High-dose Schedule Research Articles

Survival of Patients Autografted for Chemosensitive Hodgkin Lymphoma After Failure of Upfront BEACOPP Escalated Versus ABVD-Like Regimens

Abstract 3098 Background.Upfront treatment for advanced Hodgkin lymphoma (HL) is a matter of debate. The wide difference in progression-free survival (PFS) or freedom from treatment failure observed between the intensified regimen escalated (esc) BEACOPP and other standard intensity schedules - such us ABVD, ABVD hybrids and BEACOPP baseline - is in contrast with a small difference in overall survival (OS) [NEJM 2011;365 :203 and JCO 2009;27 :4548]. This fact suggests that high-dose therapy with autologous stem-cell transplantation (HDT/ASCT) can salvage more patients treated with standard intensity schedules than escBEACOPP treated patients. Methods.In order to better understand this subject we analyzed all Swiss cases of refractory/relapsed HL that received HDT/ASCT after failure of at least 4 cycles of upfront escBEACOPP (4 to 8 cycles), given alone or combined with other regimens (cases, n=22) and compared outcomes with a control group of 33 patients transplanted after failure of upfront ABVD (N=18), ABDV-based combinations (hybrids, N=7), BEACOPP baseline (N=5) or up to 3 cycles of escBEACOPP plus radiotherapy (N=3). The high-dose schedule used before transplant was BEAM for 51/55 patients and CBV in 1 case and 3 controls. Results.Controls and cases were statistically similar in terms of timing of transplant (median year 2006 vs 2007), age at transplant (median 33 vs 28 years), sex (males 64% vs 68%), HL subtype, Ann Arbor stage, international prognostic score, ESR (38 vs 59 mm/1h) and bulky presentation (35% vs 60%), but there were significantly more B-symptoms among escBEACOPP patients (77% vs 23%, p=0.007). Furthermore, chemosensitivity (94% vs 82%), timing of relapse after upfront treatment (0–3 months: 30% vs 22%, 3–12 months: 18% vs 23% and >12 months: 52% vs 55%), median number of CD34+ cells reinfused (4.11 vs 2.99 ×10*6/kg), and need for a second salvage (12% vs 27%) were not significantly different in the two groups.After a median post transplant follow up of 42.5 months, median PFS was 15.4 months for escBEACOPP, and was not reached for control cases (p=0.145). Two-years OS was 84% for controls (95% CI 65%-93%) and 72% for escBEACOPP (95% CI 45%-87%), while 5-years OS was 68% (95% CI 44%-84%) and 65% (95% CI 37%-83%) for controls and cases, respectively. Four of 33 controls (12%) and 3 of 22 (14%) upfront escBEACOPP cases received an allograft for relapsed HL after HDT/ASCT (p=NS). The incidence of severe (grade 3–4) anemia, thrombocytopenia, neutropenia, diarrhea, stomatitis and neutropenic fever was similar in the two groups. Regarding uncommon/unexpected toxicities of HDT/ASCT, one patient in the escBEACOPP group developed grade 4 encephalopathy, whilst in the control group we observed two cases of acute renal failure, one ARDS and one fatal stroke. One patient in the control group was diagnosed with a T-cell lymphoma after transplant (p=NS). Three t-MDS plus one t-AML were recorded among patients in the escBEACOPP group, with no cases of t-AML/t-MDS occurring among those treated with the less intensive approaches (p=0.023). Conclusion.In our series, overall survival of chemosensitive HL patients autografted after failure of either upfront escBEACOPP or standard intensity regimens is encouraging. HDT/ASCT consolidation of chemosensitive patients failing upfront escBEACOPP seems justified. [Display omitted] [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Safety and pharmacokinetics of high-dose gefitinib in patients with solid tumors: results of a phase I study

Previous studies established the safety of continuous gefitinib 250 or 500mg daily. It was postulated that a higher dose may have increased efficacy by inhibiting signaling in both the mitogen-activated protein kinase and AKT pathways. This study investigated the tolerability, pharmacokinetics, and antitumor activity of high-dose gefitinib in patients with refractory solid malignancies. Sequential cohorts received oral gefitinib once or twice-weekly, with dose escalation from 1,500 to 3,500mg. Twenty-three patients received gefitinib at seven dose levels (1,500, 2,000, 2,500, 3,000, and 3,500mg once-weekly; 1,500 and 2,000mg twice-weekly). Gefitinib was well tolerated, with no dose-limiting toxicities. The maximum tolerated dose was not reached. The most common gefitinib-related adverse events were nausea and diarrhea, vomiting, and rash. Pharmacokinetic data demonstrated no consistent increase in exposure to gefitinib with increasing dose across cohorts. Consequently, the study was stopped early and gefitinib 2,000mg twice-weekly was the highest dose administered. One of eight patients with non-small-cell lung cancer achieved a partial response. Exposure to gefitinib did not increase consistently with increasing dose beyond gefitinib 1,500mg once-weekly or twice-weekly. These data do not support further evaluation of gefitinib at high-dose schedules.

