AAV9-Stathmin1 gene delivery improves disease phenotype in an intermediate mouse model of spinal muscular atrophy.

Spinal muscular atrophy (SMA) is a devastating infantile genetic disorder caused by the loss of survival motor neuron (SMN) protein that leads to premature death due to loss of motor neurons and muscle atrophy. The approval of an antisense oligonucleotide therapy for SMA was an important milestone in SMA research; however, effective next-generation therapeutics will likely require combinatorial SMN-dependent therapeutics and SMN-independent disease modifiers. A recent cross-disease transcriptomic analysis identified Stathmin-1 (STMN1), a tubulin-depolymerizing protein, as a potential disease modifier across different motor neuron diseases, including SMA. Here, we investigated whether viral-based delivery of STMN1 decreased disease severity in a well-characterized SMA mouse model. Intracerebroventricular delivery of scAAV9-STMN1 in SMA mice at P2 significantly increased survival and weight gain compared to untreated SMA mice without elevating Smn levels. scAAV9-STMN1 improved important hallmarks of disease, including motor function, NMJ pathology and motor neuron cell preservation. Furthermore, scAAV9-STMN1 treatment restored microtubule networks and tubulin expression without affecting tubulin stability. Our results show that scAAV9-STMN1 treatment improves SMA pathology possibly by increasing microtubule turnover leading to restored levels of stable microtubules. Overall, these data demonstrate that STMN1 can significantly reduce the SMA phenotype independent of restoring SMN protein and highlight the importance of developing SMN-independent therapeutics for the treatment of SMA.

Survival follow-up and ipilimumab retreatment of patients with advanced melanoma who received ipilimumab in prior phase II studies.

BACKGROUND: This report provides a survival update at a follow-up of >5 years (5.5-6 years) for patients with advanced melanoma who previously received ipilimumab in phase II clinical trials. Safety and efficacy data following ipilimumab retreatment are also reported. PATIENTS AND METHODS: Patients who previously received ipilimumab 0.3, 3, or 10 mg/kg in one of six phase II trials (CA184-004, CA184-007, CA184-008, CA184-022, MDX010-08, and MDX010-15) were eligible to enroll in the companion study, CA184-025. Upon enrollment, patients initially received ipilimumab retreatment, extended maintenance therapy, or were followed for survival only. Overall survival (OS) rates were evaluated in patients from studies CA184-004, CA184-007, CA184-008, and CA184-022. Safety and best overall response during ipilimumab retreatment at 10 mg/kg were assessed in study CA184-025. RESULTS: Five-year OS rates for previously treated patients who received ipilimumab induction at 0.3, 3, or 10 mg/kg were 12.3%, 12.3%-16.5%, and 15.5%-28.4%, respectively. Five-year OS rates for treatment-naive patients who received ipilimumab induction at 3 or 10 mg/kg were 26.8% and 21.4%-49.5%, respectively. Little to no change in OS was observed from year 5 up to year 6. The objective response rate among retreated patients was 23%. Grade 3/4 immune-related adverse events occurred in 25%, 5.9%, and 13.2% of retreated patients who initially received ipilimumab 0.3, 3, and 10 mg/kg, with the most common being observed in the skin (4.2%, 2.9%, 3.8%) and gastrointestinal tract (12.5%, 2.9%, 3.8%), respectively. CONCLUSIONS: At a follow-up of 5-6 years, ipilimumab continues to demonstrate durable, long-term survival in a proportion of patients with advanced melanoma. In some patients, ipilimumab retreatment can re-establish disease control with a safety profile that is comparable with that observed during ipilimumab induction. Further studies are needed to determine the contribution of ipilimumab retreatment to OS. CLINICALTRIALSGOV: NCT00162123.

Efficacy and safety of ipilimumab in metastatic melanoma patients surviving more than 2 years following treatment in a phase III trial (MDX010-20).

