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PDF file - 22K, Supplemental Fig. S3. Effect of cytoplasmic MET immunohistochemistry (IHC) staining on objective response rate in patients treated with panitumumab (pmab) plus rilotumumab (AMG 102) versus pmab plus placebo.

PDF file - 37K, Supplemental Fig. S4. The effect of baseline IGF and IGF-related protein expression on overall survival.

PDF file - 76K, Supplemental Fig. S1. (A) Randomized phase Ib/II trial of panitumumab plus rilotumumab (AMG 102) or ganitumab (AMG 479). (B) CONSORT diagram for part 2. *Panitumumab 6 mg/kg; rilotumumab 10 mg/kg with dose de-escalation to 5 mg/kg as necessary. �Panitumumab 6 mg/kg; rilotumumab 10 mg/kg; ganitumab 12 mg/kg. �Rilotumumab 10 mg/kg; ganitumab 12 mg/kg.

PDF file - 38K, Supplemental Fig. S5. The effect of baseline IGF and IGF-related protein expression on objective response rate.

PDF file - 38K, Supplemental Fig. S2. Best percent change of the sum of longest diameters of target lesions from baseline to post-baseline. (A) Panitumumab plus rilotumumab.(B) Panitumumab plus ganitumab. (C) Panitumumab alone.

Purpose: Panitumumab, a fully human anti-epidermal growth factor receptor monoclonal antibody (mAb), has demonstrated efficacy in patients with wild-type KRAS metastatic colorectal cancer (mCRC). Rilotumumab and ganitumab are investigational, fully human mAbs against hepatocyte growth factor (HGF)/scatter factor and IGF1R, respectively. Here we evaluate combining rilotumumab or ganitumab with panitumumab in previously treated patients with wild-type KRAS mCRC.Experimental Design: Part 1 was a phase Ib dose-finding study of panitumumab plus rilotumumab. The primary endpoint was the incidence of dose-limiting toxicities (DLT). Part 2 was a randomized phase II trial of panitumumab in combination with rilotumumab, ganitumab, or placebo. The primary endpoint was objective response rate (ORR); safety, progression-free survival (PFS), and overall survival (OS) were secondary endpoints. Archival tissue specimens were collected for exploratory correlative work.Results: In part 1, no DLTs were reported. A recommended phase II dose of 10 mg/kg rilotumumab was selected. In part 2, for the panitumumab plus rilotumumab (n = 48), panitumumab plus ganitumab (n = 46), and panitumumab plus placebo arms (n = 48), the ORRs were 31%, 22%, and 21%, respectively. The median PFS was 5.2, 5.3, and 3.7 months and median OS 13.8, 10.6, and 11.6 months, respectively. Adverse events were tolerable. Exploratory biomarker analyses, including MET and IGF-related protein expression, failed to indicate conclusive predictive evidence on efficacy endpoints.Conclusions: Panitumumab plus rilotumumab met the prespecified criterion for improvement in ORR whereas ganitumab did not. This is the first study to suggest a benefit for combining an HGF inhibitor (rilotumumab) with panitumumab in previously treated patients with wild-type KRAS mCRC. Clin Cancer Res; 20(16); 4240–50. ©2014 AACR.

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The optimal protocol for mobilization of hematopoietic stem cells in patients with lymphoid malignancies has not been determined so far. We retrospectively analyzed the efficacy and safety of Ara-C at a dose of 1.6 g/m(2) compared with CY at a dose of 4.0 g/m(2), both combined with filgrastim. Seventy and forty-five patients, respectively, were included, among whom 60% were defined as 'predicted poor mobilizers'. The use of Ara-C was associated with significantly higher peak number of circulating CD34(+) cells compared with CY (P0.0001). In the Ara-C group, 95% of patients with multiple myeloma (MM) collected at least 5 × 10(6) CD34(+) cells/kg required for tandem transplantation, and 97% of lymphoma patients collected at least 2 × 10(6) CD34(+) cells/kg, needed for a single autologous hematopoietic SCT (autoHSCT), which was achieved with a single leukapheresis in 91% of cases. Results for the CY group were significantly inferior (P0.0001). No patient mobilized with Ara-C experienced febrile neutropenia, whereas 35% required platelet transfusions. Among patients who proceeded to autoHSCT, the time of both neutrophil and platelet recovery was significantly shorter for those mobilized with Ara-C than CY. We conclude that intermediate-dose Ara-C+filgrastim is a very effective and relatively safe mobilization protocol for patients with lymphoid malignancies.