High-dose thiotepa, etoposide and carboplatin as conditioning regimen for autologous stem cell transplantation in patients with high-risk non-Hodgkin lymphoma

High-dose chemotherapy conditioning regimens followed by autologous stem cell transplantation generally provide good results in non-Hodgkin lymphoma. We have evaluated the effects of a high-dose regimen comprising thiotepa, etoposide and carboplatin. After debulking and mobilization with high-dose cyclophosphamide or other schedules, forty-five patients at various disease stages were conditioned with thiotepa, etoposide and carboplatin prior to autologous stem cell transplantation. The overall response rate was 77.8% (30 CR, 66.7%; 5 PR, 11.1%). Ten patients (22.2%) did not respond. Two patients (4.4%) died from transplant-related complications. The mean 5-year overall survival was 71.1%: 12 patients relapsed within the first 5 years of follow-up. The overall response rate and 5-year overall survival were better for patients with an International Prognostic Index (IPI) 1 at diagnosis than for those with IPI 2 and IPI 3 (P<0.005 for all). The thiotepa, etoposide and carboplatin conditioning regimen for autologous stem cell transplantation in non-Hodgkin lymphoma has a good anti-lymphoma effect and provides encouraging results in terms of response to treatment and 5-year overall survival. Its good tolerance and acceptable toxicity suggest that it may a very useful in the management of non-Hodgkin lymphoma.

Pegfilgrastim to accelerate neutrophil engraftment following peripheral blood stem cell transplant and reduce the duration of neutropenia, hospitalization, and use of intravenous antibiotics: a phase II study in multiple myeloma and lymphoma and comparison with filgrastim-treated matched controls

This trial was aimed to explore the efficacy of pegfilgrastim to accelerate neutrophil engraftment after stem cell autotransplant. Twenty patients with multiple myeloma and 20 with lymphoma received pegfilgrastim 6 mg on day +1. Forty cases treated with daily filgrastim starting at median day +7 (5–7), matched by age, sex, diagnosis, high-dose chemotherapy schedule, CD34+ cell-dose, and prior therapy lines, were used for comparison. Median time to neutrophil engraftment was 9.5 vs. 11 days for pegfilgrastim and filgrastim, respectively (p < 0.0001). Likewise, duration of neutropenia, intravenous antibiotic use, and hospitalization favored pegfilgrastim, while platelet engraftment, transfusion requirement, and fever duration were equivalent in both groups. No grade ≥3 toxicities were observed. Patients with lymphoma performed similarly to the entire cohort, while patients with myeloma showed faster neutrophil engraftment and shorter neutropenia but not shorter hospitalization and antibiotic use. The possibility of different outcomes for lymphoma and myeloma suggests that stratification by diagnosis may be useful in future phase III studies.

Refractory recurrent bleeding as a late mortal complication of chest wall irradiation

Radiation therapy is used to treat breast malignancies. Old external radiotherapy protocols included high-dose schedules and were associated with late complications. We describe the case of a 72-year-old woman who was admitted with recurrent bleeding from chest wall. Arteriovenous fistulae were diagnosed. Embolization therapy was initially successful, even though the bleeding episodes became recurrent. Arteriovenous fistulae should be included among differential diagnosis of thoracic bleeding in patients with history of local radiation therapy. The prognosis is poor and endovascular treatment may be considered a first-line treatment.

Death due to intestinal obstruction in a patient treated with clozapine

A 53 year old female diagnosed with long term resistant schizophrenia, ischaemic heart disease and hypertension was treated with 700 mg/day of clozapine. Five months after commencing treatment, she complained of acute onset colicky abdominal pain and nausea with constipation of one days duration. Suspecting intestinal obstruction, she was referred from a psychiatry unit to the casualty ward. On examination, she had a distended abdomen and tenderness. No abdominal masses were detected. A stool softener and lactulose was given. However, five hours later, she died. Autopsy revealed a grossly distended intestine extending from the stomach to the rectum. There were solid and liquid faeculent material commencing from the oesophagus through to the rectum. No mechanical obstruction was evident. A sector of the ileum showed an area of patchy haemorrhage. Histology showed villous atrophy with flattened epithelial cells and fibrosis of the lamina propria. The heart had a few scattered areas of fibrosis. Other macroscopic and microscopic findings were unremarkable. The cause of death was recorded as intestinal obstruction probably induced by clozapine. The literature has reported a prevalence of constipation associated with clozapine ranging from 14-60%. Higher dose schedules and prolonged treatment are contributory factors. Deaths from clozapine have been reported due to intestinal obstruction, aspiration of faeculent matter, perforation and peritonitis and following surgery to decompress the bowel. DOI: 10.4038/sljpsyc.v1i2.2578 SL J Psychiatry 2010; 1 (2): 64-66

Possible involvement of peripheral serotonin 5-HT3 receptors in fluvoxamine-induced emesis in Suncus murinus.