BACKGROUND: In a phase III trial (ClinicalTrials.gov registration ID: NCT00094653), ipilimumab significantly improved survival versus a vaccine control in pretreated patients with metastatic melanoma. Here, we characterize outcomes of those patients who survived ≥ 2 years. METHODS: Patients were randomized (3 : 1 : 1) to receive ipilimumab 3 mg/kg + gp100 vaccine, ipilimumab 3 mg/kg + placebo, or gp100 vaccine alone. Baseline demographic data, duration of survival, responses, and safety among patients with ≥ 2 years' survival were analyzed. RESULTS: Among 676 randomized patients, 474 and 259 patients had at least 2 or 3 years of potential follow-up, respectively, and were eligible for analysis. Among these, 94 (20%) and 42 (16%) survived ≥ 2 and ≥ 3 years, respectively. Survival rates at 2 and 3 years were 25% (24 of 95) and 25% (13 of 53) with ipilimumab alone and 19% (54 of 284) and 15% (24 of 156) with ipilimumab plus gp100. Safety among patients with ≥ 2 years' survival was comparable with the overall study population, with the onset of new ipilimumab-related toxic effect (all grades) reported in 6 of 78 (8%) patients. CONCLUSIONS: Ipilimumab results in survival of ≥ 2 years in one-fifth of pretreated patients with 2 years potential follow-up in a phase III trial. New onset, low-grade events starting after administration of the last dose were infrequent. TRIAL REGISTRATION ID: NCT00094653.

A randomised, phase II study of intetumumab, an anti-αv-integrin mAb, alone and with dacarbazine in stage IV melanoma.

BACKGROUND: α(v) integrins are involved in angiogenesis and melanoma tumourigenesis. Intetumumab (CNTO 95) is a fully human anti-α(v)-integrin monoclonal antibody. METHODS: In a multicentre, randomised, phase II study, stage IV melanoma patients were randomised 1:1:1:1 to 1000 mg m(-2) dacarbazine+placebo (n=32), 1000 mg m(-2) dacarbazine+10 mg kg(-1) intetumumab (n=32), 10 mg kg(-1) intetumumab (n=33), or 5 mg kg(-1) intetumumab (n=32) q3w. The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS), objective response rate (ORR), adverse events, and pharmacokinetics. RESULTS: No statistically significant differences in efficacy were observed between groups. In the dacarbazine+placebo, dacarbazine+intetumumab, 10 mg kg(-1) intetumumab, and 5 mg kg(-1) intetumumab groups, median PFS was 1.8, 2.5, 1.4, and 1.4 months; median OS was 8, 11, 15, and 9.8 months; and ORR of complete+partial response was 10, 3, 6, and 0%. Nonlinear intetumumab pharmacokinetics and potential intetumumab-dacarbazine interactions were observed. Transient, asymptomatic, nonrecurring, grade 1-2, uveitic reactions that resolved spontaneously or with topical steroids were seen in 22-30% of intetumumab-treated patients. Low-grade infusion-reaction symptoms (headache, fatigue, nausea, vomiting, fever, chills) were observed, as expected, in 16-73% of dacarbazine-treated patients. No intetumumab-related myelosuppression, laboratory/electrocardiogram abnormalities, or deaths occurred. CONCLUSION: With its favourable safety profile and a nonsignificant trend towards improved OS, intetumumab merits further investigation in advanced melanoma.

Efficacy and safety of ipilimumab monotherapy in patients with pretreated advanced melanoma: a multicenter single-arm phase II study.