Regulatory T (Treg) cells are essential for maintaining immune tolerance. High Treg frequencies have been reported in peripheral blood and tissue samples of patients with solid tumors while their role in lymphomas, including diffuse large B-cell lymphoma (DLBCL) has not been clearly established. In this study, we analyzed the circulating Treg numbers in 27 patients with newly diagnosed DLBCL and 17 healthy individuals. Tregs were detected by flow cytometry based on CD4(+) CD25(high) FoxP3(+) phenotype. In addition, the expression of CD45RA, HLA-DR, CD62L, CD39, and CTLA4 was analyzed. The number of circulating Treg cells was lower in patients with DLBCL than in healthy controls: median 23 (range, 4-107)/μL vs. 41 (19-104)/μL (P = 0.04). In particular, the number of Tregs expressing CD45RA (naive Tregs), HLA-DR (marker of activation), and CD62L (L-selectin) was decreased in the DLBCL group. Lower (below median) number of circulating Tregs was associated with reduced chance of achieving complete remission (29% vs. 69%, P = 0.05) and reduced probability of even-free survival (24% vs. 84% at 1 yr, P = 0.0004), independently on the International Prognostic Index. We conclude that low number of circulating Tregs may be associated with poor prognosis in patients with DLBCL. However, our observations require confirmation in larger patient population.

Skin toxicity in the course of anticancer treatment occurs in majority of patients and may substantially reduce quality of life. Pegylated liposomal doxorubicin (PLD) is an anthracyclines' derivative with reducing severity of cardiotoxicity and myelosuppression but with localized skin lesions on the palms and the soles (PPE).The retrospective analysis included medical records of ovarian cancer patients who were treated with PLD due to disease progression after prior therapy. The impact of several factors on the risk and severity of PPE was analyzed.In analyzed group of ovarian cancer PPE occurred more often in patients who have previously received more than two chemotherapy lines, P=0.09. The risk of PPE increased with the number of chemotherapy cycles, P0.001 and anemia, P=0.038. In 5% of pts dose reduction was necessary due to PPE.Skin toxicity may significantly limit the possibility to continue the treatment. Good communication with patients and their families, close cooperation with family doctors, palliative care and dermatologists is essential for prompt and effective treatment of skin toxicity. Early preventive actions make to alleviate the discomfort associated with skin complications.

Currently CA 125 is a marker of choice for monitoring ovarian cancer Nonetheless, scientists are still searching for new markers, which could provide additional information for the evaluation of treatment, especially in patients with normal CA 125 levels, despite the progression of the disease. According to the latest reports, OPN can be a potential new marker:Estimation of usefulness of OPN determinations in the monitoring of ovarian cancer patients.The study included 54 ovarian cancer patients, undergoing chemotherapy Markers were measured before, during and after treatment. The dynamics of the change of OPN levels was shown on line graphs, using Microsoft Excel programme. Statistical analysis was performed by Kaplan-Meier method and log-rank test.44% of patients from the study group were found to have low CA 125 levels. In these cases only the increase of OPN concentration indicated recurrence of the disease. In 43% of patients the high initial CA 125 and OPN levels decreased during chemotherapy and complete regression was stated in these patients. Nevertheless, in 13/17 patients a repeated increase of OPN concentration signalling the recurrence, earlier than CA 125 and clinical recurrence manifestation, was observed. In 13% of patients high initial levels of markers did not decrease during chemotherapy which correlated with the progression of the disease. Our study showed that only the CA 125 levels had a significant influence (p=0.00063) on the disease-free survival time.Our data suggest a potential usefulness of the OPN determinations in estimating ovarian cancer recurrence. Nonetheless, there was no correlation between the initial OPN concentration and the disease-free survival time.

Human Development Index (HDI) is used by the United Nations Organization to measure socioeconomic achievements of countries. We evaluated the association of HDI with rates and outcomes of hematopoietic stem cell transplantation (HSCT) for patients with acute leukemia. For the analysis of HSCT rates, all adults with acute leukemia (n = 16 403) treated in 30 European countries, between 2001 and 2005, were included. Association of HDI with the outcome was analyzed for 2015 patients with acute myeloid leukemia treated with myeloablative allotransplantation. Countries were classified according to HDI quintiles. Highly significant correlation was found for HDI and the total number of HSCT per population (R = 0.78; P < .001), as well as separately for sibling HSCT (R = 0.84; P < .001), unrelated HSCT (R = 0.66; P < .001), and autologous HSCT (R = 0.43; P = .02). The probabilities of leukemia-free survival for 5 consecutive groups of countries with increasing HDI were: 56%, 59%, 63%, 58%, and 68% (P = .01). In a multivariate analysis, transplantations performed in countries belonging to the upper HDI category were associated with higher leukemia-free survival compared with the remaining ones (HR = 1.36, P = .008), which resulted mainly from reduced risk of relapse (HR = 0.72, P = .04). We conclude that, in Europe, the HDI is associated with both rates and results of HSCT for acute leukemia.