Selective serotonin reuptake inhibitors fluvoxamine and fluoxetine, as well as serotonin (5-HT), induced vomiting in Suncus murinus (a house musk shrew). Fluvoxamine- and fluoxetine-induced vomiting gradually decreased with their repeated administration. Vomiting induced by serotonin also decreased with repeated treatment with serotonin. In these shrews, fluvoxamine-induced vomiting was partially inhibited. Fluvoxamine might induce vomiting, at least partially, by indirectly activating peripheral 5-HT(3) receptors, since serotonin has been reported to induce vomiting by activating peripheral 5-HT(3) receptors and granisetron, a 5-HT(3) antagonist, partially suppressed fluvoxamine-induced vomiting in our previous finding. In addition, fluvoxamine-induced vomiting was impaired more effectively using a step-wise dose-up schedule of fluvoxamine than a fixed high-dose schedule. Therefore, a careful dosing strategy starting with a low dose might be effective for avoiding emesis associated with the clinical use of fluvoxamine.

Pegfilgrastim Accelerates Neutrophil Engraftment, Reduces the Number of Neutropenic and Hospitalization Days and the Use of Antibiotics After Autologous Peripheral Blood Stem Cell Transplant for Multiple Myeloma and Lymphoma. A Phase II Study and Comparison with a Filgrastim Treated Historical Cohort.

Abstract 2274Poster Board II-251 Introduction:Granulocyte Colony-Stimulating Factor (G-CSF) is regularly used after autologous peripheral blood stem cell transplant (ASCT) to accelerate neutrophil engraftment. The result is a reduction of the number of febrile days, antibiotic use and duration of hospitalization, resulting in a reduction of costs. Randomized trails demonstrated that further cost reduction is obtained by delaying the beginning of G-CSF therapy from day 1 to days 5-7 post transplant without significantly changing the time to neutrophil recovery, despite a trend to better results when the drug was started on day 1. Pegfilgrastim is a sustained duration form of filgrastim administered as a single-fixed s.c. dose, a schedule that is more patient friendly. Moreover, as the drug is given in a single shot, there is no need to delay the therapy to decrease treatment costs. This trial was conducted to assess the efficacy and safety of pegfilgrastim to enhance neutrophil recovery after ASCT. Patients and Methods:in this bi-institutional phase II trial 40 patients with Multiple Myeloma (N=20), Hodgkin Lymphoma (N=8) and Non-Hodgkin Lymphoma (N=12) were accrued from January 2007 to December 2008. Pegfilgrastim 6 mg s.c. was administered on transplant day 1. Results were compared with a historical control group of 40 patients (20 with myeloma and 20 with lymphoma) treated with filgrastim 5μg/kg/d s.c. starting at median day 7 after transplant (range 3-7). All lymphoma patients (cases and controls) received BEAM as high dose schedule, while the 40 multiple myeloma patients were treted with MEL200. If tandem transplants were planned, only the first procedure was eligible to the study. Differences between groups were estimated by two-sample t-test and Wilcoxon rank-sum test. A two sided p-value of <0.05 was considered statistically significant. Results:case and control populations were statistically similar in terms of age, sex, disease, conditioning regimen, CD34+ cell-dose and number of prior therapy lines. Median time to achieve a neutrophil count > 500/μl was 9.5 vs 11.3 days for case and controls, respectively (p<0.0001); median duration of neutropenia was 5.8 vs 7.4 days (p=0.0001); median time to platelet count > 20000/μl was 11.9 vs 11.4 days (p=0.42); median duration of fever was 3.4 vs 4.6 days (p=0.3); median duration of i.v. antibiotic therapy was 4.2 vs 6.5 days (p=0.0007); median hospitalization duration was 14 vs 14.8 days (p=0.0184, N.S. at t-test). Both groups received an equal number of RBC and platelet transfusions. Pain was present in 12.5% of patients in the experimental group and lasted for a median of 3 days (2-9). No other toxicities related to pegfilgrastim were observed. The control group received a median of 6.5 doses of filgrastim (range 4-10). Market prices per treatment are 2076.75 vs 1534.90 Swiss Francs for pegfilgrastim and filgrastim, respectively. Conclusions:Pegfilgrastim given as a single dose of 6 mg s.c. on transplant day 1 accelerates neutrophil engraftment, shortens the duration of neutropenia and hospitalization and reduces the use of i.v. antibiotics compared to daily filgrastim. The 25% increase in costs when using pegfilgrastim is counterbalanced by a shorter time on antibiotics and a tendency to a shorter time in hospital. Disclosures:Wannesson:AMGEN: Research Funding. Off Label Use: Pegfilgrastim is a pegilated formulation of filgrastim, a reccombinant human granulocyte colony stimulating factor. It has a long half life allowing a single dose treatment instead of multiple repeated doses. In general it has been shown equivalent results comparing to filgrastim in all clinical settings, even if still off-label for some indications, like the post-autologous transplant support (matter of the present abstract). Ghielmini:AMGEN: Research Funding. Ketterer:AMGEN: Research Funding.

