Relapse-free Interval Research Articles

Association Study of the G-Protein β3 Subunit C825T Polymorphism with Disease Progression an Overall Survival in Patients with Head and Neck Squamous Cell Carcinoma

The T-allele of a common C825T single nucleotide polymorphism (SNP) in the gene GNB3, encoding the G3 subunit of heterotrimeric G-proteins, is associated with a truncated form of the G3 protein that imparts a greater signaling capacity than the alternative C-allele encoding a nontruncated protein. We analyzed the C825T-allele status with regard to disease progression in patients with head and neck squamous cell carcinoma (HNSCC). The prognostic value of the SNP was evaluated in an unselected series of 341 patients treated with curative intent for HNSCC including all tumor stages with different therapeutic regimens. Genotype analysis was done by Pyrosequencing using DNA from paraffin-embedded tissue samples. Genotypes were correlated with relapse-free and overall survival. Proportions of 5-year relapse-free intervals were 62% for CC, 60% for TC, and 42% for TT genotypes. Kaplan-Meier curves revealed a significant genotype-dependent relapse-free interval (P = 0.036). In multivariate analysis with stage, localization, grade, gender, and smoking habits as covariates, GNB3 825T homozygous patients displayed a higher risk for relapse than C825 homozygous patients (TT versus CC, hazard ratio; 95% confidence interval, 1.4-4.8; P = 0.002). The same genotype effect was found for overall survival, TT genotypes were at higher risk for death compared with CC genotypes (hazard ratio, 2.6; 95% confidence interval, 1.6-4.3; P < 0.001), and 5-year survival proportions were 60% for CC, 52% for TC, and 33% for TT. The GNB3 C825T SNP thus represents a host derived prognostic marker in HNSCC, which allows identifying high-risk patients, which could benefit from novel and/or more aggressive therapeutic regimes.

Mistletoe in the supportive care of cancer patients—Improvement of quality-of-life

Mistletoe ( Viscum album ) preparations are often used in the adjuvant setting, together with standard chemo- or radiotherapy. Several clinical studies have shown that treatment with mistletoe preparations—often in combination with standard treatment—can improve the quality-of-life and even prolongs relapse-free intervals in cancer patients [1]. Furthermore, some patients can better stand aggressive chemotherapies if they receive mistletoe preparations at the same time. In the present clinical study, which was authorized by the ethical commission of the canton Zurich, questionnaires were used to characterise the alterations in the quality-of-life experienced by cancer patients during the treatment with mistletoe preparations. Furthermore, the patients were interviewed by the researchers to unveil their goals while accepting this therapy. A small ( N =25) cohort of patients with different types of malignant diseases received subcutaneous applications of mistletoe preparations in the course of their treatment at the Paracelsus Hospital in Richterswil. All patients filled in the following questionnaires on quality-of-life at the beginning of the treatment: EORTC QLQ-C30 Version 3.0, SELT-M and HLQ Version 2.5. Approximately 3 months later, 21 of the 25 patients filled in the questionnaires a second time, to document the variation in the quality-of-life during this time period. The scores of the different questionnaires, as well as the differences between the scores at the two visits, were determined. The statistical analysis (merely descriptive) was performed with SAS 9.1. When the patients agreed, they were interviewed by the researchers. These interviews included questions on why the patients used the mistletoe therapy including objective and subjective reasons. Another goal of the interviews was to characterise the functional meaning of the mistletoe therapy within the context of the whole therapeutic concept and some questions attempted to find out how this meaning should be interpreted. Finally, the relevance of the mistletoe therapy with respect to the maintenance/improvement of the quality-of-life was approached. The evaluation of the questionnaires showed a tendency for an improvement of the patients’ quality-of-life, which was revealed by all three types of questionnaires. The interviews’ analysis indicated that the patients adopt the mistletoe therapy with a supportive goal rather then as an anti-tumour therapy. Moreover, psychosocial considerations and ideal reasons do often play an immediate role.

