Search

2006 Background: RTOG protocol 9402 demonstrated improvement in progression-free survival (PFS), but not overall survival (OS) for adult anaplastic oligodendroglioma (O) and oligo-astrocytoma (A) patients (pts) receiving PCV+RT versus (vs) RT alone (Cairncross, JCO 24:2707, 2006). In 1998, a similar study in adult LGG was initiated by RTOG, NCCTG, SWOG, and ECOG. Methods: Eligible criteria: age 40 with any extent of resection, supratentorial WHO grade II A, O, or OA. Pts were stratified by age, histology, KPS, and presence/absence of preop contrast enhancement and randomized to RT alone (54Gy/30 fractions) or RT followed by 6 cycles of standard dose PCV. Reported results include OS rate, median OS time (MOST), PFS rate, median PFS time (MPFST) and hazard ratio (HR). Per study design, survival data are compared using the modified Wilcoxon test (sensitive to early separation of survival curves). The log-rank test (sensitive to late separation of curves) was sub...

6538 Background: Power specifications are a vital characteristic of oncology clinical trials. Preliminary data used in the design phase are of variable quality, although the impact on the eventual power characteristics of the completed trial is unclear. This study examined the relationship between a priori power specifications and preliminary data quality on the actual post hoc power achieved in a series of North Central Cancer Treatment Group (NCCTG) oncology treatment trials. Methods: Sixty-four NCCTG Phase II (52 studies) and Phase III (12 studies) trials were summarized which have had an abstract or a manuscript published since 2000. Fifty-nine studies had power specifications and study characteristics data such as study phase, tumor site, primary endpoint and preliminary data. The post-hoc power was calculated based upon the number of evaluable patients that were available for the primary point of interest. Descriptive statistics, Fisher's exact test, regression modeling and generalized linear modeli...

9515 Background: The significance of baseline QOL as a prognostic factor for survival in oncology clinical trials has been suggested in individual trials. We performed a patient-level meta-analysis...

6520 Background: Categorical tumor response (TR), via the Response Evaluation Criteria in Solid Tumors (RECIST) or previously the WHO criteria, is the historical standard for assessing anti-tumor a...

2004 Background: Vorinostat is a histone deacetylase inhibitor that represents a rational therapeutic target in GBM. Methods: Recurrent GBM patients (pts) having received = 1 prior chemo regimen for progressive disease were eligible. Vorinostat dose was 200 mg bid x 14 days q 3 weeks. We applied a phase II design which had 90% power to declare the regimen active if the study PFS6 rate was 25%, a 15% rate increase over PFS6 in historical controls (10%). Results: 68 patients were treated. Grade 3+ non-hematologic toxicity consisting mainly of fatigue, diarrhea and dehydration occurred in 23% of pts; Grade 3+ hematologic toxicity consisting mainly of thrombocytopenia occurred in 25% of pts. Intra-patient dose escalation to 300 mg bid resulted in higher incidence of grade 3+ thrombocytopenia (45%) and was aborted. Pts receiving enzyme-inducing anticonvulsants (EIAC) had significantly less grade 3 + non-hematologic toxicity (p=0.01) and grade 3/4 thrombocytopenia (p=0.04). Pharmacokinetic analysis showed lower vorninostat C-max and AUC (0–24h) values and higher vorinostat-glucuronide C-max and AUC (0–24h) values in EIAC pts, although this did not reach statistical significance. The trial met the prospectively defined primary efficacy endpoint at the planned interim analysis with 5 of the first 22 patients (23%) being progression-free at 6 mo. RNA array analysis, performed in paired baseline and post-vorinostat treatment samples in a separate subgroup of 5 surgical recurrent GBM pts, who received vorinostat for 6 doses prior to surgery, showed upregulation of E-cadherin (p=0.02), thus indicating a biologic effect of the HDAC inhibitor on the glioblastoma tumors. Histone acetylation, Akt, phospho-Akt, P21Waf1/Cip1 and P27Kip1 expression analysis in all patients and correlation with outcome is ongoing. Conclusions: Vorinostat is well tolerated in recurrent GBM patients. EIAC patients have less toxicity, likely due to increased vorinostat metabolism via glucuronidation. Interim efficacy analysis is indicative of antitumor activity. Final efficacy analysis, RNA array data and correlative tissue analysis will be reported. No significant financial relationships to disclose.

