Median Potential Follow-up Research Articles

Long Term Clinical and Functional Outcomes Following Treatment for Localized Ewing's Tumor of the Lower Extremity

Retrospective review describing the 35-year University of Florida experience with Ewing's tumors of the lower extremity. Fifty-three patients were treated from 1971–2006. Thirty patients were treated with radiotherapy (RT) alone and 23 patients were treated with surgery ± RT. Larger tumors and tumors of the femur were treated more often with definitive RT. Median potential follow-up was 19.2 years. Functional outcome was assessed using the Toronto Extremity Salvage Score (TESS). Before 1985, 24% of patients were treated with surgery; since then, the rate has increased to 61%. The 15-year actuarial overall survival (OS), cause-specific survival (CSS), freedom from relapse, and limb preservation rates were 68% vs. 47% (p = 0.21), 73% vs. 47% (p = 0.13), 73% vs. 40% (p = 0.03), and 43% vs. 40% (p = 0.52) respectively for patients treated with surgery ± RT vs. RT alone. Excluding 8 patients who underwent amputation or rotationplasty, the 15-year actuarial local control rate was 100% for the surgery ± RT group and 68% for the definitive RT group (p = 0.03). The ranges of the TESS for surgery ± RT vs. RT alone were 70–100 (mean, 94) and 97–100 (mean, 99) respectively. Twenty-six percent (6/23) of patients had complications related to surgery requiring amputation or reoperation. OS and CSS were not statistically compromised but we observed an increased risk of relapse and local failure in patients treated with RT alone thereby justifying a transition towards primary surgical management in suitable patients. However, despite an adverse risk profile, patients treated with RT alone had similar long-term amputation-free survival and demonstrated comparable functional outcomes. Poor results observed in Ewing's of the femur mandate innovative surgical and RT strategies.

Long-Term Clinical and Functional Outcomes After Treatment for Localized Ewing's Tumor of the Lower Extremity

Retrospective review describing the 35-year University of Florida experience with Ewing's tumors of the lower extremity. Fifty-three patients were treated between 1971 and 2006. Thirty patients were treated with radiotherapy (RT) alone and 23 patients were treated with surgery +/- RT. Larger tumors and tumors of the femur were treated more often with definitive RT. Median potential follow-up was 19.2 years. Functional outcome was assessed using the Toronto Extremity Salvage Score (TESS). Before 1985, 24% of patients were treated with surgery; since then, the rate has increased to 61%. The 15-year actuarial overall survival (OS), cause-specific survival (CSS), freedom from relapse, and limb preservation rates were 68% vs. 47% (p = 0.21), 73% vs. 47% (p = 0.13), 73% vs. 40% (p = 0.03), and 43% vs. 40% (p = 0.52), respectively, for patients treated with surgery +/- RT vs. RT alone. Excluding 8 patients who underwent amputation or rotationplasty, the 15-year actuarial local control rate was 100% for the surgery +/- RT group and 68% for the definitive RT group (p = 0.03). The ranges of the TESS for surgery +/- RT vs. RT alone were 70-100 (mean, 94) and 97-100 (mean, 99), respectively. Twenty-six percent (6/23) of patients had complications related to surgery requiring amputation or reoperation. Overall survival and CSS were not statistically compromised, but we observed an increased risk of relapse and local failure in patients treated with RT alone, thereby justifying a transition toward primary surgical management in suitable patients. However, despite an adverse risk profile, patients treated with RT alone had similar long-term amputation-free survival and demonstrated comparable functional outcomes. Poor results observed in Ewing's of the femur mandate innovative surgical and RT strategies.

7515 POSTER Prognostic factors in osteosarcoma. The arguments for risk adapted up-front treatment

Retrospective review describing the 35-year University of Florida experience with Ewing's tumors of the lower extremity.Fifty-three patients were treated between 1971 and 2006. Thirty patients were treated with radiotherapy (RT) alone and 23 patients were treated with surgery ± RT. Larger tumors and tumors of the femur were treated more often with definitive RT. Median potential follow-up was 19.2 years. Functional outcome was assessed using the Toronto Extremity Salvage Score (TESS).Before 1985, 24% of patients were treated with surgery; since then, the rate has increased to 61%. The 15-year actuarial overall survival (OS), cause-specific survival (CSS), freedom from relapse, and limb preservation rates were 68% vs. 47% (p = 0.21), 73% vs. 47% (p = 0.13), 73% vs. 40% (p = 0.03), and 43% vs. 40% (p = 0.52), respectively, for patients treated with surgery ± RT vs. RT alone. Excluding 8 patients who underwent amputation or rotationplasty, the 15-year actuarial local control rate was 100% for the surgery ± RT group and 68% for the definitive RT group (p = 0.03). The ranges of the TESS for surgery ± RT vs. RT alone were 70–100 (mean, 94) and 97–100 (mean, 99), respectively. Twenty-six percent (6/23) of patients had complications related to surgery requiring amputation or reoperation.Overall survival and CSS were not statistically compromised, but we observed an increased risk of relapse and local failure in patients treated with RT alone, thereby justifying a transition toward primary surgical management in suitable patients. However, despite an adverse risk profile, patients treated with RT alone had similar long-term amputation-free survival and demonstrated comparable functional outcomes. Poor results observed in Ewing's of the femur mandate innovative surgical and RT strategies.