Molecular Response to Nilotinib 600 Mg Bid for Imatinib Resistance in a Patient with CML AP with Multiple Mutations Including G250E and E255K.

Abstract 4287Resistance to imatinib has emerged as a common management problem that has been addressed first by dose escalation and later by the use of second generation tyrosine kinase inhibitors (2TKI). In about half the cases the basis for acquired resistance to imatinib is the emergence of mutant bcr-abl whose “in vitro” sensitivity to 2TKIs has been reported. In theory, mutations with intermediate “in vitro” sensitivity to nilotinib could be overcome by the use of higher doses (600mg bid).Higher doses of nilotinib have been administered safely in phase I and II clinical trials involving patients in CP, AP and BC of CML. Total steady-state drug levels were reported in 18 patients receiving the 600mg bid and a dose-proportional increase in exposure was observed between the 400mg and 600mg bid schedules. The mean serum trough level at the steady-state was 1.7(mu)M at 400mg bid and 2.3(mu)M at 600mg bid.We present and discuss the successful use of 600mg bid of nilotinib in a patient with Chronic Myeloid Leukemia (CML) resistant to imatinib 800mg qd and to nilotinib 400mg bid in whom G250E and E255K mutations were sequentially detected. Previous publications have suggested that E255K is unresponsive to nilotinib.A 44 years old male was diagnosed with chronic phase CML with intermediate risk Sokal score and no histocompatible siblings; six months after diagnosis imatinib 600mg qd was started due to progression to AP. The patient achieved hematologic and cytogenetic remissions in 2 and 12 months respectively. Nineteen months later, loss of hematologic response was detected. Trials of imatinib 800mg qd and low dose Ara-C were not effective. Mutational analysis of bcr-abl revealed G250E, a p-loop mutation, with in vitro sensitivity to nilotinib. Within six months the patient had symptomatic transfusion-dependent anemia (Hb < 7 g/dL), bone pain, hepatomegaly and painful lymphadenopathy. Nilotinib 400mg bid was initiated with significant clinical improvement (becoming asymptomatic and transfusion independent in a few weeks). Within 18 months a complete cytogenetic response and a 2 log reduction of the bcr-abl transcripts by quantitative PCR was demonstrated (IS: 1,48%). Loss of hematologic response was observed six months later. There was quick deterioration of clinical status. A second mutation analysis demonstrated G250E and E255K.Nilotinib was then increased to 600mg bid with rapid clinical improvement, followed by CHR in four weeks. Weekly CBC and chemistry profile as well as monthly EKG's were performed for safety. Due to marrow fibrosis cytogenetics was not available, but a major molecular response could be demonstrated after 3-months with 4 log reduction of bcr-abl transcripts (IS: 0,026%). The depth of molecular response has continued to improve with 5 log reduction after seven months (IS: 0,0026%). No serious side effects was seen on the higher dose schedule. Mild indirect hyperbilirrubinemia has remained stable on serial measurements. There was no significant change in the QTc interval (baseline QTc: 0,33).Due to a favourable toxicity profile, nilotinib 600mg bid may be an option for refractory patients with mutations of intermediate sensitivity to nilotinib and who have progressed, especially when a suitable bone marrow donor is not identified. Disclosures:No relevant conflicts of interest to declare.

Current experience with mIBG therapy in combination with chemotherapy and radiosensitizers

Abstract Introduction [ 131 I] meta -iodobenzylguanidine ([ 131 I]mIBG) has been used for decades to treat childhood neuroblastoma and adult neuroendocrine tumors, which express the norepinephrine transporter molecule. The scheduling has changed over time in attempts to improve its efficacy. The treatment intent has gone beyond simple palliation to the use of mIBG as part of a radical potentially curative approach in some patients. As chemotherapy is an established part of the treatment of high-risk neuroblastoma and mIBG works through a different mechanism, there is a rationale for combining these treatments. If there is no interaction, an additive effect may be seen. Some drugs interfere with repair of DNA damaged by radiation and act as radiation sensitizers so will be synergistic with mIBG therapy. Methods A literature search was undertaken to identify published reports of the use of mIBG therapy in both neuroblastoma and adult neuroendocrine tumors in combination with chemotherapy or radiosensitizers. The resulting literature has been reviewed and interpreted. Results There are convincing preclinical data to suggest that the combined use of mIBG and chemotherapy and radiosensitizers may be synergistic. Phase 1 and 2 series indicate that such combinations are practicable to deliver at both conventional doses and with high-dose schedules requiring hemopoietic support. However, there are as yet no randomized phase 3 trials proving the superiority of combined treatments over mIBG alone. Conclusions Large-scale clinical trials are required to ascertain whether the synergy of combined mIBG and chemotherapy treatment schedules predicted by preclinical studies occurs in clinical practice.