2075 Background: Multiple variables may impact endpoints used to assess therapeutic efficacy for patients with recurrent gliomas. To identify prognostic factors for each of 3 outcome variables, a master analysis file was constructed by pooling datasets summarizing key baseline factors and outcomes obtained in 15 North Central Cancer Treatment Group (NCCTG) trials (n=583, 1980–2004) and 12 North American Brain Tumor Consortium (NABTC) trials (n=596, 1998–2002). Methods: In addition to traditional variables (gender, age, performance score (PS), race, extent of primary resection, year of study entry, last known histology, time since initial diagnosis, baseline steroid use, prior chemotherapy (Y/N), prior nitrosoureas, baseline anticonvulsant use), we investigated prior t (TMZ), number of relapses, academic vs. community site and low grade at initial diagnosis. Outcome variables were: (1) overall survival (OS), (2) progression free survival (PFS) and (3) PFS6 = proportion of patients alive and progression-free 6 months after start of treatment. For all 3 endpoints, Classification and Regression Tree (CART) models and bootstrap samples were used to identify prognostic variables and to look for evidence of interactions among the independent variables affecting outcome. Results: For all outcomes the initial CART analysis selected last known grade (4 vs. 3) as the most important variable. Additional factors selected as predicting poor prognosis differed with grade and outcome measure and included prior TMZ, longer time since primary diagnosis, older age and poor PS. Community vs. academic was not a strong predictor in any of the models nor was low grade at initial diagnosis. Additional analyses are planned to better describe the impact of all the variables on outcome, including use of Cox models and logistic models considering all baseline variables with backwards selection. Conclusions: The results from analyses to date are consistent with current thinking that last known histology (grade) is an important factor. Time since initial diagnosis is likely a surrogate for number of relapses. More definitive conclusions await the completion of ongoing analyses. No significant financial relationships to disclose.

6517 Background: In NCCTG CTs a subset of AEs are assessed at each patient (pt) evaluation based on the known safety profile of agents(s). The NCCTG routinely pre-fills the “known” AE list onto CT Case Report Forms (CRFs). Newly identified AEs may expand the AE assessment list for ongoing CTs. Our survey of NCCTG AE data (JCO 2005), demonstrated that 85% of AEs reported were pre-filled on CRFs, of which, 83% did not actually occur (Grade 0). Extending this work, we evaluated the influence of pre-filling AEs on CRFs, relative to the final AE rates reported. Methods: Our non-random sample contains 507,899 AEs collected from 1/99–6/06 on 74 NCCTG CTs, 13 of which had AEs added to the CRF pre-fill list during the CT (2,604 pts, 3 Ph I/II, 8 Ph II, 2 Ph III, 9 investigational agents). Results: An average of 2.8 AEs (range 1–6) were added to CRFs for ongoing CTs, primarily for Oxaliplatin induced AEs. 58% (21/36) of AEs added during a CT were not reported prior to the addition, 22% (8) were not reported afterwards. 5 CTs had significantly higher AE rates (p No significant financial relationships to disclose.

8583 Background: Patient QOL assessment requires balancing the detail provided by multi-item assessments with the reduced burden of single-item assessments. We investigated the psychometric properties of single-item LASA assessments used in 3 North Central Cancer Treatment Group (NCCTG) phase II trials for patients with newly diagnosed high-grade gliomas. Methods: Measures included QOL LASAs (overall, physical, emotional, spiritual, intellectual), Symptom Distress Scale (SDS), Profile of Mood States (POMS), and Functional Assessment for Cancer Therapy (FACT; overall, physical, emotional). Association of LASA measures with SDS, POMS, and FACT domains and with ECOG performance score (PS) and MMSE was assessed with Spearman’s correlation. Repeated measures ANOVA models compared the change over time of LASAs and SDS, POMS, and FACT. Cox regression modeled the association of baseline QOL and survival. Results: 205 patients completed the QOL assessments across 3 time points. LASA mean scores ranged from 60–78; SDS, POMS, and FACT ranged from 68–81. No significant changes across time for overall and emotional scores were observed. FACT physical decreased over time (p No significant financial relationships to disclose.