Predictive utility of progesterone receptor (PR) and multigene expression in identifying benefit from adjuvant doxorubicin plus cyclophosphamide (AC) or docetaxel (AT) in intergroup trial E2197

557 Background: Although E2197 showed no difference in recurrence or overall survival, an exploratory analysis suggested differential benefit for AC in PR-pos disease and AT in PR-neg disease (Proc ASCO 2005, abstr 512) when PR was determined in local labs. We evaluated the predictive utility of PR protein expression by IHC in a central lab and quantitative RNA expression by RT-PCR for 371 genes (including the 21-gene recurrence score [RS]) in a representative sample of 734 patients who received at least 3–4 treatment cycles. Methods: Individual gene by treatment interactions were tested in Cox models for relapse-free interval (RFI). Permutation methods were used to control the false discovery proportion at <10%. Supervised principal components (SPC) was used to combine genes into an interaction predictor, which was evaluated via cross-validation (CV). Results: PR Analysis. There was a weak benefit for AT in PR-neg (AT vs AC hazard ratio [RR]=0.75; p=0.06) and AC in PR-pos disease (RR=1.37; p=0.05) by central IHC (Allred score > 2 positive) but not when genomic PR was evaluated by RT-PCR (> 5.5 units positive). RS and New Genes. There was little evidence that gene expression identified AT vs. AC benefit in the hormone receptor (HR)-neg, or HR-pos, RS < 18 subsets. In contrast, there were many genes that strongly predicted differential AT vs AC benefit in the HR-pos, RS > 18 subset; SPC analyses of a multigene model suggest a significant effect (CV continuous interaction permutation p=0.03), with the AT vs. AC RR in the highest and lowest third of the SPC values estimated in CV to be 0.23 and 2.48. Oncotype DX RS did not predict differential AC vs AT benefit in HR-pos disease. Conclusions: PR protein expression may identify a potentially clinically relevant association for differential taxane benefit, but requires validation in other datasets. A genomic classifier predicting differential benefit was identified in HR-pos tumors with a RS > 18, and if externally validated, might be useful in defining differential benefit in patients with HR-pos disease. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Genomic Health, sanofi-aventis Genomic Health Institute, GlaxoSmithKline, sanofi-aventis Genomic Health Genomic Health Institute, GlaxoSmithKline, sanofi-aventis sanofi-aventis

Skp2 expression is associated with high risk and elevated Ki67 expression in gastrointestinal stromal tumours

BackgroundGastrointestinal stromal tumors (GIST) exhibit an unpredictable clinical course and can rapidly progress to lethality. Predictions about the biological behavior of GIST are based on a number of canonical clinical and pathologic parameters whose validity in distinguishing between a benign and a malignant tumour is still imperfect. The aim of our study was to investigate the role of morphologic parameters and expression of cells cycle regulators as prognosticators in GIST.MethodsWe performed an immunohistochemical analysis for Ki67, p27Kip1, Jab1, and Skp2, on a Tissue Microarray (TMA) containing 94 GIST. Expression of the above proteins was correlated to classically used prognosticators, as well as to risk groups. Clinical significance of histologic and immunohistochemical features were evaluated in 59 patients for whom follow-up information was available.ResultsOverexpression of Ki67 and Skp2, and p27Kip1 loss directly correlated with the high risk group (p = 0.03 for Ki67 and Skp2, p = 0.05 for p27Kip1). Jab1 expression did not exhibit correlation with risk. In 59 cases provided with clinical follow-up, high cellularity, presence of necrosis, and Ki67 overexpression were predictive of a reduced overall survival in a univariate model. The same parameters, as well as mitotic rate, tumour size, and p27Kip1 loss were indicative of a shortened relapse free survival interval. High cellularity, and high mitotic rate retained their prognostic significance by multivariate analysis.ConclusionOur data suggest that a number of histologic parameters in combination with immunohistochemical expression of cell cycle regulators can facilitate risk categorization and predict biologic behavior in GIST. Importantly this study demonstrates, for the first time, that Skp2 expression correlates with Ki67 expression and high risk in GIST.

Impact of caregiver group psychoeducation on the course and outcome of bipolar patients in remission: a randomized controlled trial