Efficacy and toxicity of dose-adjusted EPOCH-rituximab in adults with newly diagnosed Burkitt lymphoma

8035 Background: Burkitt Lymphoma (BL) is a rare and highly aggressive lymphoma, characterized by a high tumor proliferation rate. While the standard therapy of BL is highly effective, it involves intensive, multi-agent chemotherapy that is associated with considerable treatment-related toxicity and mortality, especially in older patients. We hypothesized that the regimen DA-EPOCH may be effective in BL, based on the observation that it overcomes the adverse effect of high proliferation in diffuse large B-cell lymphoma. Methods: We investigated DA-EPOCH-rituximab (R) in untreated BL in an attempt to maintain the high cure rates of standard therapy with minimal treatment related toxicity. Eligible patients had a diagnosis of untreated BL and could be HIV negative or positive with HIV negative patients (n=13) receiving 6 cycles of DA-EPOCH-R as previously described (Blood 99: 2685, 2002) and HIV positive (n=6) patients receiving 3–6 cycles of DA- EPOCH-R for 1 cycle beyond CR for a minimum of 3 cycles. All patients received intrathecal methotrexate prophylaxis and outpatient therapy where possible. Results: The characteristics of 19 enrolled patients are: median age (range) 29 (18–66) and ECOG PS 1(1–3); stage III/IV 10 (53%); LDH > N 11 (61%); male sex 15 (79%); extranodal sites 13 (68%) and ileocecal disease 13 (68%). No patients so far had CNS involvement at diagnosis. Response is CR/CRu in 100% of patients with one patient receiving consolidative radiotherapy to a site of residual disease. OS and PFS are both 100% and EFS 93.3% at a median potential follow-up time of 29 months. Toxicities were fever/neutropenia in 16%, grade 4 neutropenia in 47% and grade 3/4 thrombocytopenia in 22% of cycles. There was one case of tumor lysis syndrome and no treatment related deaths. Conclusions: DA-EPOCH-R is highly effective in BL. It appears to be associated with much lower toxicity compared to standard high-dose regimens and may significantly advance the therapeutic index of BL treatment. Accrual continues. No significant financial relationships to disclose.

Tolerability of Accelerated Chest Irradiation and Impact on Survival of Prophylactic Cranial Irradiation in Patients with Limited-stage Small Cell Lung Cancer: Review of a Single Institution's Experience

Evidence that has been published in the last decade indicates that in patients with limited-stage small-cell lung cancer (SCLC), hyperfractionated accelerated thoracic radiotherapy (RT) given twice daily and prophylactic cranial irradiation (PCI) have each separately improved survival. Concerns about the toxicities associated with these treatments and uncertainty about their impact on survival outside the trial setting may have restricted the extent to which they have been incorporated into standard treatment protocols. We have reviewed the experience at Peter MacCallum Cancer Centre to determine the tolerability of these treatments in routine practice and to determine their effects on survival. A retrospective review of patients with limited-stage SCLC receiving a radical course of thoracic RT between June 1998 and May 2002, including either conventional fractionation at 50 Gy for 5 weeks, or hyperfractionated accelerated RT at 45 Gy for 3 weeks. Patients achieving a complete response were offered PCI at 36 Gy in 18 fractions. The main outcomes recorded were RT toxicity (graded using CTCAE v. 3.0 and RTOG/EORTC late scoring criteria), response, relapse-free survival, and overall survival. Ninety patients were identified as having undergone radical-intent thoracic RT, with a median potential follow-up of 4.2 years. Fifty-seven patients (63%) were treated with hyperfractionated accelerated RT, and 33 (37%) were treated with conventional fractionation. Forty-six patients (51%) received PCI. Patients receiving hyperfractionated accelerated RT compared with conventional fractionation had higher rates of grade 3 and 4 esophagitis (14% versus 6%; p = 0.312), a higher rate of treatment interruptions (12% versus 3%; p = 0.250), and a higher hospital admission rate (39% versus 15%; p = 0.031). The majority of patients were able to complete the planned treatment, and there were no treatment-related deaths. Median survival for all patients from commencement of RT was 14.2 months (95% confidence interval [CI]: 11.9-18.1 months), and survival at 2 years was 24.8% (95% CI: 16.9-35.0%). On multifactor analysis, the only factor associated with longer survival was PCI (hazard ratio = 0.40; p < 0.001). Hyperfractionated accelerated RT was more toxic than conventional fractionation, but it was possible to deliver treatment as planned in the majority of patients. PCI was associated with improved survival. Both treatments can be incorporated into routine practice.

Phase I Study of Radical Thoracic Radiation, Weekly Irinotecan, and Cisplatin in Locally Advanced Non-small Cell Lung Carcinoma

Irinotecan and cisplatin individually are active in non-small cell lung carcinoma (NSCLC). Each is synergistic with radiation. Dosages of 65 mg/m2 of irinotecan and 30 mg/m2 of cisplatin Q weekly times four every 6 weeks yielded a 36% response rate and median survival of 11.6 months in advanced NSCLC (Jagasia et al.; Clinical Cancer Research 7: 68, 2001). A weekly schedule for each agent (versus less frequent doses) limits toxicity and increases the opportunity for radiosensitization. We initiated a phase I study of weekly irinotecan and cisplatin during radical thoracic radiation (TRT). Cisplatin was fixed at 25 mg/m2 Q weekly times seven. Irinotecan was dosed initially at 30 mg/m2 per week for 7 weeks and was increased by 10 mg/m2 per week in three- to six-patient cohorts. TRT was administered in 34 single daily fractions to 63 Gy. Eligibility stipulated locally advanced NSCLC; Eastern Cooperative Oncology Group performance status 0 to 1; < or = 10% unintended weight loss; and adequate physiologic indices. Fifteen patients were accrued: nine were stage IIIB, five were stage IIIA, and one had isolated mediastinal node recurrence after prior surgery. Median age was 65 years (range, 47-77). Seven patients received irinotecan at a dose of 30 mg/m2 per week; (dose level 1). Seven other patients received irinotecan at a dose of 40 mg/m2 per week; (dose level 2). The one other patient received irinotecan in doses of 50 mg/m2 per week; (dose level 3). Neutropenic fever occurred in one patient each at dose levels 1 and 2. Grade 4 neutropenia occurred in three patients at each dose level. Transient grade 3 diarrhea occurred in one patient at dose level 1. Esophagitis of grade 3 or higher occurred in one patient each at dose levels 2 and 3. There was one late grade 3 pneumonitis at dose level 2. Delivered irinotecan dose intensity for dose level 1 was 27 mg/m2 per week; for dose level 2, it was 31.4 mg/m2 per week. Nine of 13 evaluable patients (69%) responded. At median potential follow-up of 5 years, 14 have progressed, and 11 have died. Projected median survival is 28 months; one patient who was treated for mediastinal node recurrence remains free from progression at 6 years. Weekly irinotecan and cisplatin combined with radical TRT (63 Gy) is active and fairly well tolerated in locally advanced NSCLC. In combination with fixed-dose cisplatin (25 mg/m2 per week), the maximum-tolerated dose of irinotecan is 30 mg/m2 per week.

