Implementation of supportive care and best supportive care interventions in clinical trials enrolling patients with cancer†.

BACKGROUND: With the growing and evolving role of palliative care in oncology, we examined how supportive care (SC) and best supportive care (BSC) are implemented in clinical trials when used as a comparison treatment arm. METHODS: We conducted a systematic review of the literature for clinical trials published between 1980 and 2012 in which systemic anticancer therapy was compared with an SC-only arm and compared SC implementation with World Health Organization (WHO) published guidelines. RESULTS: Our search identified 189 articles, 73 of which met our inclusion criteria with the following cancer types: 29 lung, 7 colorectal, 6 pancreatic, 5 gastric and 26 others. Fifty-five studies (75%) provided some definition of SC, and 48 studies (66%) used the term BSC. Twenty-one of the 55 studies that provided a definition described the use of palliative therapies as being 'at the discretion of the treating physician' without standardization. Only two studies provided SC that incorporated routine physical, psychological and social assessments including rapid referral to SC specialists. SC interventions most commonly included analgesics (47%) and radiotherapy (44%). Trials using the term BSC versus SC were more likely to include blood transfusions (P = 0.002) and antibiotics (P = 0.033), but less likely to include steroids (P = 0.05) and palliative specialists (P = 0.047). CONCLUSIONS: The implementation of SC in clinical trials in this systematic review is highly variable. The vast majority of the studies did not meet the WHO guidelines on SC because palliative care therapies were not recommended or integrated into care. Future clinical trials utilizing a SC intervention arm should define these interventions in a standardized approach that meets current guidelines such as the WHO recommendations.

Significance of DNA abnormalities in primary malignant melanoma and nevi, a retrospective flow cytometric study.

DNA ploidy of melanocytic skin tumors from 87 patients (53 primary melanomas, 34 nevi) was determined by flow cytometry from routinely prepared paraffin blocks. Ploidy data correlated strongly with conventional morphological parameters. Only 1 of 34 nevi, but 13 of 53 melanomas were aneuploid. Among the melanomas, none of 21 levels I-III melanomas was aneuploid, but 13 of 32 levels IV and V melanomas were aneuploid. There was also a significant correlation between increasing Breslow thickness and the presence of DNA aneuploidy. For 33 melanoma patients with over 2 yr of follow-up (average, 7.1 yr), only 4 of 23 diploid tumors have recurred, but 9 of 10 aneuploid tumors have recurred. We conclude that the biological potential of melanocytic skin tumors is strongly linked to DNA aneuploidy. Since this parameter can be conveniently determined from paraffin blocks, determination of ploidy abnormalities in these tumors may be clinically useful.

Human immunodeficiency virus-related lymphomas: a possible association between tumor proliferation, lack of ploidy anomalies, and immune deficiency.

In an attempt to identify a biologic basis for the aggressive clinical behavior of human immunodeficiency virus (HIV)-associated lymphomas (HAL), dual-parameter flow-cytometric analysis was performed on 22 paraffin-embedded biopsy specimens. Cases were analyzed for DNA ploidy, the percentage of cells in S-phase (proliferative activity), and content of a recently identified proliferation-associated nuclear antigen, p105. The DNA-content analysis of 22 HALs was compared with that of 109 cases of intermediate-grade non-Hodgkin's lymphoma (NHL) unrelated to the acquired immune deficiency syndrome (AIDS) studied previously in our laboratory and 125 cases of high-grade NHL reported in the literature. The proliferative activity was higher in intermediate-grade HAL relative to non-AIDS NHL (24.0% v 10.4%; P = .03), and in high-grade HAL in comparison with NHLs of similar histology unassociated with HIV infection (24.8% v 19%), although the latter did not reach statistical significance. The number of mitoses per 10 high-power fields was found to correlate with the percentage of cells in S-phase (r = .68; P = .0004). Although p105 content tended to be higher in HAL than in an AIDS-related complex (ARC)-associated hyperplastic lymph node control, no statistically significant associations were found between p105 content and proliferative activity or the number of mitoses per 10 high-power fields. When compared with non-AIDS NHLs of comparable grade, there was a trend toward a lower incidence of DNA aneuploidy in both intermediate- (25% v 56%) and high-grade (38.5% v 60%) HALs. The higher proliferative activity and lower incidence of DNA aneuploidy found in HAL relative to non-AIDS NHL of comparable histologic grade may represent differences in pathogenesis and may underlie the poor prognosis of HIV-associated NHL.