Although there are some randomized controlled trials that highlight the positive role of family-focused treatment added to pharmacotherapy in bipolar disorder, no trials using contemporary methodologies have analyzed the specific effect of working with caregiver-only groups. The aim of this study was to assess the efficacy of a psychoeducational group intervention focused on caregivers of euthymic bipolar patients. A total of 113 medicated euthymic bipolar outpatients who lived with their caregivers were randomized into an experimental and a control group. Caregivers in the experimental group received twelve 90-min group psychoeducation sessions focused on knowledge of bipolar disorder and training in coping skills. The patients did not attend the groups. Caregivers assigned to the control group did not receive any specific intervention. Patients were assessed monthly during both the intervention and the 12 months of follow-up. The primary outcome was time to any mood recurrence. Psychoeducation group intervention focused on the caregivers of bipolar patients carried a reduction of the percentage of patients with any mood recurrence (chi2 = 6.53; p = 0.011) and longer relapse-free intervals (log-rank chi(2) = 4.04; p = 0.044). When different types of episodes were analyzed separately, the effect was significant for both the number of patients who experienced a hypomanic/manic recurrence (chi2 = 5.65; p = 0.017) and the time to such an episode (log-rank chi2 = 5.84; p = 0.015). The differences in preventing depressive and mixed episodes were not significant. A psychoeducation group intervention for the caregivers of bipolar patients is a useful adjunct to usual treatment for the patients in reducing the risk of recurrences, particularly mania and hypomania, in bipolar disorder.

Outcome after relapse in childhood and adolescent osteosarcoma: single institution experience in Korea

Purpose : Osteosarcoma is the most common primary malignant bone tumor in children and adolescents. Although survival rate of osteosarcoma patients has markedly improved, about 20-30% of patients still have a relapse. This study was aimed to find factors that influence postrelapse survival of osteosarcoma in childhood and adolescents. Methods : Between 1985 and 2004, of 461 patients who were diagnosed and treated as osteosarcoma in Korean Cancer Center Hospital, 180 patients with recurrent osteosarcoma were retrospectively reviewed. We examined survival rates and analyzed prognostic factors, such as relapse site, post-relapse treatment methods, pathologic response to neoadjuvnat chemotherapy, metastasis at first diagnosis, and relapse free interval. Results : The overall recurrence rate of patients with osteosarcoma was 39%. The 5-year and 10-year postrelapse survival rates in the recurrent osteosarcoma were 13% and 4%, respectively. The 5-year post-relapse survival rate was influenced by site of relapse (lung, 39%; local, 0%; lung & bone, 25%; others, 12%; P

Prognostic Impact of Cytogenetic Abnormalities in Elderly Patients with Acute Myeloid Leukemia (AML) Enrolled in the ALFA-9803 Trial.

We have recently reported the superiority of prolonged ambulatory versus short intensive post-remission therapy in 416 patients with AML aged 65 years or more (median age, 72 years) selected to be treated intensively in the ALFA-9803 trial (C. Gardin et al. Blood 2007). We report here on the prognostic value of cytogenetic abnormalities in 339 of these patients with available karyotype (27 not done, 50 failures). When classical endpoints (CR rate, DFS, OS) were used, we were only able to identify one very unfavorable subgroup of 14% patients (N=49 with −7, abnormalities of both chromosomes 5 and 7, 3q abnormality, or complex karyotype with 5 abnormalities or more; CR rate, 30%). No significant differences in outcome were found between patients with any other abnormality and the 171 patients with a normal karyotype/−Y (overall CR rate, 62%). When cumulative incidences of AML-related events (primary refractory AML, relapses) were used as endpoints with induction deaths and deaths in first CR as competing events, three distinct subsets were more easily identified:1.14% very unfavorable-risk patients, as detailed above;2.59% standard-risk patients (N=200 with t(8;21), inv(16), normal karyotype/−Y, or isolated +8; CR rate, 65%); and3.27% unfavorable-risk patients (N=90 with other abnormalities, including notably 5q− and 7q−; CR rate, 58%).Median failure-free interval (Fig 1; P<.001, by the Gray test) and relapse-free interval (Fig 2; P<.001, by the Gray test) were 2.3, 12.4, and 8.1 months and 4.2, 15.0, and 10.5 months in these three subsets, respectively. Interestingly, prolonged ambulatory post-remission therapy was associated with longer DFS and OS in the standard-risk subset only. The results demonstrate that despite their poor general outcome, older patients with AML may be subdivided in three meaningful cytogenetic subgroups. This 3-subgroup classification should help to optimize disease management decisions such as intensive versus non-intensive or investigational therapies for induction or consolidation. [Display omitted] [Display omitted]

ASBMT Risk Group and CD 34+ Dose Predicted for the Development of aGVHD in Allogeneic MRD Transplants When the Donors Who Received a Combined Mobilization and In Vivo TCD Regimen Using rhg-CFS and Dexamethasone.