Abbreviated Treatment with EPOCH-Rituximab and HAART Suspension Is Highly Effective in AIDS-Related Lymphoma (ARL).

In ARL, the addition of Rituximab (R) to CHOP chemotherapy may improve tumor response but the benefit may be offset by increased infectious deaths in patients with low CD4 cell counts (Kaplan et al. Blood 2005; 106:1538). We hypothesized that R with EPOCH will improve tumor kill, allow fewer chemotherapy cycles and reduce toxicity. Patients received EPOCH-R (in mg/m2/d etoposide 50, vincristine 0.4 and doxorubicin 10 all CIV d 1–4; and in mg/m2 cyclophosphamide 750 IV day 5, prednisone 60 po days 1–4 and rituximab 375 IV d 1, 5; and G-CSF sc d 6–15). Prophylactic IT MTX x 6 was administered and HAART was discontinued on all cycles. Cyclophosphamide was adjusted based on absolute neutrophil count (ANC) nadir. Response was assessed by CT and PET and patients received 1 cycle beyond CR for a minimum of 3 cycles. Characteristics of 30 enrolled patients: median (range) age 41 (9–61) years; IPI 3 (0–4); ECOG PS 1 (1–4), CD4 count 213 (0–674) cells/mm3; HIV viral load 55,900 (0–6,080,000) RNA copies/mL; male sex 25 (83%); LDH > N 22 (73%); stage IV 20 (67%) and histology DLBCL 26 (87%) and Burkitt lymphoma 4 (13%). Of 28 evaluable patients (2NE), median (range) cycles given is 3 (3–5) with CR/CRu in 25 (89%) and PR in 1 (3%) patients. All 4 patients with Burkitt lymphoma are in continuous remission. At 35 months median potential follow-up, PFS and OS are 80% and 65%, respectively. For patients with CD4 > and < 100 cells/mm3 OS is 93% and 28%, respectively. IPI did not impact OS and PFS. We assessed the predictive value of early (after cycle 2 or 3) PET scanning on subsequent relapse. This was evaluated in 23 patients in follow-up. 0 of 13 patients with a negative PET study progressed (100% negative predictive value) whereas 2 of 10 patients with a positive PET progressed (20% positive predictive value). One death from MAI occurred on treatment and toxicity over 91 cycles of therapy included fever/neutropenia on 27 (30%), ANC < 500/mm3 on 36 (40%), and platelets < 50,000 on 21 (23%) cycles. EPOCH-R was associated with less CD4 loss - median 128 cells/mm3 (range +154 to −639) compared to EPOCH alone (median 189 cells/mm3 (range +19 to −973)(Little et al. Blood 2003; 101:4653). Abbreviated EPOCH-R is highly effective with acceptable tolerability in ARL and enables the administration of fewer treatment cycles (median 3 versus 6). Patients with CD4 < 100/mm3 have good tumor control with EPOCH-R with a PFS of 61% at 35 months, but survival continues to be limited by HIV-associated complications. In contrast, patients with high CD4 counts > 100/mm3 have an extremely favorable outcome with EPOCH-R. Albeit limited data, EPOCH-R was effective in all 4 patients with Burkitt lymphoma. PET scanning has a high negative but low positive predictive value for subsequent relapse. Accrual continues. [Display omitted] [Display omitted]

Novel Treatment of Burkitt Lymphoma with Dose-Adjusted EPOCH-Rituximab: Preliminary Results Showing Excellent Outcome.

Burkitt Lymphoma (BL) is a highly proliferative lymphoma with a propensity to present in extranodal sites. Standard treatment for BL involves intensive, multi-agent chemotherapy that is highly effective but associated with considerable toxicity and treatment-related mortality, particularly in older patients. Based on the observation that DA-EPOCH overcomes the adverse effect of high proliferation in diffuse large B-cell lymphomas, we hypothesized it may be effective in BL. We have undertaken a study of DA-EPOCH-Rituximab in untreated BL in an attempt to maintain a high cure rate with low treatment related toxicity. Eligible patients had untreated BL and could be HIV positive or negative. HIV negative patients (n=13) received 6 cycles of DA-EPOCH-R as previously described (Blood 99: 2685, 2002). Patients with HIV-associated BL (n=4) received 3–6 cycles of DA-EPOCH-R for 1 cycle beyond CR for a minimum of 3 cycles. All patients received intrathecal methotrexate prophylaxis and therapy was administered in the outpatient clinic where possible. Characteristics of 17 patients include median age (range) 27 (18–66) and ECOG PS 1 (1–3); stage III/IV 9 (53%); LDH > N 9 (53%); male sex 13 (76%) and; extranodal sites 11 (65%). All 11 (65%) patients with extranodal disease had abdominal or pelvic involvement at diagnosis. No patients had central nervous system disease on presentation. Response is CR/CRu in 100% of patients. One patient received consolidative radiotherapy to a single site of residual disease. At a median potential follow-up of 28 months, OS and PFS are both 100% and EFS is 92.3%. Significant toxicities include fever/neutropenia in 16%, grade 4 neutropenia in 47% and grade 3/4 thrombocytopenia in 22% of cycles. There were no treatment related deaths and no tumor lysis syndrome. In conclusion, DA-EPOCH-R appears to be highly effective with relatively low toxicity compared to standard intensive high-dose regimens for BL. Infusional chemotherapy may reduce or eliminate the risk of tumor lysis syndrome. Accrual continues. [Display omitted]

