSE/OBJECTIVESnTo explore the experiences of couples living with prostate cancer, the impact of the illness on their quality of life, their ability to manage symptoms, and their suggestions for interventions that would help them to improve their daily experiences.nnnDESIGNnDescriptive, qualitative.nnnSETTINGnSix focus groups were used to obtain the data; two were patient-only groups, two were spouse-caregiver groups, and two were dyad groups. The focus groups were conducted at two comprehensive cancer centers in the midwestern region of the United States.nnnSAMPLEn42 participants: 22 men with prostate cancer and 20 spouse-caregivers.nnnMETHODSnFocus group discussions were tape-recorded, and the content was analyzed.nnnMAIN RESEARCH VARIABLESnQuality of life, symptom experience, and areas for intervention.nnnFINDINGSnFour major themes emerged from the data: enduring uncertainty, living with treatment effects, coping with changes, and needing help.nnnCONCLUSIONSnParticipants had a need for information and support. Both men and spouse-caregivers felt unprepared to manage treatment effects. Symptoms had a broad effect on couples, not just men. Positive effects of the illness, as well as negative effects, emerged from the themes.nnnIMPLICATIONS FOR NURSINGnAttention needs to be given to methods of providing information and support to couples coping with prostate cancer. Both patients and partners need to be included in discussions about the effect of the illness and treatments so that both can feel more prepared to manage them.