We looked at factors affecting the development of acute and chronic GVHD in a cohort of 118 patients who underwent allogeneic matched sibling transplantation between 09/1998 to 05/2006 at the UAB BMT program. Donors were mobilized with rhg-CSF (10–16mcg/kg/day x4) and received dexamethasone 10mg/m2/day x3 days to effect in vivo T cell depletion (TCD). Total CD3 and CD34 cell dose were divided in to 4 quartiles (See table below). We then analyzed the influence of CD3+ and CD34+ dose quartiles on aGVHD, cGVHD, engraftment, TRM and relapse. (see table) Acute GVHD: Univariate Logistic regression indicated that the development of aGVHD is negatively associated with quartiles (q25–q50) interval of CD3 dose (p=0.0418). However this relationship was not independent of risk factor and CD34 dose. After using Multivariable Logistic regression analysis with adjustments for age, race and sex, we found that ASBMT risk factor and CD34 quartiles dose are strong predictors of aGVHD: patients who had high risk are about three times more likely to have aGVHD (OR=2.829, 95% CI 1.142–7.020, p=0.0250). The higher the CD34 dose also predisposed to higher incidence of aGVHD (p=0.0432). Median Survival: Patients who received the CD3 (P=0.00141) and CD34 (P=0.0270) in the q25–q50 quartile did better with improved median survival. Relapse and CD 3 quartiles: Using the - 2 log (LR) test shows the relapse free interval was longer if the CD3 dose is between q25 and q50 (p=0.0058); there was no relation between CD34 and relapse. TRM: Not associated with CD3 or CD 34 dose. WBC engraftment: Multivariable analysis indicated that the relationship is mainly an age effect. After adjusted for risk factor, GVHD status, CD3 or CD34 dose, the engraftment day is still significantly related to age at BMT (p=0.0252). No associations are observed for the relationship between engraftment day and GVHD risk. cGVHD: Neither CD34 dose (p=0.5339) nor CD3 (p=0.4209) dose were statistically associated with incidence and severity of cGVHD. To summarize, higher CD34 dose and higher risk ASBMT category predicted for higher incidence of aGVHD; neither CD3 nor CD 34 dose predicted for the development of cGVHD. Age was the single most important predictor of WBC engraftment.CD3+ and CD34 QuartilesQuartile<2525–5050–75>75CD3 X10E8<2.52.53–3.603.60–5.30>5.30CD34 X10E6<4.924.92–7.797.79–11.2>11.2

Topoisomerase I protein expression in primary colorectal cancer and recurrences after 5-FU-based adjuvant chemotherapy

Our aim was to investigate whether chemotherapy with 5-FU induces an alteration in the levels of topoisomerase I (topo I) in colorectal neoplastic tissues Twenty-five colorectal cancer patients were included in our study; these had undergone surgical resection of the primary tumor, received post-operatively 5-FU-based adjuvant chemotherapy and then suffered from recurrences. In a standard three-step immunohistochemical procedure, a monoclonal antibody to topo I was applied in both specimens from each patient (one from the primary location and a second one from the recurrence). Statistical analysis was subsequently performed. Malignant cells from the recurrences displayed a statistical significant increase, concerning the levels of topoisomerase I, by comparison with the primary tumors (P=0.01). The increase in topo I levels did not demonstrate significant correlations with Duke's stage (Fisher's Exact Test P value=0.496), differentiation grade (P value=0.661), localization (P value=0.072), patient sex (P value=0.434), nor with relapse free interval (P value=0.493). There was a statistically significant relationship between the age of patients and increase in topo I levels (P=0.011). Topo I expression may be part of the malignant cells' phenotype in recurrent colorectal carcinomas, suggesting a potential role for Topo I in the acquisition of a metastatic phenotype. The increase of topo I immunohistochemical status is likely to be attributed to 5-FU and given the fact that high levels of topo I correlate with sensitivity to camptothecin, advanced colorectal cancer patients seem to benefit from topo I targeted anticancer drug therapy.