DA-EPOCH-R Is Highly Effective in Both BCL-6+ and BCL-6− Untreated De Novo Diffuse Large B-Cell Lymphoma (DLBCL): Study Update and Analysis of Survival Outcomes for Multiple Biomarkers.

Gene expression profiling has yielded a new molecular taxonomy of DLBCL in which 3 subtypes are distinguished; germinal center B-cell (GCB) subtype, derived from a germinal center B-cell; activated B-cell (ABC) subtype, derived from a post-germinal center B-cell; and primary mediastinal B-cell (PMBL) subtype, likely derived from a “thymic” B-cell. To define the effect of pathobiology on treatment outcome, immunophenotype has been used as an “approximate surrogate” biomarker for molecular taxonomy. Recent studies suggest that rituximab (R) benefit is primarily in BCL-6− (Winter et al Blood 107: 4207, 2006) and BCL-2+ (Mounier et al Blood 101:4279, 2003) DLBCL, both more frequent in post-germinal center subtypes. Conversely, R-CHOP appears equivalent to CHOP in BCL-6+ DLBCL, which comprise up to 75% of all cases. We analyzed the outcome of DA-EPOCH-R using the immunophenotypic biomarkers BCL-6, BCL-2, MIB-1, CD10, MUM-1, and GCB vs ABC subtypes by the method of (Hans et al Blood 103:275, 2003). Patients had untreated de novo DLBCL excluding PMBL, stage II-IV, HIV-, and adequate organ function. No patients received radiation. Characteristics of 72 patients include median (range) age 50 (19–85); stage III/IV 69%; and High Intermediate/High International Prognostic Index (3–5) (IPI) 40%. Of 71 evaluable patients, response is CR/CRu 94%. At the median potential follow-up of 43 months, PFS is 82% and OS is 79% (Fig 1). PFS by Low/Low Intermediate (0–2) and High Intermediate/High (3–5) IPI is 93% and 64%, respectively, at 43 months. PFS by BCL-6 (Fig 1), and BCL-2 and GCB vs. ABC (Fig 2) is shown. PFS of DLBCL with MIB-1 < and > 80% was 92% and 81%, respectively. There was no significant difference in survival outcome by CD10 or MUM-1 expression (data not shown). Distribution by immunophenotype is shown below for patients with available tissue.Biomarker DistributionBiomarkerNumberPercentBCL-6 Neg1424BCL-6 Pos4476BCL-2 Neg2441BCL-2 Pos3559GCB3467ABC1733MIB-1 < 80%1333MIB-1 > 80%3967CD10 Neg3663CD10 Pos2137Mum-1 Neg3064Mum-1 Pos1736In conclusion, DA-EPOCH-R appears equally effective among all biomarker subgroups. Of note, DA-EPOCH-R is highly effective in BCL-6+ DLBCL, in which R does not appear to be very useful, suggesting the DA-EPOCH regimen itself may be highly effective in this group. The CALGB has initiated a Phase III randomized study of R-CHOP vr. DA-EPOCH-R to determine if DA-EPOCH-R represents a treatment advance. Gene expression profiling will be performed to assess the effect of the new molecular taxonomy and tumor biology on outcome. [Display omitted]

Primary Mediastinal Large B-Cell Lymphoma (PMBL) Outcome May Be Significantly Improved by the Addition of Rituximab to Dose-Adjusted (DA)-EPOCH and Obviates the Need for Radiation: Results from a Prospective Study of 44 Patients.

PMBL is a distinct clinicopathologic entity characterized by young age, female preponderance, localized disease, prominent sclerosis and CD30+. Gene expression profiling reveals a unique molecular signature, distinct from other DLBCL subtypes, with similarity to classical Hodgkin lymphoma (HL) (J Exp Med 198: 851, 2003). HL is typically CD20 negative whereas PMBL has robust CD20 staining. As with HL, the risk of local failure after anthracycline-based therapy in PMBL has led to routine mediastinal radiation. Given the young median age, female predominance and high cure rates, long-term toxicities from secondary malignancies and coronary artery disease can be life threatening. We prospectively evaluated the role of DA-EPOCH± R without routine radiation in 44 patients with untreated PMBL. The first 18 patients received DA-EPOCH alone and the subsequent 26 received DA-EPOCH+R. DA-EPOCH was administered for 6–8 cycles as described (Blood 99: 2685, 2002). Most patients had adverse prognostic features with bulky disease, elevated LDH and extranodal sites, which were balanced among the 2 groups.Patient CharacteristicsCharacteristicsAll PatientsDA-EPOCHDA-EPOCH-RTotal Patients441826Gender (F/M)26:18 (1.44)10:8 (1.25)19:9 (1.88)Median age, y (range)34 (12–70)34 (20–62)34 (12–70)Median Mass cm (range)9.8 (3–19.7)8.4 (5.1–15.7)10.2 (3–19.7)Bulky mass > 6 cm34 (83%)13 (87%)21 (81%)ECOG PS > 14 (9%)2 (11%)2 (8%)Stage III or IV19 (43%)9 (50%)10 (38%)LDH > Normal32 (73%)14 (78%)18 (69%)Extranodal sites25 (57%)9 (50%)16 (63%)Pleural effusion15 (34%)4 (22%)11(42%)IHC profiling was similar in both groups and consistent with gene expression profiling of PMBL. Analysis of 40 cases showed CD20+ 40/40 (100%), CD10+ 2/30 (7%), BCL-6+ 21/26 (81%), MUM-1+ 10/24 (42%) and high MIB-1 with median (range) of 82% (54–98). At a median potential follow-up of 9.5 and 4.2 years, EFS and OS are shown below for DA-EPOCH and DA-EPOCH-R, respectively. Rituximab was associated with a significantly improved EFS (p=.038) and OS (p=0.023) by 2-tailed exact log-rank test with caveats associated with any non-randomized comparison. Three patients on DA-EPOCH-R had positive PET and biopsy after treatment. One received radiation (event), one recieved salvage chemotherapy and radiation (event), and one no further treatment after biopsy. DA-EPOCH-R is highly effective in PMBL with OS of 100% and obviated the need for radiation/surgery in 23/26 (88%) patients. Rituximab may significantly improve EFS and OS with DA-EPOCH-based treatment. Accrual continues. [Display omitted]