BACKGROUND: This phase II study evaluated the safety and activity of ipilimumab, a fully human mAb that blocks cytotoxic T-lymphocyte antigen-4, in patients with advanced melanoma. PATIENTS AND METHODS: Patients with previously treated, unresectable stage III/stage IV melanoma received 10 mg/kg ipilimumab every 3 weeks for four cycles (induction) followed by maintenance therapy every 3 months. The primary end point was best overall response rate (BORR) using modified World Health Organization (WHO) criteria. We also carried out an exploratory analysis of proposed immune-related response criteria (irRC). RESULTS: BORR was 5.8% with a disease control rate (DCR) of 27% (N = 155). One- and 2-year survival rates (95% confidence interval) were 47.2% (39.5% to 55.1%) and 32.8% (25.4% to 40.5%), respectively, with a median overall survival of 10.2 months (7.6-16.3). Of 43 patients with disease progression by modified WHO criteria, 12 had disease control by irRC (8% of all treated patients), resulting in a total DCR of 35%. Adverse events (AEs) were largely immune related, occurring mainly in the skin and gastrointestinal tract, with 19% grade 3 and 3.2% grade 4. Immune-related AEs were manageable and generally reversible with corticosteroids. CONCLUSION: Ipilimumab demonstrated clinical activity with encouraging long-term survival in a previously treated advanced melanoma population.

Molecular detection of metastatic melanoma cells in cerebrospinal fluid in melanoma patients.

Melanoma frequently metastasizes to the central nervous system (CNS). The diagnosis of CNS metastases typically is made following the onset of clinical symptoms. Thus, more sensitive diagnostic approaches are needed to identify subclinical CNS metastases. Currently, standard cytologic analysis of the cerebrospinal fluid (CSF) is limited by its poor sensitivity. A more sensitive assay was therefore developed using multiple reverse transcriptase-polymerase chain reaction (RT-PCR) markers. CSF was collected and assessed by RT-PCR for three known melanoma-associated markers (MAGE-3, MART-1, and tyrosinase) to detect occult metastatic melanoma cells in the CSF of 37 American Joint Committee on Cancer (AJCC) stage IV melanoma patients. Cytologic analysis of CSF was performed on all patients, and immunohistochemistry (IHC) analysis was performed on 33 CSF samples using anti-S100 and anti-HMB-45 antibodies. Only one patient (3%) had tumor-positive CSF cytology and IHC upon entry into the study, whereas 12 patients (32%) were positive for at least one RT-PCR marker. The correlation between CSF RT-PCR positivity of MART-1 and/or MAGE-3 and the development of CNS metastases at 3 mo was significant (p = 0.04). Fifteen of 37 patients (41%) had either positive MRI and/or positive RT-PCR results. Multimarker RT-PCR is more informative and sensitive than cytology/IHC in assessing the CSF of melanoma patients.

High-dose tamoxifen added to concurrent biochemotherapy with decrescendo interleukin-2 in patients with metastatic melanoma.

BACKGROUND: In vitro cell culture data and preclinical models suggest that tamoxifen modulates tumor cell sensitivity to a wide range of therapeutic agents. In the current study, the authors examined whether high-dose tamoxifen (HDT) improved the overall and complete response in patients with metastatic melanoma who were treated with concurrent biochemotherapy. METHODS: Forty-nine patients were treated with a biochemotherapy regimen of dacarbazine, vinblastine, cisplatin, decrescendo interleukin-2, interferon-alpha-2b, and tamoxifen. The study had a 2-step design, beginning with a tamoxifen dose escalation from 40 mg to 320 mg (17 subjects) to evaluate safety and tolerability, followed by Phase II accrual of 32 patients to HDT (320 mg) to assess clinical efficacy. Efficacy was compared with a similar modified biochemotherapy regimen with low-dose tamoxifen (LDT). Pharmacokinetic studies were performed to determine in vivo tamoxifen levels. RESULTS: Tamoxifen dose escalation was completed without any reported dose-limiting toxicity. The overall response rate in the HDT group was 50% (95% confidence interval, 33.2%-66.8%), with a complete response rate of 6% and a median survival of 9.5 months. The overall response rate was not improved and the complete response and survival appeared inferior compared with that of patients recently treated with concurrent biochemotherapy and LDT. Serum tamoxifen levels were found to correlate with the dose administered, with a mean of 0.9 microM at the 40-mg dose to 4.6 microM at the 320-mg dose. Ultrafiltered protein-free sera demonstrated low (< 0.01 microM) concentrations of tamoxifen. CONCLUSIONS: The addition of HDT to a regimen of concurrent biochemotherapy did not appear to improve response rates or overall survival, despite reaching the targeted plasma concentration. Unknown drug interactions or high protein binding of tamoxifen may account for the lack of clinical effectiveness.