Effective treatment options for patients with metastatic breast cancer (MBC) resistant/refractory to anthracyclines and/or taxanes are limited. Intravenous and oral combination of vinorelbine (VRL) and capecitabine were shown to be feasible and effective in first-line MBC. In order to evaluate the activity of the combination of an all oral regimen in a more advanced setting, we investigated a regimen combining oral VRL and capecitabine in a phase II study as second-line chemotherapy of MBC patients previously treated with anthracyclines and taxanes.Forty patients (median age 52 years) with MBC received the combination of oral VRL 60 mg/m(2) on days 1, 8 and 15 plus capecitabine 1,000 mg/m(2) bid given from day 1 to day 14 in an open-label, international, multicentre, phase II study. Cycles were repeated every 3 weeks. The primary endpoint was response rate (RR) evaluated by an independent panel review. Secondary objectives included safety, duration of response, progression-free survival, overall survival and quality of life.All the patients had received prior chemotherapy with anthracyclines and taxanes, 75% were refractory/resistant to anthracycline and/or taxane, 72.5% presented with visceral involvement and the last prior chemotherapy for 87.5% of the patients was for advanced disease setting. The median number of administered cycles per patient was 4 (range 1-31). Eight responses were documented and validated by an independent panel review, yielding RRs of 20% [95% CI: 9-35.6] in the intent-to-treat (treated) population and 23.5% [95% CI: 10.7-41.2] in the 34 evaluable patients. Median progression-free survival and median overall survival were 3.4 months [95% CI: 2.3-5.5] and 11.3 months [95% CI: 8.1-16.4], respectively. The principal toxicities were anaemia, neutropenia (rarely complicated; only one patient experienced febrile neutropenia), fatigue and gastrointestinal toxicities with very few grade 3-4 non-haematological toxicities.In second-line treatment of MBC patients previously treated with anthracyclines and taxanes, oral VRL plus capecitabine is a safe regimen with an efficacy comparable to the other available combination regimens used in this heavily and resistant/refractory (75% of patients) pre-treated patients' population. Moreover, this well-tolerated combination offers the advantages of an all oral regimen.

To present our own experience with pegylated liposomal doxorubicin applied in ovarian cancer patients.The group of 32 patients with ovarian cancer was treated with pegylated liposomal doxorubicin (LPD) in Klinika Onkologii Klinicznej Centrum Onkologii Branch Gliwice between the years 2004 and 2007. Median age was 47 years. The histoclinical variables potentially influencing the occurrence of the hand-foot syndrome were analyzed.Hand-foot syndrome has been observed in 11 patients (34.4%) treated with the LPD. The lesions have been present on the skin of hands, feet, elbow and knee joints and armpits. In the analyzed group of patients, the risk of the hand-foot syndrome occurrence increased, however non-significantly, with the increase of number of cycles including LPD (p=0.069) and the number of previous lines of chemotherapy (p=0.067). Other analyzed factors had no negative influence on the hand-foot syndrome occurrence.It is important to inform the patients about the risk of the hand-foot syndrome occurrence and its management. Early diagnosis allows to prevent the worsening of the hand-foot syndrome and makes it possible to continue the chemotherapy without the necessity of dose reduction and breaking from the therapy.

Selection of treatment schedule in patients with small cell lung cancer (SCLC) appears to be a subject of controversies. One of the most controversial issue is influence of planned and unplanned gaps in radiotherapy and chemotherapy on efficacy of radical treatment of patients with limited disease. These controversies created the basis for current research.245 patients with LD-SCLC treated in Cancer Center in Gliwice between 1989 and 2001 were included in the present analysis. There were 60 women and 185 men, median age 58 years; All these patients were in good general condition. Cisplatine based chemotherapy and total radiation dose higher than 30Gy were used in all of them.Overall survival was analyzed using Kaplan-Meier analysis. The variables potentially influencing overall survival including dose-intensity of chemotherapy and radiotherapy were analyzed using multivariate Cox regression model.3-year actuarial overall survival in a whole group of patients was 10 percent. The following variables had negative influence on overall survival in multivariate Cox model: performance status ZUBROD higher than 0 (p0.0001), metastases to supraclavicular nodes (p=0.001), dyspnoea according to Borg scale higher than 2 (p=0.004) and radiation dose intensity less than 80% (p=0.02). Gaps in chemotherapy did not appear significant.Radiation treatment gaps had significant negative influence on survival of the patients with LD-SCLC, while interruptions of chemotherapy did not. This may suggest that within the range of doses and dose-intensities used in this group, interruptions of chemotherapy due to treatment toxicity are justified, while interruptions of radiotherapy should be promptly avoided.