A prospective study of adjuvant CMF in males with node positive breast cancer: 20-year follow-up

To determine the long-term overall survival of male patients with stage II node positive breast cancer treated with adjuvant chemotherapy. Between 1974 and 1988, 31 male breast cancer patients were prospectively enrolled on study MB-82 in the National Cancer Institute. Following mastectomy, patients were treated with 12 cycles of cyclophosphamide, methotrexate, and fluorouracil (CMF) chemotherapy. Median patient age was 61 years (38-74 years). Twenty-one patients (68%) had 1-3 positive axillary lymph nodes while ten patients (32%) had four or more positive nodes. Estrogen receptor status was positive in 22 (71%), negative in 1 (3%), and unknown in 8 (26%) tumors. Progesterone receptor status was positive in 18 (58%), negative in 3 (10%), and unknown in 10 (32%) tumors. Median potential follow-up for all patients is 22.5 years with a median survival of 16.3 years. Twenty-one of 31 patients have died; one from a treatment-related complication, nine patients from recurrent breast cancer, five from other cancers, one from non-cancer related causes, and five from unknown causes. Ten patients remain alive at a median of 19.2 years. The overall survival probability at 10 years is 64.5% (95% CI: 46.9-78.9%), at 15 years is 51.6% (95% CI: 34.8-68%), and at 20 years is 42.4% (95% CI: 25.8-60.8%). To our knowledge, 20-year prospective data with adjuvant chemotherapy in male breast cancer has never been reported. Adjuvant chemotherapy may benefit male breast cancer patients with positive nodes.

Targeted immune depletion prior to reduced-intensity allogeneic stem cell transplantation results in rapid and complete donor chimerism with low treatment-related mortality

6540 Background: Significant variation in host immune status may influence outcomes after reduced-intensity (RI) allogeneic stem cell transplantation (alloSCT). We have investigated a strategy of targeted immune depletion (TID) with conventional chemotherapy to deplete host T cells and achieve a minimal disease state prior to RI alloSCT. The aim of TID is to rapidly establish complete donor chimerism after RI alloSCT in order to potentiate a graft-versus-tumor (GVT) effect. In a prospective phase II trial (NIH 03-C-0077), we evaluated the effect of TID on donor chimerism, acute graft-versus-host disease (GVHD), and clinical outcome. Methods: Thirty-one patients (pts) with relapsed and refractory hematologic malignancies (NHL = 16; HL = 4; CLL/PLL = 4; MDS/AML = 3; other = 4) were enrolled. Median age was 57 years (range: 31–71). All pts received EPOCH-F (etoposide, prednisone, vincristine, cyclophosphamide, adriamycin, fludarabine) ± rituximab (R) as TID to deplete host CD4+ cells &lt;100/μL. All pts then received a RI conditioning regimen consisting of fludarabine and cyclophosphamide followed by a T-cell replete allograft from HLA-matched siblings. GVHD prophylaxis consisted of cyclosporine plus short-course mini-methotrexate. Results: EPOCH-F(R) achieved the target host T-cell level in 74% of pts. All 31 pts engrafted after RI alloSCT. Complete donor chimerism (&gt; 95%) was observed in 74% and 81% of pts at day +14 and +28 post-transplant, respectively. The incidence of grade II-III acute GVHD was 42% with no cases of grade IV acute GVHD. The median potential follow-up from transplant is 25 months. Actuarial treatment-related mortality at 1 and 2 years was 3% and 8%, respectively. Event-free survival probabilities at 1 and 2 years post-transplant are 65% and 49%, respectively. Ten pts are alive and event-free &gt;24 months post-transplant. The overall survival probabilities at 1 and 2 years are 84% and 64%, respectively. Conclusions: TID prior to RI alloSCT results in rapid, complete donor engraftment and may potentiate GVT effects. This treatment strategy was associated with very low TRM and favorable outcomes in an older patient population with advanced hematologic malignancies. No significant financial relationships to disclose.