Interleukin-2 binds to ganglioside GD(1b).

We have developed a solid matrix immunoassay to determine the binding of interleukin-2 (IL-2) to specific gangliosides. The assay establishes that recombinant human IL-2 binds to ganglioside GD(1b) but not to any other gangliosides (GM(1), GM(2), GM(3), GD(1a), GD(2), GD(3), and GT(1b)). The binding varies with the ratio of GD1b and IL-2. This assay enables distinguishing the nature of the sugar moiety of the ganglioside recognized by IL-2 and establishes the dosimetry of the ganglioside-IL-2 interaction. Since rIL-2 is administered systematically into stage IV melanoma patients, we have examined 45 tumor biopsies for GD(1b) content. The incidence of GD(1b) in tumor biopsies is 51%. We postulate that GD(1b) associated on the tumor or in the circulation of cancer patients may bind to rIL-2 and prevent the availability of rIL-2 to augment antitumor-immune response.

Intrathecal treatment of neoplastic meningitis due to breast cancer with a slow-release formulation of cytarabine.

DepoCyte is a slow-release formulation of cytarabine designed for intrathecal administration. The goal of this multi-centre cohort study was to determine the safety and efficacy of DepoCyte for the intrathecal treatment of neoplastic meningitis due to breast cancer. DepoCyte 50 mg was injected once every 2 weeks for one month of induction therapy; responding patients were treated with an additional 3 months of consolidation therapy. All patients had metastatic breast cancer and a positive CSF cytology or neurologic findings characteristic of neoplastic meningitis. The median number of DepoCyte doses was 3, and 85% of patients completed the planned 1 month induction. Median follow up is currently 19 months. The primary endpoint was response, defined as conversion of the CSF cytology from positive to negative at all sites known to be positive, and the absence of neurologic progression at the time the cytologic conversion was documented. The response rate among the 43 evaluable patients was 28% (CI 95%: 14-41%); the intent-to-treat response rate was 21% (CI 95%: 12-34%). Median time to neurologic progression was 49 days (range 1-515(+)); median survival was 88 days (range 1-515(+)), and 1 year survival is projected to be 19%. The major adverse events were headache and arachnoiditis. When drug-related, these were largely of low grade, transient and reversible. Headache occurred on 11% of cycles; 90% were grade 1 or 2. Arachnoiditis occurred on 19% of cycles; 88% were grade 1 or 2. DepoCyte demonstrated activity in neoplastic meningitis due to breast cancer that is comparable to results reported with conventional intrathecal agents. However, this activity was achieved with one fourth as many intrathecal injections as typically required in conventional therapy. The every 2 week dose schedule is a major advantage for both patients and physicians.

The clinical utility of multimarker RT-PCR in the detection of occult metastasis in patients with melanoma.