1500 Background: Treatment of adult LGG is controversial. Favorable patients (pts) (age No significant financial relationships to disclose.

8527 Background: Minority patients (MP) suffer deficits in access to care and socioeconomic status. This study uses a patient-level pooled analysis to explore whether these deficits translate into quality of life (QOL) differences between MP and non-MP on clinical trials. Method: Baseline QOL scores were combined from 47 clinical trials (6,513 patients) conducted either at the Mayo Clinic Cancer Center or in the North Central Cancer Treatment Group. QOL scales used were the Uniscale, Linear Analogue Self Assessment (LASA), Symptom Distress Scale (SDS), Profile of Mood States (POMS) and Functional Assessment of Cancer Therapy - General (Fact-G). Fisher’s Exact tests and linear regression adjusted for age, site, and performance score. Survival data was compared using the method of Kaplan-Meier. Results: Eight percent (531) of patients self-reported as MP (0.45% American Indian/Alaskan Native, 0.7% Asian, 5% Black/African American, 1.5% Hispanic, 0.1% Native Hawaiian and 0.3% Other). MP had no meaningful deficits in overall QOL or the SDS and were slightly worse on FACT-G total score, physical, social/family, functional, and SDS nausea severity. MP among lung cancer patients reported greater nausea (58 vs 69) and sleep problems (34 vs 54), with neurological cancers reported worse emotional well-being (53 vs 74), and with GI tumors had lower social/family well-being (60 vs 67). Regression models confirmed these results. Median survival time was shorter for MP (198 vs 310 days, p=0.001) but was not significant after adjusting for disease severity. Conclusions: MP on these clinical trials did not report large QOL deficits at baseline relative to non-MP. MP did indicate small deficits in physical, social, and emotional subscales. MP experienced large tumor-specific deficits for a few QOL domains that might bear further attention. [Table: see text] No significant financial relationships to disclose.

1520 Background: Multiple variables may impact endpoints utilized to assess efficacy of investigational therapies for pts with recurrent gliomas. Understanding the nature of these variables should aid interpretation of results. Methods: 583 pts were enrolled to 15 consecutive recurrent glioma clinical trials conducted between 1980 and 2004. Identical patient, tumor, treatment and time variables were identified for each trial. Central neuropathology review was completed and pts were grouped by WHO diagnoses. Pts alive and progression-free at 6 months after start of treatment were a PFS6 ‘success’. Pts whose outcome was progression at first evaluation were classified as “Immediate Progression (ImmProg)”. Response was defined as regression, partial regression, or complete regression in the absence of worsening neurologic symptoms or increased corticosteroid dose. Univariable and multivariable Classification and Regression Trees (CART) models were used to identify factors associated with OS, PFS, PFS6, ImmProg, and Response. Results: Variables associated with outcomes for each endpoint assessed by CART models are shown in Table below. Conclusions: In clinical trials of recurrent glioma, age, PS, duration of disease, primary and recurrent histologic diagnosis, and primary and recurrent extent of resection are associated with outcomes. These variables should be validated in additional datasets for potential inclusion in reports of future clinical trials. [Table: see text] No significant financial relationships to disclose.