Fumagillin analog in the treatment of Kaposi's sarcoma: a phase I AIDS Clinical Trial Group study. AIDS Clinical Trial Group No. 215 Team.

PURPOSE: Angiogenesis is a major component of Kaposi's sarcoma (KS) and a critical process in tumor growth. The present study was designed primarily to test the toxicity and pharmacokinetics (PK) of the angiogenesis inhibitor TNP-470 and secondarily to evaluate tumor response in patients with early AIDS-related KS. PATIENTS AND METHODS: Patients with AIDS-related KS were required to have cutaneous disease with > or = 5 measurable lesions and no evidence of pulmonary, symptomatic gastrointestinal, or acutely life-threatening KS. Thirty-eight patients received TNP-470 by weekly intravenous infusion over 1 hour at one of six dose levels for up to 24 weeks. RESULTS: The dose levels tested included 10, 20, 30, 40, 50 and 70 mg/m2. Median CD4 count was 24 cells/microl (range, 0 to 460). Fourteen patients (36%) had > or = 50 cutaneous lesions and 19 (49%) had oral lesions. Adverse events included neutropenia (n = 2), hemorrhage (n = 3), and urticaria (n = 1). PK studies showed wide interpatient and intrapatient variability. Elimination half-life values were short (range, 0.01 to 0.61 hours). Seven patients (18%) achieved a partial response. The median time to partial response was 4 weeks (range, 2 to 25), and the median duration of response was 11 weeks (range, 3 to 26+). CONCLUSION: TNP-470, administered as a weekly, 1-hour infusion to patients with early AIDS-KS is well-tolerated at doses up to and including the highest dose tested. Tumor responses were observed in a substantial number of cases and occurred at various dose levels. TNP-470 should be evaluated further in patients with AIDS-KS as a single agent and in combination with other biologic response modifiers in early disease or after initial response to cytotoxic chemotherapy.

Efficacy of pegylated-liposomal doxorubicin in the treatment of AIDS-related Kaposi's sarcoma after failure of standard chemotherapy.

PURPOSE: To determine the efficacy and safety of pegylated-liposomal doxorubicin in patients with AIDS and Kaposi's sarcoma (AIDS-KS) who experienced failure of standard chemotherapy. METHODS: Fifty-three patients with advanced AIDS-KS who experienced disease progression or intolerable toxicities while receiving standard doxorubicin/bleomycin/vincristine (ABV) or bleomycin/vincristine (BV) chemotherapy were identified from a cohort of patients who were then treated with pegylated-liposomal doxorubicin. Patients received 20 mg/m2 pegylated-liposomal doxorubicin (Doxil; Sequus Pharmaceuticals, Inc, Menlo Park, CA) every 3 weeks. RESULTS: Nineteen patients (36%) had a partial response (PR) and one patient had a clinical complete response (CCR). The median duration of response and time (from study entry) to treatment failure were 128 and 134 days, respectively. Of 28 patients who experienced disease progression while receiving combination regimens that contained standard doxorubicin, the PR rate was 32%, which suggests that the pegylated-liposomal encapsulation increases the therapeutic effect of doxorubicin. Patients obtained clinical benefits such as flattening of lesions (48%), improved lesion color (56%), relief of pain (45%), and loss of edema (83%). Forty-nine percent of patients had more than one clinical benefit. The most common adverse effect was leukopenia, which occurred in 40% of patients. Only 15% of patients had nausea and/or vomiting, none of which was severe; 9% experienced alopecia, also generally mild. CONCLUSION: Pegylated-liposomal doxorubicin offers a new alternative for treatment of patients who have experienced failure of standard chemotherapy for AIDS-KS.

Randomized phase III trial of liposomal daunorubicin versus doxorubicin, bleomycin, and vincristine in AIDS-related Kaposi's sarcoma.