Reduced-intensity allogeneic stem cell transplantation for diffuse large B-cell lymphoma: Clinical evidence of a graft-versus-lymphoma effect

6546 Background: Despite being the most common non-Hodgkin’s lymphoma, there have been no specific reports on the use of reduced-intensity (RI) allogeneic stem cell transplantation (alloSCT) to treat patients (pts) with diffuse large B-cell lymphomas (DBCL). This may be due to a lack of definitive evidence for a therapeutic graft-versus-lymphoma (GVL) effect against DLBC. We undertook a retrospective analysis to assess clinical outcomes and evidence of a GVL effect in DLBC pts undergoing RI alloSCT. Methods: The analysis was limited to 18 pts with primary refractory (n = 6) or relapsed (n = 12) DLBC. The median age was 43 years (range: 31–61); median number of previous treatments was 3 (range: 2–9). Nine (50%) pts had undergone autologous transplantation. Three (16%) pts were determined to have chemo-sensitive disease to last treatment prior to RI alloSCT. All pts received a RI conditioning regimen consisting of fludarabine (30 mg/m2/d × 4d) and cyclophosphamide (1200 mg/m2/d × 4d) followed by a T-cell replete allograft from HLA-matched siblings. Results: Median potential follow-up from transplant is 43 months. Seven (39%) pts developed grade II-IV acute GVHD. Response at day +100 post-transplant was as follows: complete response (CR/CRu) = 5; partial response = 5; progressive disease = 8. Nine of 17 (53%) evaluable pts developed chronic GVHD. Median progression-free survival (PFS) was 4.8 months; however, PFS after 9 months post-transplant was 31% with 5 pts in continuous CR/CRu &gt; 12 months post-transplant. Among 14 pts who were not in CR/CRu (n = 12) or progressed after achieving a CR/CRu (n = 2) at day +100 post-transplant, 8 (57%) subsequently achieved a CR/CRu after removal of immune suppression and/or donor lymphocyte infusion (DLI) ± chemotherapy. Seven of these 8 pts remain in continuous (median = 34 months; range: 6–55+) CR/CRu without further treatment. Median survival for all 18 pts was 19 months with survival probability of 40% plateauing at 25 months post-transplant. Conclusions: The clinical observations of sustained CR/CRu after withdrawal of immune suppression and DLI suggest that a GVL effect exists against DLBC. RI alloSCT should be considered as a treatment option for pts with primary refractory and relapsed DLBC. No significant financial relationships to disclose.

Patient-Reported Symptoms and Quality of Life During Treatment With Tamoxifen or Raloxifene for Breast Cancer Prevention

Tamoxifen has been approved for breast cancer risk reduction in high-risk women, but how raloxifene compares with tamoxifen is unknown. To compare the differences in patient-reported outcomes, quality of life [QOL], and symptoms in Study of Tamoxifen and Raloxifene (STAR) participants by treatment assignment. STAR was a double-blind, randomized phase 3 prevention trial designed to evaluate the relative efficacy of raloxifene vs tamoxifen in reducing the incidence of invasive breast cancer in high-risk postmenopausal women. Between July 1, 1999, and November 4, 2004, 19,747 participants were enrolled at centers throughout North America, with a median potential follow-up time of 4.6 years (range, 1.2-6.5 years). Patient-reported symptoms were collected from all participants using a 36-item symptom checklist. Quality of life was measured with the Medical Outcomes Study Short-Form Health Survey (SF-36), the Center for Epidemiologic Studies-Depression (CES-D), and the Medical Outcomes Study Sexual Activity Questionnaire in a substudy of 1983 participants, median potential follow-up 5.4 years (range, 4.6-6.0 years). Questionnaires were administered before treatment, every 6 months for 60 months and at 72 months. Primary QOL end points were the SF-36 physical (PCS) and mental (MCS) component summaries. Among women in the QOL analysis, mean PCS, MCS, and CES-D scores worsened modestly over the study's 60 months, with no significant difference between the tamoxifen (n = 973) and raloxifene (n = 1010) groups (P>.2). Sexual function was slightly better for participants assigned to tamoxifen (age-adjusted repeated measure odds ratio, 1.22%; 95% CI, 1.01-1.46). Of the women in the symptom assessment analyses, the 9769 in the raloxifene group reported greater mean symptom severity over 60 months of assessments than the 9743 in the tamoxifen group for musculoskeletal problems (1.15 vs 1.10, P = .002), dyspareunia (0.78 vs 0.68, P<.001), and weight gain (0.82 vs 0.76, P<.001). Women in the tamoxifen group reported greater mean symptom severity for gynecological problems (0.29 vs 0.19, P<.001), vasomotor symptoms (0.96 vs 0.85, P<.001), leg cramps (1.10 vs 0.91, P<.001), and bladder control symptoms (0.88 vs 0.73, P<.001). No significant differences existed between the tamoxifen and raloxifene groups in patient-reported outcomes for physical health, mental health, and depression, although the tamoxifen group reported better sexual function. Although mean symptom severity was low among these postmenopausal women, those in the tamoxifen group reported more gynecological problems, vasomotor symptoms, leg cramps, and bladder control problems, whereas women in the raloxifene group reported more musculoskeletal problems, dyspareunia, and weight gain. clinicaltrials.gov Identifier: NCT00003906.

Study of Failure Pattern Among High-Risk Breast Cancer Patients With or Without Postmastectomy Radiotherapy in Addition to Adjuvant Systemic Therapy: Long-Term Results From the Danish Breast Cancer Cooperative Group DBCG 82 b and c Randomized Studies

Postmastectomy radiotherapy (RT) in high-risk breast cancer patients can reduce locoregional recurrences (LRRs) and improve disease-free and overall survival. The aim of this analysis was to examine the overall disease recurrence pattern among patients randomly assigned to receive treatment with or without RT. A long-term follow-up was performed among the 3,083 patients from the Danish Breast Cancer Cooperative Group 82 b and c trials, except in those already recorded with distant metastases (DM) or contralateral breast cancer (CBC). The end points were LRR, DM, and CBC, and the follow-up continued until DM, CBC, emigration, or death. Information was selected from medical records, general practitioners, and the National Causes of Death Registry. The median potential follow-up time was 18 years. The 18-year probability of any first breast cancer event was 73% and 59% (P < .001) after no RT and RT, respectively (relative risk [RR], 0.68; 95% CI, 0.63 to 0.75). The 18-year probability of LRR (with or without DM) was 49% and 14% (P < .001) after no RT and RT, respectively (RR, 0.23; 95% CI, 0.19 to 0.27). The 18-year probability of DM subsequent to LRR was 35% and 6% (P < .001) after no RT and RT, respectively (RR, 0.15; 95% CI, 0.11 to 0.20), whereas the probability of any DM was 64% and 53% (P < .001) after no RT versus RT, respectively (RR, 0.78; 95% CI, 0.71 to 0.86). Postmastectomy RT changes the disease recurrence pattern in high-risk breast cancer patients; fewer patients have LRR as first site of recurrence, and overall fewer patients have DM.