Cutaneous melanoma is characterized by a high propensity for metastasis. Currently, surgical intervention remains the mainstay of therapy. This approach has proven most beneficial when the diagnosis is of early stage primary lesions. Likewise, patients undergoing resection for a solitary site of metastasis have shown a survival advantage. Identification of metastatic disease depends predominantly on radiographic techniques requiring the presence of significant tumor burdens for successful imaging. However, at that time, the role of surgery and/or biochemotherapy may be of limited value. Techniques to identify minimal disease states may permit more accurate assessment of prognosis. The detection of occult tumor cells by RT-PCR in the blood, lymph nodes, and bone marrow of melanoma patients provides one such approach to monitor tumor progression. Single-marker RT-PCR has been used as one such approach but is noted to have limitations in sensitivity and specificity based on the heterogeneity of tumor marker expression among tumors as well as within an individual tumor lesion or among multiple lesions in individual patients. We employed a multimarker reverse transcriptase polymerase chain reaction assay that demonstrates improved sensitivity over a single-marker approach. Currently, the consequences of detecting systemic subclinical metastasis remain unknown pending longer-term follow-up. The detection of occult melanoma cells using molecular techniques in conjunction with known clinicopathologic prognostic factors may provided a novel and efficient approach in monitoring tumor progression and further identify high-risk patients diagnosed early in the disease course.

Stereotactic radiosurgery in the treatment of metastatic disease to the brain.

OBJECTIVE: In recent years, stereotactic radiosurgery has been growing in popularity as a treatment modality for metastatic disease to the brain. The technique has advantages of reduced cost and low morbidity compared with open surgical treatment. Furthermore, it avoids the potential cognitive side effects of fractionated whole-brain radiotherapy. We undertook this study to determine the usefulness of adjuvant radiation therapy and to determine prognostic factors in patients treated with stereotactic radiosurgery. METHODS: We reviewed our series of patients with metastatic tumors treated using gamma knife stereotactic radiosurgery from August 1994 to February 1999. Nonparametric methods were used to compare treatment subgroups by demographic features including age, Karnofsky Performance Scale score, diagnosis, and systemic disease status. Univariate and multivariate analyses of survival and freedom from progression were performed using Kaplan-Meier and Cox proportional hazards regression techniques. RESULTS: This study included 190 patients harboring 431 lesions who were treated in 263 treatment sessions. The median follow-up after radiosurgery was 36 weeks for all patients. The median actuarial survival from the time of radiosurgery in all patients was 34 weeks. When patients were stratified according to tumor histology, those without melanoma had a median survival of 39 weeks, and those with melanoma had a median survival of 28 weeks. The cause of death could be determined in 122 (92%) of the patients known to have died during the data capture period. For patients harboring melanoma, death was attributable to systemic disease in 31 (47%), to central nervous system-related processes in 29 (44%), and to unknown causes in 6 (9%). For non-melanoma patients, death was attributable to systemic disease in 45 (68%), to central nervous system-related processes in 17 (26%), and to unknown causes in 4 (6%). Significantly improved survival (P = 0.002) was observed in patients with controlled systemic disease. No significant difference in survival could be ascertained for patients presenting with up to four lesions, although patients with a total tumor volume greater than 9 cc had shortened survival. No survival benefit could be demonstrated for whole-brain radiotherapy administered either concomitantly or after radiosurgery. CONCLUSION: Factors correlated with significantly improved survival included controlled systemic disease and non-melanoma histology. We found no significant survival benefit that could be discerned from adjuvant whole-brain radiotherapy in this patient group.

Advantages of concurrent biochemotherapy modified by decrescendo interleukin-2, granulocyte colony-stimulating factor, and tamoxifen for patients with metastatic melanoma.