1521 Background: Gliomas are known to progress from low to high grade at relapse, but the frequency is not well understood. It is unclear whether survival of these pts differ as a function of histologic subtype, and as measured from initial diagnosis and from relapse; yet such pts are frequently combined in clinical trials. Methods: Central review of paired glioma tissues obtained at initial diagnosis (DX) and recurrence was performed in 208 pts enrolled in prospective NCCTG trials (recurrence ≤ 90 d excluded). Kaplan-Meier, log rank, ANOVA, and chi-square tests were utilized. Results: Relapse from low (1–2) to high grade (3–4) occurred in 18/42 (43%) oligodendrogliomas (oligo), 28/41 (68%) oligoastrocytomas (OA), and 14/20 (70%) astrocytomas (astro); p=0.031. There were differences in median OS (in yrs; 95% CI) from initial DX: oligo-7.5 (5.0, 12.6); OA-4.5 (3.8, 5.6); and astro-3.3(1.8, 5.1), p=0.002; and OS from high grade recurrence: oligo-2.1 (0.9,3.0); OA-1.0 (0.8,1.3); and astro-0.7 (1.8, 5.1); p=0.02. Median OS from initial DX (yrs, 95% CI) also differed between primary (initial DX) GBM-1.7 (1.5–2.2); secondary (at recurrence) GBM-3.7 (2.8, 4.2) and non-GBM (initial+recurrence)- 5.5, (4.9–7.0) respectively, p < 0.001. Mean time to recurrence (TTR), (yrs ± S.D.) also differed: 1.1±1.1; 2.9±1.8; and 4.0±2.9, respectively, p < 0.001; as did median OS from recurrence (yrs, 95% CI) [0.7 (0.5, 1.1); 0.6, (0.5, 1.0); and 1.6 (1.1, 2.1), respectively], p [Table: see text] No significant financial relationships to disclose.

1505 Background: Combined deletion of chromosomes 1p and 19q is associated with improved prognosis in pts with anaplastic oligodendroglioma. We recently discovered that the combined deletion is mediated by a chromosome 1;19 translocation: t(1;19)(q10;p10). The prognostic significance of this alteration in pts with low-grade gliomas is not known. Methods: Paraffin-embedded tumor tissue was obtained from 134 pts enrolled in two NCCTG trials for newly-diagnosed low-grade glioma: 86–72–51: a randomized phase III trial of 50.4 Gy vs 64.8 Gy radiation therapy (RT) and 93–72–02: a phase II trial of PCV for 6 cycles followed by RT. Interphase fusion of a CEP1 probe and a BAC contig probe for 19p12 was used to detect the 1;19 translocation. Analysis of 1p and 19q deletions had been previously performed by FISH. Kaplan-Meier distributions of overall survival (OS) and progression-free survival (PFS) for pts whose tumors did or did not exhibit CEP1/19p12 fusion were compared using the Wilcoxon test. Results: Of 134 pts, CEP1/19p12 fusion testing was informative for 92. CEP1/19p12 fusion prevalence was 55% among 42 oligodendrogliomas, 47% among 30 mixed oligoastrocytomas, and 5% among 20 astrocytomas. 91% of gliomas with and 11% without 1p/19q deletion had CEP1/19p12 fusion (p [Table: see text] No significant financial relationships to disclose.

1562 Background: Prior studies have shown additive effects of CPT-11 in combination with BCNU, and radiosensitizing effects of CPT-11 in gliomas. Methods: All pts had GBM by central review prior to registration. With MTD based on a pilot study (Arm A), those not receiving anticonvulsants (non-EIAC, Arm C) received RT with concomitant CPT-11 (125 mg/M2/wk × 4, cycle 1), followed by BCNU (100 mg/M2 q 6 wk) + CPT-11 (75 mg/M2/wk × 4, q 6 wks, cycles 2–5) beginning within 4 wks of RT. Pts on EIAC (Arm B) received CPT-11 (400 mg/M2/wk × 4, cycle 1) during RT, then post-RT BCNU (100 mg/M2 q 6 wk) + CPT-11 (400 mg/M2/wk q 6 wks, cycles 2–5). Dose de-escalations (but no escalations) were allowed. Toxicity was graded by CTC v. 3.0. Primary endpoint was overall survival at 12 mo (OS12), with a interim futility analysis after 12 mos. follow up in the first 35 patients. 18 “successes” (survival > 12 mo) were required to proceed. Results: There were 56 pts treated (20 Arm A, 12 Arm B, 24 Arm C). Six pts on Arm A developed toxicity at the pilot CPT-11 cycle 2–5 dose of 125mg/M2, requiring reduction (75 mg/M2) for the remainder of Arm A and all Arm C pts. The decision rule for the first 35 patients was not met, with inclusion of the 6 Arm A pts (14 successes, 19 failures, 2 incomplete data) or without these pts ( 13 successes, 20 failures, 2 incomplete). In the 35 pts with mature data, the best confirmed response was PR in 2 (6%), REGR in 4 (11%) and stable (>4 wks, STAB) disease in 7 (20%). For the 56 pts (51 with mature data), PR, REGR and STAB were noted in 4%, 16%, and 39% respectively. Reason for end of treatment (N=56) was: completion of study treatment (13%); pt refusal (11%); adverse event (9%); progression (39%); all cause death (9%); too early (13%) or other (7%). In the 51 pts whose data is mature, progression free survival at 6 mos (PFS6) was 29.8% (95% CI: 19.1, 46.3); PFS12 was 16.5% (95% CI: 8.3, 32.9) and OS at 12 mos was 45.4% (95% CI: 32.7, 63). Overall median survival was 10.7 mos (95% CI: 7.8, 14.5). Conclusions: Although limited activity (PR+REGR+STAB) of this combination was demonstrated, the decision rule (minimum OS12 “successes”) was not reached, and tolerability of this regimen was only moderate. We consider the regimen as not superior to results obtained with other regimens in prior NCCTG studies. No significant financial relationships to disclose.