Abstract Submission

526 Background: Evidence suggests modern chemotherapy (CT) regimens are only marginally more effective in HR-pos breast cancer (Berry et al. JAMA 2006: 295: 1658). Genomic classifiers may be useful for selection of high-risk subjects for more aggressive CHT. Methods: A case-cohort sample of 776 patients enrolled on E2197 who did (N=179) or did not have a recurrence after CT (if HR-neg) or CHT (if HR-pos) and had available tissue were evaluated for Oncotype DX™ Recurrence Score (RS). E2197 included 2885 evaluable patients with 0–3 positive nodes treated with four 3-week cycles of doxorubicin (60 mg/m2) plus cyclophosphamide 600 mg/m2 (AC) or docetaxel 60 mg/m2 (AT) and hormonal therapy (if HR-pos). Median follow-up was 76 months. Results: There was no difference in DFS between treatment arms. In multivariate analysis, RS was a significant predictor of recurrence in HR-pos disease (p=0.0007, recurrence risk 21% lower for each 10 point drop in RS, 95% confidence intervals 9% to 31%). Recurrence risk was significantly elevated for an intermediate RS 18–30 (n=138, hazard ratio [HR] 2.96 [p=0.0002]) or a high RS ≥ 31 (n=108, HR 4.00, p=0.0001) compared with low RS &lt; 18(n=196), but not for high compared with intermediate RS (HR 1.34, [p=0.32]); results were similar if only HER2-neg disease was included. The 5-year relapse free interval(RFI), breast cancer free survival (BCFS), disease-free survival (DFS), and overall survival (OS) for patients with HR-pos, HER2-neg disease are shown below (%); patients with both node-neg or node-pos breast cancers whose RS was &lt; 18 had excellent outcomes. Conclusions: Oncotype DX™ RS identifies individuals with HR-pos, HER2-neg breast cancer with 0–3 positive axillary lymph nodes at 3–4-fold increased risk of relapse despite standard CHT, and may serve as a means to distinguish between those who do well with standard CHT (RS &lt;18) from those who may be suitable candidates for clinical trials evaluating alternative CT regimens or other strategies (RS ≥ 18). [Table: see text] [Table: see text]

Long-term follow-up of patients treated by adoptive transfer of melanoma tumor-infiltrating lymphocytes as adjuvant therapy for stage III melanoma.

The first analysis of our clinical trial on interest of using tumor-infiltrating lymphocytes (TIL) as adjuvant therapy for stage III (regional lymph nodes) melanoma was published in 2002 [5]. The aim of this paper is to update clinical results of 7 years of follow-up after the last treated patient. In the trial conducted between December 1993 and January 1999, patients without any detectable metastases after lymph node excision were randomly assigned to receive either TIL plus interleukin-2 (IL-2) for 2 months, or IL-2 only. The duration of the relapse-free interval was the primary objective. Eighty-eight patients were enrolled in the study. Currently, the last analysis performed in June 2006, after a median follow-up of 114.8 months, did not show change of non-significant extension of the relapse-free interval or overall survival. However, this second analysis strengthens our first hypothesis about the relationship between number of invaded lymph nodes and TIL treatment effectiveness. In the group with only one invaded lymph node, the estimated relapse rate was significantly lower (P (adjusted) = 0.0219) and the overall survival was increased (P (adjusted) = 0.0125) in the TIL+IL-2 arm compared with the IL-2 only arm. No differences between the two arms, either with regard to the duration of disease-free survival (P (adjusted) = 0.38) or overall survival (P (adjusted) = 0.43), were noted in the group with more than one invaded lymph node, whatever the number of invaded lymph nodes. Treatment was compatible with normal daily activity. This study, with a very long follow up (median of almost 10 years), postulates for the first time relationship between TIL efficiency in stage III melanoma (AJCC) and number of invaded lymph nodes, indicating that tumor burden might be a crucial factor in the production of an effective in vitro expansion of T cells specific for autologous tumor antigen, a finding which could be of value in future vaccine development for the treatment of melanoma.

Role of pegylated liposomal doxorubicin (Caelyx) in the treatment of relapsing ovarian cancer

The most significant factor predicting response to second-line chemotherapy is the time interval elapsed from the end of chemotherapy to relapse occurrence. Two types of situations may be considered: patients with platinum-sensitive relapse (relapse-free interval longer than 6 months) and patients with platinum-refractory relapse (progression during treatment or relapse-free interval under 6 months). Pegylated liposomal doxorubicin is a doxorubicin formulation. Encapsulation in liposomes confers it different pharmacokinetic characteristics and a more favorable toxicity profile. The following review examines the efficacy and safety of pegylated liposomal doxorubicin for the treatment of relapsing epithelial ovarian cancer.