CONCEITOS DE CINÉTICA TUMORAL APLICADOS À QUIMIOTERAPIA PARA O CÂNCER DE MAMA

A maioria das pacientes com câncer de mama está sujeita à quimioterapia, e os comprovados benefícios da quimioterapia adjuvante na sobrevida global e livre de doença podem ser explicados pelos conceitos de eliminação celular. A aplicação dos conceitos de eliminação logarítmica de Skipper ao crescimento do câncer de mama humano, o qual parece seguir a cinética gompertziana, sugere que não apenas o uso de drogas sem resistência cruzada seja importante, mas a dose e a intensidade da quimioterapia administrada sejam variáveis clinicamente importantes que podem ser manipuladas para aumentar a sobrevida dos pacientes. Esta revisão da literatura apresenta alguns conceitos teóricos de cinética tumoral importantes para o entendimento de dados empíricos no campo da quimioterapia adjuvante do câncer de mama. A elaboração dos esquemas quimioterápicos é abordada com relação a dose e eficácia dos agentes componentes e quanto ao conceito de intensidade de dose da dose administrada, com aumento das doses e redução dos intervalos entre os ciclos objetivando a otimização, formulando esquemas de alta-dose e dose-denso. A hipótese de Norton-Simon, em que a terapia seqüencial poderia tornar o esquema de administração de agentes citotóxicos dose-densa e que estes esquemas teriam vantagens sobre os esquemas convencionais de administração de drogas também são discutidos.

A phase I dose escalation pharmacokinetic (PK) and pharmacodynamic (PD) study of weekly and twice weekly erlotinib in advanced stage solid malignancies

3594 Background: Erlotinib is a potent oral TKI of the epidermal growth factor receptor (EGFR). At the current recommended daily dose of 150 mg/day there is activity in advanced stage NSCLC, but with frequent grade 1/2 rash and diarrhea. We performed a phase I dose escalation study of erlotinib with a once and twice weekly schedule to assess the PKs, PDs, and to determine if toxicities would be less on an intermittent but high dose schedule. Methods: A standard dose escalation schedule starting at 1,400 mg once/week and 600 mg twice/week with increments of 200 mg to 4 dose cohorts/schedule was utilized with three patients per cohort. A cycle consisted of 3 weeks of therapy. PKs were performed on cycle 1 and 2. PDs on normal skin punch biopsies were performed at baseline and after cycle 1. Tumour evaluation was done following every 2nd cycle. Subjects were treated until progression or unacceptable toxicity. Results: 32 patients were enrolled from Oct 2004-April 2006. Median age 58 years (28–74 years); median PS 1 (0–2); and median prior palliative systemic regimens 2 (0–6). In the once weekly schedule the maximum tolerated dose (MTD) was not reached with the top dose of 2,000 mg/week. A median of 2 cycles were delivered (1–14), with 3/13 patients achieving stable disease = 3 months. 4/13 patients had G1 rash and 6/13 patients G1 diarrhea during the first 2 cycles. In the twice weekly schedule the MTD was reached at 1,200 mg twice/week with 2/6 subjects experiencing G3 rash. The recommended dose level is 1,000 mg twice/week. A median of 4 cycles were delivered (1–28) with 2 partial responses, 1 minor response and 6 stable disease = 3 months out of 19 patients in total. G1/2 rash or diarrhea occurred in 13 and 9 patients respectively. No corneal toxicity was seen. The PK data demonstrated a variable but linear pattern. At 1,000 mg twice/week the median Cmax, Tmax and AUC0–24 hr was 6.28 μg/ml, 2 hours and 135 μg.h/ml respectively. PD analysis is ongoing. Conclusions: A once weekly and twice weekly high dose schedule of erlotinib is feasible, with MTD not reached in the once weekly schedule. A recommended dose of 1,000 mg twice/week has clinical activity, is generally well tolerated, and results in significantly higher systemic exposure than the 150 mg once daily dose. No significant financial relationships to disclose.

A multicenter phase 2 clinical trial testing a combination of oxaliplatin, bolus 5-fluorouracil, leucovorin and capecitabine in patients with metastatic colorectal cancer (MCRC)