1513 Background: EGFR inhibitors may potentiate the therapeutic efficacy of RT in GBM patients. To evaluate the toxicity and maximum tolerated dose (MTD) of erlotinib plus RT in patients with GBM, we performed the following phase I trial. Methods: Patients were stratified based upon the use of enzyme-inducing anticonvulsants (EIACs). Patients with resected or biopsied GBM were treated with erlotinib for a week prior to concurrent erlotinib and 6 weeks (60 Gy) of RT and maintained on erlotinib until progression. The erlotinib dose was escalated in cohorts of 3 with a starting dose of 100mg/day. Intrapatient dose escalation was not allowed. Response was evaluated by MRI and clinical assessment of neurological status every two months. Results: 20 patients were enrolled; 19 are evaluable. There were 14 males/5 females, median age 54 years; 7 had undergone biopsy only/ 5 subtotal resections/ 7 gross total resections. Current dose level is 150mg/day erlotinib for patients not on EIACs (group 1) and 200mg/day fo...

5534 Background: Esthesioneuroblastoma is a rare tumor arising from the olfactory epithelium in the upper nasal cavity. Prior reviews have found efficacy of chemotherapy for high grade tumors in th...

1505 Background: CCI-779 is a small molecule inhibitor of the mammalian target of rapamycin (mTOR), and represents a rational therapeutic target in GBM. Methods: Recurrent GBM pts with ≤ 1 chemo re...

1508 Background: Common endpoints for GBM Phase II trials are 6 mo progression-free survival (PFS6) & 12 mo OS (OS12). OS12 can be accurately measured, but may be confounded with subsequent therapi...

1502 Background: Tumor deletions of chromosomes 1p and 19q are associated with improved prognosis and responsiveness to chemotherapy in pts with anaplastic oligodendroglioma. Their significance in ...

1500 Background: Anaplastic oligodendrogliomas (AOs) and anaplastic oligoastrocytomas (AOAs) are treated with surgery and RT at diagnosis. They also respond to procarbazine, lomustine and vincristine (PCV), raising the possibility that PCV plus RT at diagnosis may improve outcome. Furthermore for AOs, response to PCV and long survival have been associated with 1p and 19q allelic loss. Methods: A RCT was conducted to test whether dose-intense, pre-RT PCV prolongs overall survival (primary endpoint) or progression-free survival (secondary endpoint) versus RT alone. Serious toxicity rates and quality of life were other endpoints. Patients with AOs or AOAs confirmed by central review, who were age ≥18 years, had a Karnofsky score (KPS) ≥60 and consented, were study-eligible. Tumor sections and peripheral blood were also collected. Results: 291 eligible patients were randomized; 60% were male, 68% were < age 50, 88% had a resection, 90% had a KPS ≥ 80 and 70% had an AO. 148 patients had PCV plus RT and 143 had...