PURPOSE: Concurrent biochemotherapy results in high response rates but also significant toxicity in patients with metastatic melanoma. We attempted to improve its efficacy and decrease its toxicity by using decrescendo dosing of interleukin-2 (IL-2), posttreatment granulocyte colony-stimulating factor (G-CSF), and low-dose tamoxifen. PATIENTS AND METHODS: Forty-five patients with poor prognosis metastatic melanoma were treated at a community hospital inpatient oncology unit affiliated with the John Wayne Cancer Institute (Santa Monica, CA) between July 1995 and September 1997. A 5-day modified concurrent biochemotherapy regimen of dacarbazine, vinblastine, cisplatin, decrescendo IL-2, interferon alfa-2b, and tamoxifen was repeated at 21-day intervals. G-CSF was administered beginning on day 6 for 7 to 10 days. RESULTS: The overall response rate was 57% (95% confidence interval, 42% to 72%), the complete response rate was 23%, and the partial response rate was 34%. Complete remissions were achieved in an additional 11% of patients by surgical resection of residual disease after biochemotherapy. The median time to progression was 6.3 months and the median duration of survival was 11.4 months. At a maximum follow-up of 36 months (range, 10 to 36 months), 32% of patients are alive and 14% remain free of disease. Decrescendo IL-2 dosing and administration of G-CSF seemed to reduce toxicity, length of hospital stay, and readmission rates. No patient required intensive care unit monitoring, and there were no treatment-related deaths. CONCLUSION: The data from this study indicate that the modified concurrent biochemotherapy regimen reduces the toxicity of concurrent biochemotherapy with no apparent decrease in response rate in patients with poor prognosis metastatic melanoma.

A Phase II study of adjuvant therapy with anti-B4-blocked ricin after autologous bone marrow transplantation for patients with relapsed B-cell non-Hodgkin's lymphoma.

This Phase II trial was undertaken to determine the safety, toxicity, and potential efficacy of the B-cell restricted immunotoxin anti-B4-blocked ricin (Anti-B4-bR) when administered as adjuvant therapy to patients in complete remission (CR) after autologous bone marrow transplantation (ABMT) for B-cell non-Hodgkin's lymphoma (NHL). Forty-nine patients with B-cell NHL in CR 46-202 days (median, 112 days) post-ABMT received Anti-B4-bR at a dose of 30 microg/kg lean body weight/day for 7 days by continuous i.v. infusion. Patients were eligible for up to two additional courses of therapy at 14-day intervals. A total of 83 courses of Anti-B4-bR were administered, with 31 patients receiving two or more courses of therapy. The mean serum level on day 7 of the first course was 0.77+/-0.41 nM. Reversible toxicities included hepatic transaminase elevations, thrombocytopenia, myalgias, fatigue, nausea, hypoalbuminemia, and dyspnea. Human antimouse antibody (HAMA) and/or human antiricin antibody (HARA) responses occurred in 23 patients at a median of 22 days from the initiation of Anti-B4-bR therapy (range, 11-100 days). The 4-year disease-free survival and overall survival are estimated at 56 and 72%, respectively. Twenty-six patients remain in CR after a median follow-up of 54.5 months. This study demonstrates that Anti-B4-bR can be administered safely to patients as adjuvant therapy early after ABMT for B-cell NHL. The toxicities are tolerable and reversible. Although the early estimate of disease-free survival was very encouraging in this single-armed trial, the 4-year follow-up data demonstrate continued relapse.

Gamma knife radiosurgery for metastatic melanoma: an analysis of survival, outcome, and complications.