14526 Introduction: The combination of oxaliplatin (OX) with bolus and infusional 5FU has shown high activity in MCRC. Substituting capecitabine (CAPE) for 5FU in a novel high-dose schedule designed to mimic FOLFOX-6 is a feasible and well tolerated treatment (Hegeman, ASCO, 2005, #2058). A multicenter phase 2 study of this combination was performed to evaluate efficacy in first-line treatment of MCRC. Methods: Eligible patients have ECOG PS 0–2, no grade 2 or higher neuropathy, and no prior systemic treatment for metastatic cancer. Patients are treated with OX 100 mg/m2, leucovorin (LV) 20 mg/m2 and 5FU 400 mg/m2 IV bolus followed by CAPE 1500 mg/m2 PO Q8H x 6 doses, repeated every two weeks. The primary endpoint was confirmed antitumoral response. Patients were allowed to come off study to pursue surgical resection, if feasible. Results: 36 out of a planned 45 patients have been enrolled since 6/04. Survival (OS) and time to progession (TTP) data are available for all 36 patients. Toxicity and efficacy data is available for 33 patients. The median age of enrolled patients is 65.5 years (range 42–78). 16 (44%) of patients are male. 94% of patients are ECOG PS 0 or 1. Toxicity data is presented in the table . 14/33 (42%) of patients had a grade 3/4 toxicity (see table ). The response rate was 33% (95% confidence interval [CI] 18–52%): 11 patients achieved a partial response (33%), 14 (42%) had stable disease, and 8 (24%) had progressive disease. Median overall survival was 17.1 months (M) (CI 0.7+-27.5+ M). The one-year survival rate was 67%. The median TTP/TTF was 4.1 M (CI 0.3–14.3 M). Four (11%) patients have come off of the study protocol to pursue metastatectomy. Conclusion: OX, infusional 5FU, LV and CAPE is active and well tolerated in MCRC. This regimen had fewer episodes of grade 3–4 hand-foot syndrome and mucositis than prior regimens including longer durations of capecitabine. Study supported by sanofi-aventis. [Table: see text] [Table: see text]

In-vitro differential metabolism and activity of 5-fluorouracil between short-term, high-dose and long-term, low-dose treatments in human squamous carcinoma cells

Although continuous infusion of 5-fluorouracil (5-FU) has been clinically demonstrated to be superior to bolus administration, the mechanistic difference between the treatments still remains unclear. Here, we investigated in vitro whether there were any differences in the metabolism and activity of 5-FU between these schedules. To simulate bolus and infusional treatments of 5-FU, HST-1 human squamous carcinoma cells were treated with short-term, high-doses and long-term, low-doses so that the area under the curve (AUC) of 5-FU became equivalent between both schedules, and compared the cytotoxicity, fluorinated RNA (F-RNA) levels, 5-fluorodeoxyuridine monophosphate (FdUMP) content and thymidylate synthase (TS) activity. F-RNA and FdUMP were measured by capillary gas chromatography-mass spectrometry and competitive ligand-binding assay, respectively. The [H]FdUMP binding site in TS was determined as an index of the amount of TS using the radio-binding assay. Long-term, low-dose treatment of 5-FU was found to be 1.3-1.7 times more cytotoxic than the short-term, high-dose treatment. F-RNA content increased as the AUC of 5-FU was increased and was 2-4 times significantly higher in the cells treated with the long-term, low-dose than those with the short-term, high-dose schedule, indicating that the levels of F-RNA are AUC and schedule dependent. In contrast, there were no significant differences in FdUMP levels, TS activity and TS inhibition rate between the schedules. These data suggest that the superior activity of 5-FU administered long-term, low-dose over short-term, high-dose could be explained by more 5-FU incorporated into RNA during a long-term, low-dose exposure, thus providing a strategic rationale for the clinical advantage of continuous infusion over bolus administration.

Rapidly progressing high o,p'DDD doses shorten the time required to reach the therapeutic threshold with an acceptable tolerance: preliminary results

It has been reported that the therapeutic threshold of mitotane, plasma level above 14 microg/ml, is achieved within 3-5 months after o,p'DDD treatment initiation in patients with adrenocortical carcinoma (ACC). We evaluated pharmacokinetic and tolerance of a high-dose schedule of pure o,p'DDD treatment given in 500-mg tablets of mitotane (Lysodren, Bristol-Myers Squibb, HRA Pharma, Paris, France) in four patients with ACC and two patients with Cushing's syndrome-related endocrine tumours. It was administered at a starting dosage of 3 g/day, which was rapidly increased to 6-9 g/day within 2 weeks according to digestive tolerance and then adjusted according to tolerance and plasma o,p'DDD monitoring. Patients were followed up until they reached the therapeutic threshold of mitotane, and toxicity was recorded. A relationship between o,p'DDD dose and plasma level was sought. The highest starting dosage given ranged between 6 and 9 g a day, during the first two weeks. The daily maintenance dose ranged 4.5-9 g during the next 2 weeks and 3-9 g by the second month of treatment. The therapeutic threshold was reached in all four patients who received o,p'DDD treatment for at least 1 month. Among these four patients, the toxic threshold (plasma mitotane level > 20 microg/ml) was even reached at 6 weeks of therapy in three patients. Grade 1, 2 or 3 toxicity was observed in 3, 2 and 1 patients, respectively. Toxicity resolved after reduction or discontinuation of o,p'DDD therapy. A significant linear correlation was found between plasma mitotane dose and plasma level. These results suggest that a high-dose o,p'DDD therapeutic schedule is feasible with an acceptable toxicity and may shorten the time required to reach the therapeutic schedule from 3-5 months to 4 weeks. These patients require a close follow-up, combining clinical and plasma o,p'DDD level monitoring every second week. A confirmatory study is ongoing.