1508 Background: Egf receptor variant III (vIII) is an aberrant tyrosine kinase that lacks a substantial portion of full length Egf receptor's extracellular domain, and has been suggested as being exclusively expressed in human glioblastoma. Little is known, however, with regard to the prognostic significance vIII expression in glioblastoma. Methods: To assess associations between vIII expression and malignant glioma classification, as well to asses its prognostic significance, tumor tissues were collected from malignant glioma patients enrolled in 10 prospective clinical trials, and these were examined for vIII expression by immunohistochemistry. Of the 168 evaluable specimens, 63 were classified as being of grade III malignancy (56 anaplastic astrocytomas and 7 anaplastic oligoastrocytomas), and 105 as grade IV tumors (glioblastoma multiforme), based on WHO criteria. All patients received radiation therapy and nitrosourea-based adjuvant chemotherapy without any difference in outcome related to treatment...

1524 Background: To assess QOL and the prognostic importance of QOL in adult patients with newly diagnosed high grade gliomas (HGG), QOL and outcome data collected in three prospective cooperative group clinical trial were analyzed. Methods: The QOL study was a companion protocol for three phase II protocols; 98–72-51 and 98–72-52 examined pre-irradiation and concurrent chemotherapy with radiation therapy for patients with anaplastic astrocytomas and glioblastomas (GBM) respectively, while N0074 investigated maintenance EGFR inhibitor after radiation was completed for GBMs. At study entry and at regular intervals, 5 self-administered forms were completed by the patient to assess (i) overall QOL (Linear Analogue Scale [LASA] and the Functional Assessment of Cancer Therapy-Brain [FACT-BR Version 4]), (ii) fatigue (Profiles of Mood States short form [POMS-SF] and the Symptom Distress Scale [SDS]), (iii) excessive daytime somnolence (Epworth Sleepiness Scale [ESS]), and (iv) depression (Profiles of Mood State...

1503 Background: CCI-779 is a small molecule inhibitor of the mammalian target of rapamycin (mTOR). mTOR is a rational therapeutic target in GBM, being downstream from important pathways such as EG...

1525 Background: P450 enzyme-inducing anticonvulsants (EIAC) reduce serum levels of chemotherapeutic agents metabolized by CYP3A4 and CYP2A6. Although decreased toxicity of chemotherapy (e.g, CPT-11) has been observed in EIAC vs. non-EIAC patients, effects on survival are less clear. Methods: Univariable and multivariable analyses were performed on our last 3 completed prospective Phase II/III NCCTG trials (937252, 987251, and N0074; N=642) of newly-dx glioblastoma (GBM), to assess relationships between AC/EIAC treatment and overall- (OS) and progression-free survival (PFS). Baseline seizure history was available on 1 of the 3 studies (N=93). OS was measured from surgery until death or last follow-up; PFS from time of study enrollment. Results: There were 463 AC-treated and 447 EIAC-treated patients. AC use was univariately positively associated with steroid use (p=0.003), age (p=0.005) and MMSE (p=0.028); extent of resection distributions also differed between patients on AC and those not (p=0.0001). OS-...

1505 Background: Amplification of the EGFR represents one of the most frequent gene alterations in glioblastoma (GBM). In the current study, our objectives were to evaluate ZD1839 (Iressa), a potent EGFR inhibitor, in the treatment of adults with newly diagnosed GBM, and to correlate response with tumor EGFR status. Methods: By the end of the study, 98 patients (96 evaluable) were accrued. All were newly diagnosed GBM patients who were radiographically stable/improved following radiation treatment (enrollment within in 5 weeks of radiation completion). No prior chemotherapy was permitted. EGFR amplification/mutation, as assessed by FISH and immunohistochemistry, was not required for treatment with ZD1839 but was studied when tissues were available. ZD1839 was administered at 500mg QD; for patients receiving dexamethasone and/or enzyme-inducing (CYP3A4) agents, dose was escalated to a maximum of 1000mg QD. Treatment cycles were repeated at 4-week intervals with tumor response assessed by brain MRI at 8-wee...

The authors designed a clinical trial to assess the impact of aspirin (ASA) (600 mg four times daily) on the constitutional sequelae of recombinant leukocyte A interferon (IFN-alpha 2A), 20 X 10(6) U/m2 thrice weekly, in 29 patients with advanced renal cell cancer (RCC). Aspirin provided no meaningful amelioration of side effects compared to our prior experience of IFN-alpha 2A alone. Interestingly, the objective response rate of 34% (10/29) was considerably higher than the 15% recently reported from an aggregate of 344 patients participating in 14 prospective clinical trials. In light of small numbers, subtle selection biases, and the well-recognized hazards of retrospective analyses, currently it is unclear if the apparent therapeutic advantage from ASA plus IFN-alpha 2A reflects chance occurrence or therapeutic potentiation from ASA. A randomized trial is planned to determine if ASA may have enhanced the efficacy of IFN-alpha 2A in patients with advanced RCC.