Moderate Dietary Temperance Effectively Prevents Relapse of Crohn Disease

The authors examined the influence of diet (dietary fat intake and dietary temperance) on relapse of patients with Crohn disease. A 1-year prospective study of 76 patients with Crohn disease was conducted. The criterion for eligibility was a Crohn Disease Activity Index score of 150 or lower for at least 1 month. The primary end point was defined as the relapse-free interval from the baseline until the first relapse. Fat intake was assessed using a validated diet history questionnaire. The degree of dietary temperance was assessed using a single-item nominal scale. The Cox proportional hazards model was used to evaluate the influence of diet. Crohn disease relapse was seen in 25 patients (33%), and 47 patients (62%) remained in continuous remission. A decreased ratio of n-6 polyunsaturated fatty acid (PUFA) to n-3PUFA (odds ratio = .38; p = .005) was associated with a poor prognosis. Dietary temperance also was significantly associated with prognosis (p = .014). More moderate dietary temperance decreased the risk of relapse (odds ratio = .22; p = .006). Effective prevention of relapse for Crohn disease patients might be achieved through moderate dietary temperance, particularly when the disease condition is unstable.

Narrowband UVB and PUVA in the Treatment of Mycosis Fungoides: A Retrospective Study

Psoralen plus ultraviolet A (PUVA) is widely used as first-line therapy for treatment of mycosis fungoides. Narrowband ultraviolet B (NB-UVB) has also been shown to be effective for treatment of early mycosis fungoides. The aim of this retrospective study was to analyse the response to treatment and relapse-free interval for PUVA and NB-UVB therapies in mycosis fungoides. Forty patients were treated with PUVA or NB-UVB between 1980 and 2003. All patients had failed to respond to topical therapy or were unwilling to use it. PUVA therapy was used between 1980 and 1997. Thereafter, the choice between PUVA (twice a week) and NB-UVB therapy (three times a week) depended on stage and extent of the disease as well as on how far patients had to travel). Twelve patients (stage IA-IIB) were treated with NB-UVB and 28 patients (stage IA-IVA) with PUVA. No maintenance therapy was given. Six patients (50%) had a complete response, 4 (33%) had a partial response and 2 (16%) had a failed response to NB-UVB but had stable disease. PUVA led to a complete response in 18 (64%), a partial response in 6 (21%) and a failed response in 4 (14%) patients. The median relapse-free interval was 11.5 months in the NB-UVB treated group and 10 months in the PUVA group. The majority of the patients (79%) had stage IA and IB disease. Of these, 6 of 10 (60%) in the NB-UVB group and 13/21 (62%) in the PUVA group had a complete response to treatment. These results show that PUVA and NB-UVB are effective treatments for early mycosis fungoides.

Assessment of angiogenesis expression and its relationship with prognosis of colorectal cancer by conventional and computer-assisted histopathological image analysis

To quantify the degree of angiogenesis by conventional method (microvessel density, MVD) and computerized method (endothelial area, EA), and to evaluate their relationships with the prognosis of patients operated on for colorectal adenocarcinoma. Tumoral angiogenesis was studied by means of an immunohistochemical technique, using CD 34, on 126 patients; to quantify the angiogenesis, MVD (defined as number of microvessels per mm(2)) and EA measurement (defined as the area occupied by EA in the microscope field). A computerized method, IMAGELab software was utilized to quantify endothelial area. The mean number of microvessels was 128.6 MV/mm(2) (SD = 44.5) and the mean EA was 4.3% (SD = 2.1). The Pearson method demonstrated a low correlation coefficient between MVD and EA (r = 0.429). No relationship between MVD and EA was observed with regard to relapse-free interval and overall survival. The histological analysis of angiogenesis expression in patients with colorectal adenocarcinoma can be performed either by computer-assisted image analysis of endothelial area or by conventional microvessels counting. Both methods did not show any significant relationship between these angiogenesis parameters with relapse-free interval and overall survival.

Phase I Study of Cladribine, Cytarabine (Ara-C), Granulocyte Colony Stimulating Factor (G-CSF) (CLAG Regimen) and Simultaneous Escalating Doses of Imatinib Mesylate (Gleevec) in Relapsed/Refractory AML.