PURPOSE: To compare the safety and efficacy of liposomal daunorubicin (DaunoXome; NeXstar Pharmaceuticals, Inc, Boulder, CO) with a reference regimen of doxorubicin, bleomycin, and vincristine (ABV) in advanced AIDS-related Kaposi's sarcoma (KS). PATIENTS AND METHODS: In a prospective randomized phase III trial, 232 patients were randomized to receive DaunoXome 40 mg/m2 or a combination regimen of doxorubicin 10 mg/m2, bleomycin 15 U, and vincristine 1 mg, administered intravenously every 2 weeks. Treatment was continued until complete response (CR), disease progression, or unacceptable toxicity. RESULTS: Of 232 patients randomized, 227 were treated: 116 with DaunoXome and 111 with ABV. The overall response rate (CR or partial response [PR]) was 25% (three CRs and 26 PRs) for DaunoXome and 28% (one CR and 30 PRs) for ABV. The difference in response rates was not statistically significant. The median survival time was 369 days for DaunoXome patients and 342 days for ABV patients (P = .19). The median time to treatment failure was 115 days for DaunoXome and 99 days for ABV (P = .13). ABV patients experienced significantly more alopecia and neuropathy (P < .0001). DaunoXome patients experienced more grade 4 neutropenia (P = .021). Cardiac function remained stable, with no instances of congestive heart failure on either treatment arm. CONCLUSION: In this large phase III trial, the efficacy of DaunoXome was comparable to that of ABV. Response rates, time to treatment failure, and overall survival were similar on both treatment arms. DaunoXome is a safe and effective primary therapy for advanced AIDS-related KS.

Megestrol acetate for treatment of anorexia and cachexia associated with human immunodeficiency virus infection.

Cachexia is a common problem in persons infected with the human immunodeficiency virus (HIV). Megestrol acetate, an agent used for the treatment of metastatic breast cancer, is associated with appetite stimulation and weight gain. To determine whether this drug might benefit HIV-positive patients, 22 such subjects (14 previously reported) were treated with oral megestrol acetate, beginning at a dose of 80 mg four times daily. All patients had lost at least 10% of their preillness weight prior to treatment; the median loss was 11.4 kg (range, 5.5 to 26.8). Preliminary data from patients observed during therapy from 2 to 72 weeks showed that 21 of the 22 patients gained weight; the average weight gain was 7.3 kg (range, -4.1 to 17.3). Three patients failed to gain weight on 320 mg per day of megestrol acetate; both appetite stimulation and weight gain were achieved with 460 mg per day in one and 640 mg per day in another. One patient continued to lose weight despite 480 mg per day megestrol acetate. The median time to peak weight during megestrol acetate treatment was 14 weeks. Seven patients returned to within 1 kg of their normal body weight. In three of the 22 patients treated, megestrol acetate and zidovudine were started simultaneously. For these three patients, weight gain was potentially due to the recognized weight gain associated with the initiation of zidovudine. For the remaining 18 patients, however, appetite stimulation and weight gain were a result of megestrol acetate. All patients tolerated the drug well. One patient developed a deep vein thrombosis. No patient developed peripheral edema or drug-related impotence. The appetite improvement and weight gain seen in this initial series are encouraging. The true effectiveness of megestrol acetate for HIV-related cachexia and the effects of treatment on quality of life are currently being assessed in a national prospective, randomized, double-blind, placebo-controlled trial.

Quantitative estrogen and progesterone receptor levels related to progression-free interval in advanced breast cancer patients treated with megestrol acetate or tamoxifen.