OBJECTIVE: Although the mainstays for treatment of metastatic brain disease have been surgery and/or external beam radiation therapy, an increasing number of patients are being referred for stereotactic radiosurgery as the primary intervention for their intracranial pathological abnormalities. The lack of efficacy and cognitive and behavioral consequences of whole brain irradiation have prompted clinicians to select patients for alternative therapies. This study analyzes the effectiveness of Leksell gamma unit therapy for metastatic melanoma to the brain. METHODS: We present our experience with 59 Leksell gamma unit treatment sessions in 45 consecutive patients who presented with metastatic melanoma to the brain. Five of these procedures were performed as salvage therapy for patients who needed second radiosurgical treatment for new lesions that were remote from the previous targets and were not included in the overall analyses. RESULTS: The population included 78% male patients. The mean patient age was 53 years (age range, 24-80 yr). The mean time from diagnosis of primary melanoma to discovery of brain metastasis was 43 months (median, 27.5 mo; range, 1-180 mo). At the time of diagnosis of brain disease, 35.5% of the patients (16 of 45 patients) had neurological symptoms, 77.7% (35 of 45 patients) had known visceral metastases, and 11.1% (5 of 45 patients) had seizure disorders. Eighty-six percent of the lesions (80 of 93 lesions) were cortical, 12% (11 of 93 lesions) were cerebellar, 1% (1 of 93 lesions) were pontine, and 1% (1 of 93 lesions) were thalamic. Fifty-seven percent of the sessions (31 of 54 sessions) were performed for a single lesion, 24.1% (13 of 54 sessions) for two lesions, 9.2% (5 of 54 sessions) for three lesions, 7.4% (4 of 54 sessions) for four lesions, and 1.8% (1 of 54 sessions) for five lesions. The mean treatment volume was 5.6 cc, with a mean prescription of 21.6 Gy to the 56.0% mean isodose line. The median survival time of the patients in our population, using Kaplan-Meier curves, was 43 months from the time of diagnosis of primary melanoma (range, 3-180 mo) and 8 months (range, 1-20 mo) from the time of gamma knife treatment. Complications included seizures within 24 hours of the procedure in four patients, with transient nausea and vomiting in three patients, transient worsening of preprocedure paresis responsive to steroids in three patients, and increased confusion in one patient. All 45 patients were located for follow-up (mean follow-up duration, 1 yr). After gamma knife treatment, 78% of the patients (35 of 45 patients) experienced either improved or stable neurological symptomatology before death or at the time of the latest follow-up examination. There were 26 deaths (58%). The cause of death was determined to be neurological in only 2 of 45 patients (7.7%). Follow-up magnetic resonance images revealed a 97% local tumor control rate of gamma knife-treated lesions, with 28% radiographic disappearance (9 of 32 cases). Six patients developed new lesions remote from radiosurgical targets and underwent second procedures. CONCLUSION: Although metastatic melanoma to the brain continues to have a foreboding prognosis for long-term survival, gamma knife radiosurgery seems to be a relatively safe, noninvasive, palliative therapy, halting or reversing neurological progression in 77.8% of treated patients (35 of 45 patients). The survival rate matches or exceeds those previously reported for surgery and other forms of radiotherapy. Only 7.7% of the patients in our study population who died as a result of metastatic melanoma (2 of 26 patients) died as a result of neurological disease. The routine use of therapeutic level antiseizure medication is emphasized, considering the findings of our review.

Stereotactic radiosurgery in the treatment of metastatic disease to the brain.

We review 190 consecutive patients with 434 metastatic tumors treated by gamma knife stereotactic radiosurgery, from August 1994 to February 1999. Median actuarial survival for all patients was 34 weeks. Factors correlated with significantly improved survival included controlled systemic disease and nonmelanoma histology. We found that no significant survival benefit could be discerned from adjuvant whole brain radiotherapy in this patient group. Survival was not statistically different for patients initially presenting with 1-4 metastases at initial treatment.

Phase II clinical trial of bolus infusion anti-B4 blocked ricin immunoconjugate in patients with relapsed B-cell non-Hodgkin's lymphoma.

Immunotoxins, composed of a monoclonal antibody conjugated to a protein toxin, mediate cell death through novel cytotoxic mechanisms. Anti-B4-blocked ricin (anti-B4-bR) recognizes CD19-positive cells, which includes most B-cell non-Hodgkin's lymphomas (NHLs). Previous Phase I clinical studies of anti-B4-bR, using both bolus and continuous dosing regimens, demonstrated no safety or efficacy advantage to the continuous infusion regimen. This Phase II trial in 16 patients with relapsed CD19-positive NHL was conducted to evaluate the efficacy of anti-B4-bR when administered at the previously established maximum tolerated dose using a daily bolus for a 5 consecutive days schedule. Serum pharmacokinetics were measured in selected patients. Tissue samples of involved lymph nodes and bone marrow were also obtained from a portion of patients for determination of anti-B4-bR penetration into tissues. Toxicity was similar to what has been described previously for anti-B4-bR and consisted mainly of reversible elevations of hepatic transaminases and mild to moderate thrombocytopenia. No sustained clinical responses were documented. Pharmacokinetic measurements demonstrated that serum levels compatible with 3 logs of cell kill in vitro could be sustained for several hours in most patients. Immunohistochemical analysis of tissue samples provided some insight into the low efficacy. The immunotoxin could be detected in three of the four bone marrow aspirate samples but in only two of the seven lymph node specimens. Thus, anti-B4-bR, using a single daily bolus for a 5 consecutive day schedule, is not an active agent in relapsed NHL. Poor penetration into certain sites of disease may be one explanation for its lack of efficacy.