Background: Receptor activated tyrosine kinases like c-kit, c-fms and PDGFR are known targets of inhibition by imatinib mesylate (Gleevec) and are expressed on AML blasts. Marrow stromal cells and monocytes express the ligands KIT ligand, M-CSF and PDGF capable of activating survival pathways in these leukemic cells. Imatinib mesylate is a substrate of the multidrug resistance and ABC - transporters expressed in AML cells and displays a modest activity alone in AML in vitro and in vivo. Given the synergy in vitro between Ara-C and Gleevec on AML cell growth inhibtion, we initiated a Phase I study combining CLAG + Gleevec in AML patients.Method: Patients with relapsed, refractory AML or CML myeloid blast crisis were eligible to receive Cladribine 5 mg/m2 Days 3–7, Cytarabine 2 gm/m2 Days 3–7, G-CSF 300 mcg Days 2–7, and escalating doses of imatinib mesylate given on Days 1–15. The level 1 Gleevec dose was 400 mg, while level 2 was 600 mg and the level 3 dose 800 mg. Patients were allowed to receive a second course of treatment if a CR was not attained after the first course, and were eligible for allogeneic stem cell transplantation (ASCT) if a donor was available.Results: A total of 15 patients have been enrolled 14 AML and 1 CML blast crisis, 6 patients with relapse within 6 months following initial induction/consolidation, 5 patients relapsed within 6–12 months of therapy, 3 patients had refractory disease and 3 patients relapse following myeloablative ASCT. No dose limiting toxicity was reached. The dose escalation occured as planned and there was no clear evidence of added toxicity due to Gleevec. One patient with an extensive cardiac history died of cardiac causes on day 1 of therapy, no other deaths occured within 30 days of starting therapy. One patient had a grade 3 skin rash at level 2 and did not receive imatinib on the second induction therapy. None of the 15 patients treated have had a drug- related cause of death: the most common toxicities encountered during induction therapy were nausea, vomiting, ALT and AST increase, rash and diarrhea and were transient and/or reversible. There were two drug-nonrelated deaths one CNS bleed in a persistently thrombocytopenic patient after ANC recovery and ovelwhelming sepsis in another patient. Out of 14 evaluable patients 12 achieved a hypocellular marrow after initial induction with one additional patient achieving a hypocellular marrow following a second course of the same regimen. One patient had persistence of disease and was switched to another treatment. Out of the 12 evaluable patients 5 acheived a complete response (42%) with 4 of these patients achieving a complete cytogenetic response as well (33%). The relapse free interval ranged from 35 to 206 + days in evaluable patients. Imatinib mesylate (up to 800 mg) plus CLAG is a safe and well tolerated non anthracycline based salvage regimen in patients with relapsed/refractory AML.

Factors causing early relapse after lung metastasis surgery

Haematogenous lung metastases are usually considered a sign of widespread metastatic disease. However, in most primary cancers, the first filter for distant tumours are the lungs. In some patients, the metastatic process may stop at the lungs. In these selected patients, there are studies that have shown the benefits of metastasectomy. The objective of this paper is to analyse the morbidity and mortality of lung metastasectomy and determine the factors that predispose to early relapse. Forty-two patients operated on for lung metastases, and four were excluded as they were assessed intraoperatively to be unresectable, leaving 38 patients to be analysed. The variables analysed were: age, sex, primary tumour, disease-free interval, number of metastases, bilaterality, morbidity and mortality, relapse, reinterventions, relapse-free interval after metastasectomy and survival. The surgical technique was a posterolateral thoracotomy, and there were no perioperative deaths. Morbidity was 11% (n = 4), and surgical reintervention of the haemothorax was necessary. Survival after 1, 2 or 3 years was 87%, 61% and 25% respectively, and the percentage of relapse-free patients was 71%, 56% and 17% respectively. The main factors associated with early relapse were histological type of tumour (more relapse in sarcoma, and less in adenocarcinoma), the disease-free interval between the primary tumour and lung metastases, and the number of metastases. Surgery was required a second time in five patients who had relapsed lung metastases, but extirpation could be performed in only four patients, of whom three were relapse free after 6, 12 and 24 months respectively, and the fourth had relapsed lung metastases after 18 months. Resection of lung metastases can be performed with low morbidity and mortality. The main prognostic factors for survival are complete surgery, histological type, disease-free interval between the primary tumour and metastases, and the number of lung metastases.