Phase II, 3-arm study of CCI-779 in combination with letrozole in postmenopausal women with locally advanced or metastatic breast cancer: preliminary results

544 Background: CCI-779, a novel mTOR kinase inhibitor, is well tolerated and has shown antitumor activity in heavily pretreated patients (pts) with metastatic breast cancer (MBC). The combination of CCI-779 (CCI) and antiestrogens has an additive effect in preclinical models of breast cancer. Thus, the objective of this clinical trial is to evaluate preliminary activity of CCI in combination with letrozole. Methods: Randomization is in a 1:1:1 ratio (∼30 evaluable pts/arm), letrozole alone: letrozole with CCI daily (CCI daily arm): letrozole with CCI daily for 5 days every 2 weeks (CCI intermittent arm). All pts receive 2.5 mg letrozole daily. Results: Fifty-five pts have been enrolled. Initially, 6 pts were enrolled on each of the high-dose (HD) schedules, 25 mg CCI daily and 75 mg CCI intermittent; 3 pts in each arm had toxicity that resulted in dose delay/reduction or discontinuation. Thus, the protocol was amended and doses were reduced to low-dose (LD) schedules, 10 mg CCI daily and 30 mg CCI intermittent. As of 01 Dec 2003, 12 and 23 pts were enrolled on the HD and LD schedules, respectively. The median age was 60 yrs (range, 42–81). Safety data are available for 12 pts treated with the HD schedules (25 mg, 6 pts; 75 mg, 6 pts), 11 pts treated with the LD schedules (10 mg, 4 pts; 30 mg, 7 pts), and 12 pts treated with letrozole alone. The most frequently occurring grade 3–4 CCI-related toxicity was stomatitis for the HD schedules (2/6 pts, 2/6 pts) and diarrhea for the LD schedules (0 pts, 1/7 pts). No grade 3–4 toxicities were reported for pts treated with letrozole alone. Of 55 pts, 7 have been on study for 40+ wks. Preliminary tumor responses (RECIST) are available for 19 evaluable pts. CCI pts (n=13) had 1 complete response (HD schedule), 3 partial responses (HD schedules), 9 stable disease (6 pts on HD schedules, 3 on LD schedules; SD ≥ 24 wks for 4 pts on HD schedules). Letrozole-alone pts (n=6) had 2 PR and 4 SD (SD ≥ 24 wks for 1 pt). Conclusions: The combination of letrozole with 10 mg CCI daily or 30 mg CCI intermittent showed favorable results for tolerability. Accrual is continuing. A phase 3 study will be performed to confirm efficacy. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Wyeth Research Wyeth Pharmaceuticals Wyeth Pharmaceuticals Wyeth

Phase II, 3-arm study of CCI-779 in combination with letrozole in postmenopausal women with locally advanced or metastatic breast cancer: preliminary results

544 Background: CCI-779, a novel mTOR kinase inhibitor, is well tolerated and has shown antitumor activity in heavily pretreated patients (pts) with metastatic breast cancer (MBC). The combination of CCI-779 (CCI) and antiestrogens has an additive effect in preclinical models of breast cancer. Thus, the objective of this clinical trial is to evaluate preliminary activity of CCI in combination with letrozole. Methods: Randomization is in a 1:1:1 ratio (∼30 evaluable pts/arm), letrozole alone: letrozole with CCI daily (CCI daily arm): letrozole with CCI daily for 5 days every 2 weeks (CCI intermittent arm). All pts receive 2.5 mg letrozole daily. Results: Fifty-five pts have been enrolled. Initially, 6 pts were enrolled on each of the high-dose (HD) schedules, 25 mg CCI daily and 75 mg CCI intermittent; 3 pts in each arm had toxicity that resulted in dose delay/reduction or discontinuation. Thus, the protocol was amended and doses were reduced to low-dose (LD) schedules, 10 mg CCI daily and 30 mg CCI intermittent. As of 01 Dec 2003, 12 and 23 pts were enrolled on the HD and LD schedules, respectively. The median age was 60 yrs (range, 42–81). Safety data are available for 12 pts treated with the HD schedules (25 mg, 6 pts; 75 mg, 6 pts), 11 pts treated with the LD schedules (10 mg, 4 pts; 30 mg, 7 pts), and 12 pts treated with letrozole alone. The most frequently occurring grade 3–4 CCI-related toxicity was stomatitis for the HD schedules (2/6 pts, 2/6 pts) and diarrhea for the LD schedules (0 pts, 1/7 pts). No grade 3–4 toxicities were reported for pts treated with letrozole alone. Of 55 pts, 7 have been on study for 40+ wks. Preliminary tumor responses (RECIST) are available for 19 evaluable pts. CCI pts (n=13) had 1 complete response (HD schedule), 3 partial responses (HD schedules), 9 stable disease (6 pts on HD schedules, 3 on LD schedules; SD ≥ 24 wks for 4 pts on HD schedules). Letrozole-alone pts (n=6) had 2 PR and 4 SD (SD ≥ 24 wks for 1 pt). Conclusions: The combination of letrozole with 10 mg CCI daily or 30 mg CCI intermittent showed favorable results for tolerability. Accrual is continuing. A phase 3 study will be performed to confirm efficacy. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Wyeth Research Wyeth Pharmaceuticals Wyeth Pharmaceuticals Wyeth

Fludarabine and cyclophosphamide using an attenuated dose schedule is a highly effective regimen for patients with indolent lymphoid malignancies.