We have evaluated the results of salvage systemic therapy in 257 patients with breast cancer recurrent after surgical adjuvant treatment with cyclophosphamide, fluorouracil, and prednisone (CFP) with or without tamoxifen. The overall objective response rate to salvage hormonal therapy was 29% (47 responses in 161 patients) and to salvage chemotherapy was 28% (43 responses in 156 patients). Response rates to salvage chemotherapy were similar whether or not prior salvage hormonal therapy or local modalities had been administered. Retreatment with CFP as a salvage chemotherapy yielded responses in 11 of 44 patients (25%). Response rates were similar for patients who began salvage CFP less than or equal to 12 months or greater than 12 months after completion of adjuvant CFP. We conclude that when this unselected population of patients failing adjuvant CFP is considered, 1) response rates to salvage chemotherapy were low regardless of whether or not prior salvage hormonal or local therapies were given, 2) repeating adjuvant chemotherapy (CFP) following relapse produced a low response rate, and 3) response rates to salvage hormonal therapy were low, but on the order of those observed in patients with advanced disease unselected by estrogen receptor status who are treated with first line hormonal maneuvers.

Between April 1987 and July 1988, 44 adults with histologically proven, objectively assessable advanced nonosseous sarcomas were treated with 2.5 g of ifosfamide/m2, 100 mg of etoposide/m2, and 2.5 g of mesna/m2 (500 mg/m2 X 5) daily for 3 consecutive days every 4 weeks. This regimen was generally well tolerated as outpatient treatment. Because of the potential CNS effects of ifosfamide, we recommended that elderly patients, persons receiving high doses of opiates, and patients susceptible to the syndrome of vertigo, perspiration, and hypotension (without tachycardia) be hospitalized for treatment. At initial treatment, leukocyte count nadirs were less than 1,000/microL and platelet count nadirs were less than 100,000/microL in 38% and 15%, respectively, of the 39 patients for whom such data were available. Objective tumor regression occurred in approximately 16% (95% confidence interval, 7%-30%) of the 44 patients (six, partial responses; one, complete response). For the 44 patients, median time to disease progression was 2.3 months; median time to death was 9.4 months. While this regimen was effective in three of 20 patients who had been previously treated with a doxorubicin-based regimen, only one of the 12 patients whose tumors had been primarily refractory to the doxorubicin-based regimen experienced objective tumor regression on our ifosfamide-based regimen.

Carboplatin was administered by iv bolus every 28 days to 26 patients who had extensive metastatic or recurrent endometrial adenocarcinoma and no prior chemotherapy exposure. The dose level was 400 mg/m2 in 5 patients with and 4 patients without prior irradiation and 300 mg/m2 in 16 patients with prior pelvic irradiation. Partial disease regressions were seen in 28% of patients (95% confidence interval, 12%-50%), with a median response duration of 129 days. Median survival of all patients was 215 days; median time to disease progression for all patients was 117 days. We conclude that carboplatin is an active agent in advanced endometrial carcinoma and is worthy of further investigation in single-agent and combination chemotherapy.

Menogaril, an anthracycline analog of nogalamycin, is reported to have greater cytotoxicity against certain malignant cell lines and less cardiotoxicity in rabbits than doxorubicin. To evaluate the possible therapeutic benefit of this drug, we studied menogaril in 21 patients with metastatic sarcomas who had received no prior chemotherapy. Menogaril was administered intravenously over 1 h every 3-4 weeks at a dose of 200 mg/m2 in 500 ml of 5% dextrose in water. One patient experienced a partial regression of pulmonary metastases from malignant fibrous histiocytoma of bone (response rate of 5% with 95% confidence interval of 0.1-23.8%). Two additional patients experienced minor reductions in tumor size. The remaining 18 patients had no improvement from menogaril. The median time to disease progression was 7 weeks in all patients treated. Toxicity was acceptable, consisting primarily of leukopenia with 12 patients (57%) and 19 patients (90%) developing nadir leukocyte counts less than 2000 and 3000/microL, respectively. Cardiac toxicity was not encountered; however, only seven patients received greater than or equal to 3 cycles of menogaril. We conclude that menogaril does not appear to be useful at this dose and schedule in the treatment of metastatic sarcomas despite the use of near maximal doses in patients with no prior chemotherapy exposure.