Impact of cyclins E, neutrophil elastase and proteinase 3 expression levels on clinical outcome in primary breast cancer patients

Uncontrolled cell proliferation is one of the hallmarks of cancer and the transition from the G1 to S phase is the most commonly reported cell cycle abnormality in tumors. It has been shown that the oncogenic activity of G1 cyclin E (CCNE) can be amplified by generating hyperactive low molecular weight forms (LMW) through elastase-mediated proteolytic processing. Neutrophil elastase (NE) and proteinase 3 (PR3) are 2 proteases that are aberrantly expressed in breast cancer cells and seem to be involved in cell proliferation. In this study, we evaluated the effect of the expression of these 2 proteases in addition to 2 potential intracellular targets of NE (CCNE1 and CCNE2) on clinical outcome in a population of 205 primary breast cancer patients. By univariate analysis, CCNE1, CCNE2, estrogen receptor and grade significantly predicted relapse free interval (RFI). NE and PR3 did not achieve statistical significance. In a multivariate analysis, elevated CCNE2 [hazard ratio (HR) 2.10, p = 0.008] predicted shorter RFI. In subgroup analyses of the tamoxifen-only treated patients, high CCNE1 levels predicted treatment resistance, while high levels of CCNE2 were associated with poor RFI in untreated patients. Investigation of the relationship between CCNE1, CCNE2 and NE did not show any impact on RFI. To conclude, this study was the first to evaluate these markers at the mRNA level by RT-PCR in a series of primary breast cancer patients, and our results confirmed the impact of high CCNE levels on clinical outcome in systemically untreated and of CCNE1 in tamoxifen-only treated early breast cancer patients.

BAY 43–9006 as single oral agent in patients with metastatic breast cancer previously exposed to anthracycline and/or taxane

577 Background: BAY 43–9006 targets the ras/raf signaling pathway and inhibits VEGFR-2, VEGFR-3 and or PDGFR-β growth factors. A study was conducted to assess anti-tumor activity and the toxicity profile in patients (pts) with metastatic breast cancer (MBC). Methods: A two-stage phase II study was conducted with pts with MBC who had measurable disease and were candidates for 1st or 2nd line chemotherapy and had previously received an anthracycline and/or a taxane in the neoadjuvant, adjuvant, or metastatic setting. Pts started with a dose of 400 mg twice daily on days 1–28 of each 4 week cycle. Based on interval adverse events (AEs), a dose reduction was considered as 400 mg given one time daily. Primary endpoint was tumor response defined as a complete or partial response (PR) according to RESIST. The study required 40 pts, but was to be terminated if 0 or 1 responses occurred among 1st 20 eligible pts. Results: 23 pts enrolled with a median age of 54 (range 37–70) but 3 were declared ineligible. All 23 pts were included in all analyses except efficacy analysis as stated per protocol. Fifteen (65%) had visceral metastasis; 22 (96%) had prior anthracycline treatment (tx); 16 (70%) had prior taxane tx.; 10 (44%) had received prior chemotherapy for metastatic disease and 14 (61%) had a prior relapse free interval of 12 months (mos) or more. Pts received tx for a median of 2 cycles (range 1–8) with a median follow-up of 7.2 mos. Dose reductions were due to dermatitis/skin rash (3), hand/foot skin reaction (2), hypertension (1) and cramping hands/feet (1). No grade 4 AEs occurred and grade 3 AEs included acne (2), hand/foot skin reaction (1), neutropenia (1), cough (1), wound infection (1), and prolonged PTT (1). Among the 20 pts eligible for efficacy analysis one pt (5%; 95% CI 0.5–20.5%) achieved a PR with duration of 3.6 mos and one pt achieved stable disease for at least 6 mos. The 6-month overall survival rate was 81% and the progression-free survival rates were 53% at 2 mos, 24% at 4 mos and 6% at 6 mos. Median time to progression was 2 mos. Based on the lack of sufficient response, we did not proceed with the 2nd stage of this study. Conclusion: Treatment with oral BAY 43–9006, while well tolerated, does not have sufficient activity to warrant further testing as a single agent in this disease setting. [Table: see text]

Misspecified regression model for the subdistribution hazard of a competing risk

We consider a competing risks setting, when evaluating the prognostic influence of an exposure on a specific cause of failure. Two main regression models are used in such analyses, the Cox cause-specific proportional hazards model and the subdistribution proportional hazards model. They are exemplified in a real data example focusing on relapse-free interval in acute leukaemia patients. We examine the properties of the estimator based on the latter model when the true model is the former. An explicit relationship between subdistribution hazards ratio and cause-specific hazards ratio is derived, assuming a flexible parametric distribution for latent failure times.