Preclinical data have supported the use of fludarabine and cyclophosphamide (FC) in combination for the treatment of indolent lymphoid malignancies. Previously reported schedules were highly effective, but were complicated by significant myelotoxicity and infectious complications. In the current study, the authors analyzed their experience with an attenuated dose regimen to determine whether equivalent efficacy could be achieved with reduced toxicity. Sixty-four patients with indolent lymphoid malignancies were treated with intravenous fludarabine at a dose of 25 mg/m(2) and cyclophosphamide at a dose of 250 mg/m(2), each given on Days 1-3 for a median of 4 cycles. The median age of the patients was 60 years. Nineteen percent of the patients were previously untreated, and 45% had refractory disease; the patients had received a median of 2 prior therapies. With regard to histology, 41% of the patients had chronic lymphocytic leukemia or its variants, whereas the remainder of patients had low-grade non-Hodgkin lymphoma, predominantly follicule center cell lymphoma. A total of 237 cycles were delivered. The principal toxicities reported were neutropenia (NCI CTC Grade 4 in 17% of cycles) and infection (Grade >/= 3 in 6% of cycles). The overall response rate and complete response rate were 86% and 29%, respectively. No significant difference could be discerned with regard to response rates for patients with untreated, recurrent, or refractory disease. The FC schedule used in the current study was found to be highly effective in patients with indolent lymphoid malignancies. Toxicity was lower compared with higher dose schedules, whereas efficacy appeared to be equivalent.

In regard to ?the return of the snake oil salesman? (IJROBP 2003;55:561?562, and 56:1507?1508)

As a UK clinical oncologist with a major interest in developing radiotherapy techniques, I have followed with wry amusement the recent correspondence. We do not have a “snake oil salesman” for intensity modulated radiotherapy (IMRT) in the UK—quite the opposite. We have to produce the evidence to hard-headed, cost-conscious Health Service managers before implementing changes of routine practice. We need to do the research in approved protocols to enable patients to have access to new technologies in the National Health Service. Thus trials of conformal and dose-escalated radiotherapy have been performed in prostate cancer (1, 2), and conformal radiotherapy is now recommended in national guidelines (3). Trials with IMRT are under way, including Phase I/II dose escalation trials in head-and-neck cancer and pelvic lymph node treatment for prostate cancer, but most importantly phase III studies have commenced in head-and-neck cancer with a parotid-sparing protocol and in breast cancer to assess the potential benefits of IMRT in producing a more uniform dose distribution to improve cosmesis. A study group has been formed to design a pelvic IMRT trial comparing standard dose therapy delivered with IMRT compared to conventional field shaping and will include a wide range of pelvic cancers. Additionally, the UK Department of Health is supporting the development of a Phase III national trial of IMRT in localized prostate cancer comparing conventional high-dose treatment with hypofractionated (4-week) high-dose schedules. The spinoff from such studies will be not only the outcome data that Dr. Glatstein calls for, but also quality assurance and technology transfer programs that will help the safe and efficient introduction of IMRT into the majority of UK radiotherapy departments.

Dose optimization of recombinant factor VIIa for control of mild to moderate bleeds in inhibitor patients: improved efficacy with higher dosing

Optimal dosing schedules of recombinant factor VIIa (rFVIIa) for the treatment of mild to moderate bleeding episodes in hemophilia patients with inhibitors are currently the subject of much debate. Standard doses of 90 to 110 μg/kg have provided hemostatic efficacy in many cases in the current literature. However, recent studies using doses greater than 200 μg/kg suggest that high-dose regimens may not only be more effective, but may also reduce the number of doses required. Work using in vitro models has indicated that the increased efficacy of high-dose rFVIIa may be attributed to accelerated clot formation and a stronger, more rapid thrombin burst on the surface of activated platelets. Before higher dosing schedules become more widely used, however, a number of unanswered questions remain to be resolved. It is expected that ongoing and future trials will help to clarify some of these issues. Until such information is available, it is recommended that children and adolescents may be treated with a single bolus dose of 300 μg/kg rFVIIa within 1 to 2 hours of bleed onset. Due to a current lack of information regarding high-dose rFVIIa therapy in adults, however, it would be prudent to use standard doses (90 μg/kg every 2 to 3 hours for two or three doses) in this patient population.