Factors influencing long-term survival following salvage total laryngectomy after initial radiotherapy or conservative surgery

This retrospective study investigated survival outcomes of salvage total laryngectomy (STL) after initial radiation therapy (RT) or larynx conservation surgery (CS) at an academic center. A chart review yielded 64 patients with STL: 53 with RT failures, six with CS failures, and five after RT + CS. Median potential follow-up after STL was 9.4 years (mean, 9.2 years; range, 0.3-17.4 years). Five- and 10-year actuarial overall survival (OS) after STL was 65.2% and 37.7%, respectively. Mean survival after STL was 7.2 years (median, 6.8 years; range, 0.2-17.4 years). No significant survival difference was found between the three treatment groups (p = .50). For 21 patients with nodes assessed at STL, 9-year OS was 45.4% for patients with N0 disease versus 26.7% for patients with N+ disease (p = .25). These data suggest that STL after radiation failure is associated with equivalent long-term survival as STL after RT + CS or after failure of CS alone.

Radiotherapy Following Extrapleural Pneumonectomy(EPP) for Mesothelioma: The Brigham and Women’s Hospital Experience

Purpose/Objective: We have previously published the world’s largest series of patients undergoing EPP for malignant pleural mesothelioma (MPM). (Sugarbaker et al. JCTS 99’) Building on those results we have published the patterns of failure of patients treated with low dose hemithoracic radiation of 30-40Gy (Baldini et al. Ann Thor Surg 97’) demonstrating a benefit to post-operative RT but with a high local failure rate of 65%. Following that publication, two attempts at the BWH/DFCI have been made to improve local control. The first was moderate dose RT 40Gy with concurrent platinum based chemotherapy and the second was high dose hemithoracic RT alone to 54Gy as per the technique of Yajnik et al.(IJROBP 03′) from MSKCC. We report the treatment details and outcome of those patients. Materials/Methods: Between 1999 and 2004, 68 patients were referred to our department following EPP for adjuvant therapy. We reviewed their treatment as part of an IRB approved study. Forty-three patients were treated closer to home and twenty-five patients received adjuvant RT @ BWH/DFCI. Of the 25 patients Median age was 57 years (44–75). 19 patients were male and six were female. 16 patients had epithelial histology with seven patients having mixed and two patients with sarcomatoid histology. Brigham stage 1 in 11 patients, ten had stage 2 and four stage 3. Ten patients were treated with APPA fields to 30Gy to the entire hemithorax with a limited chest wall boost to 40Gy and any grossly positive nodes were boosted to 54Gy. All of these patients received concurrent cisplatin chemotherapy at 50mg/m2 weekly. A second cohort of patients was treated with high dose RT to 54 Gy as per the study of Yajnik et al. The high dose cohort were treated with either sequential adjuvant,(5 patients with pemetrexed based), or neoadjuvant, (9 patients with gemcitabine and platinum)chemotherapy. Results: With a median potential follow-up of 30 months, the median survival of the entire group is 17.5 (95% CI 12.3–22.8) months. Eight patients (32%) remain alive and disease free, seven of these patients were treated with high dose hemithoracic RT and sequential chemotherapy. All had epithelial histology, and 3/8 were node positive. Of the remaining 17 patients who have experienced disease failure, 6 patients have experience death from distant failure alone, 5/6 with diffuse peritoneal disease. 11/25 (44%) patients have had documented local failure. Three patients have experience local only failure 2/3 died of local recurrence in the ipsilateral mediastinum alone. All three failures were in the radiation field. Eight patients experienced local and distant failure with in-field local failure occurring as the first site of failure in 6/8 patients. Of the eleven local in-field failures all were in an areas of the chest that received 30Gy or less because of normal tissue constraints. Conclusions: High dose hemithoracic radiation appears to benefit patients with favorable histology following EPP for MPM. In-field local failure remains a significant obstacle to improvement in outcome for these patients. Alternatives such as IMRT, intraoperative chemotherapy and concurrent RT and pemetrexed regimens are being pursued.

A randomized, phase II trial of ketoconazole plus alendronate versus ketoconazole alone in patients with androgen independent prostate cancer and bone metastases: Figg WD, Liu Y, Arlen P, Gulley J, Steinberg SM, Liewehr DJ, Cox MC, Zhai S, Cremers S, Parr A, Yang X, Chen CC, Jones E, Dahut WL, Center for Cancer Research, National Cancer Institute, Warren Grant Magnuson