Relationship between cancer patients' predictions of prognosis and their treatment preferences.

CONTEXT: Previous studies have documented that cancer patients tend to overestimate the probability of long-term survival. If patient preferences about the trade-offs between the risks and benefits associated with alternative treatment strategies are based on inaccurate perceptions of prognosis, then treatment choices may not reflect each patient's true values. OBJECTIVE: To test the hypothesis that among terminally ill cancer patients an accurate understanding of prognosis is associated with a preference for therapy that focuses on comfort over attempts at life extension. DESIGN: Prospective cohort study. SETTING: Five teaching hospitals in the United States. PATIENTS: A total of 917 adults hospitalized with stage III or IV non-small cell lung cancer or colon cancer metastatic to liver in phases 1 and 2 of the Study to Understand Prognoses and Preferences for Outcomes and Risks of Treatments (SUPPORT). MAIN OUTCOME MEASURES: Proportion of patients favoring life-extending therapy over therapy focusing on relief of pain and discomfort, patient and physician estimates of the probability of 6-month survival, and actual 6-month survival. RESULTS: Patients who thought they were going to live for at least 6 months were more likely (odds ratio [OR], 2.6; 95% confidence interval [CI], 1.8-3.7) to favor life-extending therapy over comfort care compared with patients who thought there was at least a 10% chance that they would not live 6 months. This OR was highest (8.5; 95% CI, 3.0-24.0) among patients who estimated their 6-month survival probability at greater than 90% but whose physicians estimated it at 10% or less. Patients overestimated their chances of surviving 6 months, while physicians estimated prognosis quite accurately. Patients who preferred life-extending therapy were more likely to undergo aggressive treatment, but controlling for known prognostic factors, their 6-month survival was no better. CONCLUSIONS: Patients with metastatic colon and lung cancer overestimate their survival probabilities and these estimates may influence their preferences about medical therapies.

A phase II study of continuous infusion recombinant human granulocyte-macrophage colony-stimulating factor as an adjunct to autologous bone marrow transplantation for patients with non-Hodgkin's lymphoma in first remission.

Recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) clearly hastens myeloid recovery in patients with relapsed hematologic malignancies undergoing autologous bone marrow transplantation (ABMT). In efforts to further improve neutrophil engraftment and shorten hospital stay in ABMT patients, rhGM-CSF was administered by a potentially more potent route (continuous infusion) to non-Hodgkin's lymphoma (NHL) patients with better BM reserve (first remission). Time to myeloid engraftment was compared with that of NHL patients treated in first remission at our institution on a similar ABMT protocol but without growth factor support (controls). Median neutrophil engraftment (absolute neutrophil count, 500 cells/microL) in first remission patients treated with rhGM-CSF was 14 days, compared with 22 days in controls (P = .0001). Hospital stays were also significantly reduced for rhGM-CSF patients (P = .0003). Platelet engraftment did not differ between the two groups. Persistent fever and generalized serositis were the primary toxicities. rhGM-CSF, delivered by this route, was efficacious but more toxic than 2-hour rhGM-CSF infusions previously reported by other investigators. Future alterations in both dose and schedule may retain comparable efficacy yet diminish toxicity.