Estrogen receptor (ER) and progesterone receptor (PgR) levels have been reported to have prognostic significance with respect to disease-free survival in early-stage breast cancer patients. The current retrospective study was undertaken to determine whether ER and PgR levels, as well as other potential prognostic factors, might be related to a progression-free interval (PFI) during additive hormonal therapy in advanced-stage breast cancer patients. Eligibility requirements for this study included the following: histologically confirmed recurrent or metastatic breast cancer, known quantitative ER and PgR levels, postmenopausal status, treatment with either megestrol acetate or tamoxifen, and Eastern Cooperative Oncology Group (ECOG) performance status less than or equal to 2. The characteristics of the 105 patients included in these analyses were as follows: median age, 62 years; median disease-free interval (DFI), 523 days; median ER level, 44 fmol/mg; median PgR level, 52 fmol/mg; soft tissue-dominant disease, 37 patients (35%); bone-dominant disease, 36 patients (34%); visceral-dominant disease, 32 patients (31%); one site of disease, 60 patients (58%); two or more sites of disease, 45 patients (42%); treatment with megestrol acetate, 62 patients (59%); treatment with tamoxifen, 43 patients (41%). All of the independent variables listed immediately above were included in a multiple linear regression analysis in which PFI, expressed as log PFI, was the dependent variable. In this analysis, a positive linear relationship was observed between log PFI and the following independent variables: log ER, log PgR, and age (r2 = 0.329). An alternative model (r2 = 0.350) was derived, in which previous treatment with chemotherapy was negatively related to log PFI. However, it appears that previous treatment with chemotherapy could be a "proxy variable," because patients who had been treated with chemotherapy previously were significantly younger and had significantly lower ER (P = 0.0001) and PgR levels (P = 0.0004). None of the other independent variables were included in these models. If the assumption that PFI is a measure of the effectiveness of hormonal therapy is true, these results suggest that quantitative ER and PgR levels and age supersede other traditional predictor variables in predicting the hormonal responsiveness of individual breast carcinoma.(ABSTRACT TRUNCATED AT 400 WORDS)

Megestrol acetate as primary hormonal therapy for advanced breast cancer.

The records of 133 patients treated with megestrol acetate as primary hormonal therapy for advanced breast cancer were reviewed retrospectively, using International Union Against Cancer (UICC) criteria for response. The median age was 65 years, 121 patients were over age 50, and the age range was 39 to 94 years. Response rates (complete response [CR] + partial response [PR]/total) by qualitative receptor level, with levels of 10 fmol/mg of protein considered positive, were as follows (ER = estrogen receptor, PgR = progesterone receptor): For ER + PgR+, 13 + 15/56 (50%); for those with one positive receptor, 0 + 12/47 (26%); for ER - PgR-, 0 + 0/12 (0%); and for receptor-unknown cases, 2 + 3/18 (14%). Response for ER less than 30 fmol/mg was 2 + 6/39 (21%); for ER 30 to 50, 1 + 5/16 (40%); and for ER greater than 50 fmol/mg, 11 + 15/56 (46%). For PgR less than 30, response was 0 + 6/37 (16%); for PgR 30 to 50 fmol/mg, 1 + 4/14 (36%); and for PgR greater than 50 fmol/mg, 12 + 13/54 (46%). For the 75 patients with a disease-free interval (DFI) of 2 years or less, the response rate was 5 + 1/75 (8%), and for the 58 patients with DFI greater than 2 years, 10 + 12/60 (37%). For patients with prior chemotherapy, 3 + 8/49 (22%) had an objective response. For those with no prior chemotherapy, 12 + 19/84 (37%) responded. Response by dominant site of disease was as follows: soft tissue 12 + 9/43 (49%), bone 2 + 13/49 (31%), viscera 2 + 5/41 (17%). Of these seven patients with visceral dominant disease who responded, all had PgR levels greater than 50 fmol/mg, all but one had an ER level over 100 fmol/mg, all but one were over age 65, and all but two received no prior chemotherapy. We conclude that megestrol acetate is effective initial hormonal therapy for patients with advanced breast cancer. It may have some role to play in the treatment of carefully selected cases with visceral disease.

Sequential hormone therapy for advanced breast cancer.

Sequential hormone therapy for advanced breast cancer can offer significant and prolonged disease control with minimal morbidity. Predictors of response to sequential hormone therapy have not previously been identified. Sixty postmenopausal women with advanced or recurrent breast cancer treated with sequential megestrol acetate and tamoxifen were evaluated to identify factors which predict response to sequential therapy. The response rate to first-line therapy was 28% (17/60). Forty-seven percent of patients who responded to the first therapy responded to the second (8/17). Four of 16 patients (25%) who failed the first hormone therapy responded to the second. The response rate to a second hormone therapy was 25% (15/60). Chi-square tests were used to test the association between a response to sequential hormonal therapy and prior chemotherapy, age at first hormone trial, number of sites of disease, dominant site of disease, sequence of hormonal therapy, second response on the basis of first response, presence of soft tissue disease or bone disease alone, and receptor value. A one-tailed Fisher exact probability test revealed that a greater proportion of receptor-positive patients exhibited positive responses to sequential hormonal therapies than did receptor-negative patients. All of the patients who responded to a second hormonal therapy were estrogen receptor (ER)- and progestogen receptor (PgR)-positive. Fisher exact probability tests revealed a statistically significant association between response to initial hormone therapy and response to a subsequent hormone trial. This study suggests that patients who fail their initial hormone trial should be considered for a second hormonal trial if they are ER- and PR-positive.