5-fluorouracil (FUra) has definite, albeit limited, antitumor activity against breast carcinoma (1). Inhibition of the enzyme, thymidylate synthetase (TS) by FdUMP, an active FUra metabolite, has been postulated as one biochemical mechanism for this antitumor activity (2). TS inhibition is markedly augmented by the presence of increased concentrations of the reduced folate, citrovorum factor (CF) (3). In 1985, preliminary information suggested that FUra plus CF resulted in more substantial activity against heavily pretreated metastatic breast cancer than would have been expected with FUra alone (4). This current study was designed 1) to study the antitumor activity and toxicity of FUra plus CF in metastatic breast cancer patients who had not been “heavily pretreated” with chemotherapy, 2) to examine the impact of this regimen on tumor TS activity, and 3) to correlate the degree of TS inhibition with clinical outcome. The protocol continues to accrue patients and this communication provides a progress report relating to antitumor activity and toxicity.

Background Single-item assessments have been the most often-used measures in National Cancer Institute (NCI) cancer control clinical trials, but normative data are not available. Our objective was to examine the normative data and clinically significant effect sizes for single-item numerical linear analogue self-assessment (LASA) scale for overall quality of life (QOL). Methods We analyzed baseline data from 36 clinical trials and 6 observational studies with various populations, including healthy volunteers, cancer trial patients (patients with advanced incurable cancer or patients receiving treatment with curative intent) and hospice patients as well as their caregivers. The overall QOL LASA was rated 0 (as bad as it can be) to 10 (as good as it can be). We calculated the summary statistics and the proportion of patients reporting a clinically meaningful deficit (CMD) of a score equal to 5 or less on the 0–10 scale. Results In total, for the collective sample of 9,295 individuals, the average overall QOL reported was 7.39 (SD = 2.11) with a markedly skewed distribution with roughly 17% reporting a score of 5 or below indicating a clinically significant deficit in overall QOL. Hospice patients report a much worse average score of 5.7 upon entry to hospice; hospice caregivers average 7.4. Cancer patients vary within these two extremes with most patients averaging in the 7’s on the 0–10 scale (range, 0 to 10 p-value

Purpose: Relative to more abundant neoplasms, endocrine cancers have been historically neglected, yet their incidence is increasing. We therefore sought to build interest in endocrine cancers, improve physician experience, and develop innovative approaches to treating patients with these neoplasms. Methods: Between 2005 and 2010, we developed a multidisciplinary Endocrine Malignancies Disease Oriented Group involvingallthreeMayoCliniccampuses(Rochester,MN;Jacksonville, FL; and Scottsdale, AZ). In response to higher demand at the Rochester campus, we sought to develop a Subspecialty Tumor Group and an Endocrine Malignancies Tumor Clinic within the Division of Medical Oncology. Results: The intended groups were successfully formed. We experienced difficulty in integration of the Mayo Scottsdale campus resultingfromlocaluncertaintyastowhetherpatientvolumeswould be sufficient to sustain the effort at that campus and difficulty in developing enthusiasm among clinicians otherwise engaged in a busy clinical practice. But these obstacles were ultimately overcome. In addition, with respect to the newly formed medical oncology subspecialty endocrine malignancies group, appointment volumes quadrupled within thefirst year and increased seven times within two years. The number of active therapeutic endocrine malignancies clinical trials also increased from one in 2005 to five in 2009, with all three Mayo campuses participating. Conclusion: The development of subspecialty tumor groups for uncommon malignancies represents an effective approach to building experience, increasing patient volumes and referrals, and fostering development of increased therapeutic options and clinical trials for patients afflicted with otherwise historically neglected cancers.