Alendronate (AL), a potent oral bisphosphonate, blocks the secretion of matrix metalloproteinase-2 and the establishment of bone metastases in animal models. Ketoconazole (KT) has demonstrated activity in androgen independent prostate cancer (AIPC). In this study we determined whether KT plus AL produced acceptable disease responses compared with KT alone. As the experimental design, 72 patients with progressive AIPC metastatic to bone were randomized to receive KT (1,200 mg daily) plus hydrocortisone (H) (30 mg daily) with or without AL (40 mg daily). Prostate specific antigen (PSA) consensus criteria and radiographic scans were used to determine the proportion of patients with a PSA decrease, time to progression and response duration. The pharmacokinetics of KT and AL were characterized and changes in circulating angiogenic factors were assessed. At a median potential followup of 23.9 months the proportion of patients with a greater than 50% decrease in PSA was similar in the KT/H/AL and KT/H, groups (50% and 47%, respectively). The median duration of response was 8.9 and 6.3 months in the KT/H/AL and KT/H groups, respectively (p = 0.125). Median progression-free survival was not significantly prolonged in the KT/H/AL group (4.6 vs 3.8 months, p = 0.27). There was no significant difference in overall survival between the 2 treatment arms but there was a trend toward improved survival in the KT/H arm (p = 0.074). Toxicity in the 2 groups was mild and there were no clear associations between changes in circulating angiogenic factor levels and clinical outcomes in either treatment arm. There were no statistically significant differences in response rate, progression-free survival or overall survival between KT/H alone and KT/H plus AL treatment in patients with AIPC. The addition of AL to KT/H may increase the response duration with an acceptable safety profile compared with treatment with KT/H alone. However, the addition of AL offers no survival benefit in patients with AIPC.

Treatment of newly diagnosed children with lower-risk leukemia: A collaborative Children’s Cancer Group (CCG)/NCI pilot trial incorporating 6-thioguanine

8539 Background: Although mercaptopurine (MP) is the thiopurine antimetabolite conventionally used in the treatment of childhood acute lymphoblastic leukemia (ALL), thioguanine (TG) is more potent than MP in vitro; and in patients, oral or intravenous TG achieves cytotoxic concentrations in CSF. We therefore performed a pilot study of TG administered orally and by 24 h continuous IV infusion (CIVI), as part of multi-agent chemotherapy, in children with standard risk ALL. Methods: Children with newly diagnosed standard risk ALL (age 1 - 10 yrs, WBC < 50k) were eligible. Treatment was based on the best regimen of the CCG 105 trial, with the addition of CIVI TG (480mg/m2) once during consolidation, twice during each interim maintenance and every 8 weeks during the first year of maintenance, and the substitution of oral TG (60mg/m2/d) for oral MP during maintenance. Red blood cell thioguanine nucleotides (TGNs) concentrations were determined periodically. Results: 58 (31 female) pts, median age 4.3 (range 1.4 - 9.9) yrs, were enrolled. The 8 year event-free survival was 84% (plateau reached at 4 yrs), with an 8 year overall survival of 88% (median potential follow-up 8.9 yrs). There were no CNS relapses and no toxic deaths. Toxicities following CIVI-TG included reversible neutropenia and elevated hepatic transaminases. Six pts experienced reversible veno-occlusive disease (VOD) while receiving oral TG. As the contribution of CIVI-TG to the later development of VOD was not known, the study was amended following the 5th case of VOD to discontinue CIVI TG and change all pts to oral MP. TGN concentrations during oral TG administration averaged 95 ng/8x108 RBC (range 12 -447), greater than observed with oral MP administration. Conclusions: Substituting TG for MP is associated with reversible VOD. However, the lack of CNS relapses in this pilot study suggests that TG may lower the risk of developing CNS leukemia. A subsequent randomized study of oral TG vs. MP was performed by the CCG based, in part, on the results of this trial. No significant financial relationships to disclose.

A phase II trial of docetaxel (D), estramustine (E) and thalidomide (T) in patients with metastatic androgen-independent prostate cancer (AIPC)

4764 Background: We recently published the results of a randomized phase II trial of D+T vs. D alone. With a median potential follow-up of 46.7 mo., the median OS of D+T was 25.9 mo. and 14.7 mo. with D alone (p=0.04 for the overall difference). We subsequently conducted preclinical evaluations of this and other combinations in a PC3 xenograft prostate cancer model using SCID mice which demonstrated that the combination of D+E+T synergistically and superiorly reduced tumor volume when compared with both D alone and the combination of D+T. This may represent the synergistic effects of joining an active chemotherapy regimen with an antiangiogenic agent. To build upon these findings, we initiated a phase II trial of D+E+T in patients with AIPC. Methods: We have enrolled 12 of a planned 60 patients (pts) using standard phase II eligibility criteria. No prior chemotherapy is allowed. Baseline characteristics include a median age of 70 (55–76), Gleason 8 (6–10), PSA 54 (5–486), Alk Phos 108 (68–336), Hb 12.4 (10.5–13.2). Pts received weekly doses of D (30 mg/m2) and E (420 mg/tid on d1, 280 mg/tid on d2, 3) for 3/4 weeks as well as daily T (200 mg/day (d)). Pts also received enoxaparin (1 mg/kg/d to a max. of 80 mg/d) for thrombosis prophylaxis. Results: 12 of 12 pts (100%) have had PSA declines of > 50%. Of the 7 pts with measurable soft tissue disease, 3 had a PR (43%) and 4 had SD (57%). Toxicities likely related to treatment: 1 Gr 3 fatigue, 1Gr 3 neuropathy and 1 Gr 3 docetaxel infusion reaction. There was no Gr 3 or 4 neutropenia. 2 pts developed Gr 3 or 4 thromboses. 1 had a pulmonary embolus (but had not taken prophylactic enoxaparin consistently) and the 2nd had a DVT. T was discontinued in 5 pts after a median of 3 cycles (range 1–7 cycles) largely due to fatigue or thromboses. E was discontinued in 3 pts. 2 pts have gone off study (one due to toxicity and one due to disease progression). The median number of cycles is 5.5, 10 pts are currently receiving therapy. Conclusions: D+E+T has led to PSA decline of > 50% in all 12 pts enrolled on study. Further accrual is ongoing to better define the response rate and characterize the toxicity of this regimen. No significant financial relationships to disclose.