Management of HIV-related bodyweight loss.

Involuntary bodyweight loss is a frequent manifestation of HIV infection and ultimately affects the majority of patients. Because it portends a poor prognosis and adversely affects quality of life, nutritional intervention has an important role in the care of all HIV-infected persons. The mechanism of HIV-related bodyweight loss is multifactorial and includes complex interactions between decreased caloric intake, malabsorption and metabolic and/or hormonal abnormalities. Treatment of reversible and identifiable causes of bodyweight loss such as opportunistic infections and adverse effects of therapy are essential for the maintenance of bodyweight. For patients with anorexia of unclear aetiology, there are effective appetite stimulants available. Enteral and parenteral alimentation are under evaluation for their role in maintenance and/or repletion of bodyweight for patients with HIV infection.

Topical treatment of cutaneous lesions of acquired immunodeficiency syndrome-related Kaposi sarcoma using alitretinoin gel: results of phase 1 and 2 trials.

OBJECTIVE: To evaluate the efficacy and safety of topical alitretinoin gel (9-cis-retinoic acid [LGD1057], Panretin gel; Ligand Pharmaceuticals, Inc, San Diego, Calif) in cutaneous Kaposi sarcoma (KS). DESIGN: Open-label, within-patient, controlled, dose-escalating phase 1 and 2 clinical trials. In all patients, 1 or more cutaneous KS lesions were treated with alitretinoin gel, and at least 2 other lesions served as untreated controls for up to 16 weeks. Alitretinoin (0.05% or 0.1% gel) was applied twice daily for the first 2 weeks and up to 4 times daily thereafter, if tolerated. SETTING: Nine academic clinical centers. PATIENTS: One hundred fifteen patients with biopsy-proven acquired immunodeficiency syndrome (AIDS)-related KS. MAIN OUTCOME MEASURES: AIDS Clinical Trials Group response criteria. RESULTS: Statistically significant clinical responses were observed in 31 (27%) of 115 patients for the group of treated index lesions compared with 13 (11%) for the group of untreated control lesions (P<.001). Responses occurred with low CD4(+) lymphocyte counts (<200 cells/microL) and in some patients with refractory response to previous systemic anti-KS therapy. The incidence of disease progression was significantly lower for treated index lesions compared with untreated control lesions (39/115 [34%] vs 53/115 [46%]; P =.02). Alitretinoin gel generally was well tolerated, with 90% of treatment-related adverse events confined to the application site and only mild or moderate in severity. CONCLUSIONS: Alitretinoin gel has significant antitumor activity as a topical treatment for AIDS-related KS lesions, substantially reduces the incidence of disease progression in treated lesions, and is generally well tolerated.

Anorexia/cachexia in patients with HIV: lessons for the oncologist.

Early intervention and attention to nutritional status are essential in patients with cachexia. Identification of reversible causes of decreased energy intake and/or weight loss is the first step in treatment. When such factors cannot be identified, pharmacologic interventions should be considered. To date, megestrol acetate is the most effective appetite stimulant. Appetite and weight gain occur to a greater and more rapid degree as megestrol dose increases. Unfortunately, the weight gain is due predominantly to an increase in fat mass. Whether this is due to a lack of exercise in the face of increased caloric intake and/or to the hypogonadal effects of megestrol acetate is being tested in ongoing clinical trials. Anabolic agents, particularly growth hormone, are exciting potential therapies. No data are yet available on alternate doses and schedules of growth hormone or on its effect in patients with decreased oral intake. Current studies addressing combination therapy with anabolic agents and appetite stimulants should clarify their respective therapeutic roles.

Metastatic breast carcinoma in pleural fluid. Correlation of morphology with estrogen receptor activity and morphology of the primary carcinoma.

Sixty-nine breast carcinoma patients with malignant pleural effusions were studied (1) to compare the morphology of the carcinoma cells in the effusions with the morphology in the primary carcinomas and (2) to correlate the morphologic findings with the estrogen receptor (ER) activity of the carcinomas and with the survival of the patients. Twenty-six patients had effusions containing carcinoma cells forming hollow spheres (morula-positive cases) while 43 had pleomorphic tissue fragments or tumor giant cells or both (morula-negative cases). Twenty-nine of 44 primary carcinomas with hormone receptor determination were ER positive. The median survival of patients with ER-positive tumors was 77 months while the median survival of ER-negative patients was 46 months. Thirteen patients with morula-positive effusions and 16 patients with morula-negative effusions had ER-positive primary carcinomas (P less than .001). Thirteen of 17 patients with morula-positive effusions and 4 of 23 patients with morula-negative effusions had duct or tubule formation in their primary carcinomas (P less than .001). The median survival of 26 patients with morula-positive effusions was 92 months, compared with 49 months for 43 patients with morula-negative effusions (P less than .001). Patients with ER-positive/morula-negative carcinomas had a significantly better survival rate than did patients with ER-negative/morula-negative carcinomas, but a significantly poorer survival rate than did patients with morula-positive carcinomas.

AIDS and palliative medicine: medical treatment issues.

Caring for patients with AIDS in hospice programs presents numerous challenges. These go beyond the strictly medical decisions discussed in this article to include unique problems with social support, emotional support, and bereavement. This discussion centers on medical issues as they are commonly encountered. They can be stumbling blocks, or even surrogates, for addressing the other important issues at the end of life. Communication between all people involved in the multidisciplinary treatment of these patients is essential. Common goals should be identified and general approaches agreed upon among the physicians, nurses (clinic, hospice, home care), therapists, clergy, and volunteers. In this way we feel that the principles of hospice and palliative care can be effectively applied to most patients with endstage AIDS.

AIDS and hospice.

Which AIDS patients should be admitted to hospice programs? Many health care professionals feel that any anti-viral drug or treatment directed against the opportunistic infections characteristic of AIDS to be incompatible with hospice philosophy. Others argue that inclusion of AIDS patients blurs the distinction between hospice and community service programs. We argue that achieving consensus on this issue is best served by focusing on the defining characteristic of hospice programs--the care of the dying. Consensus is not served by dwelling on the specific palliative or supportive measures used to achieve the hospice goal. We suggest a framework by which AIDS patients may be accommodated in existing hospice programs while maintaining hospice program integrity. It is further suggested that these may be used for the consideration of any patient for hospice care.

Hospice and palliative care: attitudes and practices of the physician faculty of an academic hospital.

It has been suggested that physicians, particularly in academic hospitals, are resistant to the hospice approach to palliative care for terminally ill patients. It is of interest, therefore, to assess the attitudes and practices of the physician faculty of an academic hospital where a hospice program has been in existence for more than 10 years. This was assessed with two faculty surveys. All 966 physician faculty that were on staff at Northwestern Memorial Hospital in the fall of 1993 were sent a survey about their opinion of hospice care (Survey A). Then, all physicians who had referred patients to the hospice program between September 1993 and September 1994 at Northwestern Memorial Hospital received a survey letter after the death of their patient (Survey B). Seventy-seven percent of faculty physician respondents to Survey A had either referred patients, or knew of colleagues who had referred patients to a hospice program. Ninety-four percent of those who answered "yes" to the question about referrals reported satisfaction with their care. Ninety-four percent would refer patients in the future and 96 percent thought the hospice program was a valuable resource to the medical center. Of the respondents to Survey B, nearly 100 percent thought the referral had been handled in an "excellent" or "good" fashion, that communication with hospice staff was "excellent" or "good," that symptom control was "excellent" or "good," that their patients and families had received "excellent" or "good" psychosocial support, and that their patients and families were satisfied with the hospice care they received.(ABSTRACT TRUNCATED AT 250 WORDS)