Τρίτη, 20 Φεβρουαρίου 2018

Phase I study of primary treatment with 5-FU, oxaliplatin, irinotecan, levofolinate, and panitumumab combination chemotherapy in patients with advanced/recurrent colorectal cancer involving the wild-type RAS gene: the JACCRO CC-14 study

Abstract

Background

FOLFOXIRI is now regarded as the chemotherapy regimen that offers the best platform for the treatment of colorectal cancer. However, the safety and efficacy of FOLFOXIRI + panitumumab has not been demonstrated. We conducted a phase I study to determine the recommended dose of FOLFOXIRI + panitumumab as first-line treatment for RAS wild-type metastatic colorectal cancer (mCRC).

Methods

Patients received combination therapy consisting of panitumumab (6 mg/kg on day 1) + FOLFOXIRI [irinotecan (CPT-11), oxaliplatin (L-OHP) 85 mg/m2, and folinate (LV) 200 mg/m2] on day 1, followed by fluorouracil (5-FU) 3200 mg/m2 infused as a 46-h continuous infusion starting on day 1) repeated every 2 weeks as first-line treatment of RAS wild-type mCRC patients. A decrease in CPT-11 dose was planned (started at level 1: CPT-11 165 mg/m2).

Results

Seven patients were enrolled, and six were assessed for safety and efficacy. Maximum tolerated dose was not reached at level 1; all patients were treated at these levels. The common Grade 3 or 4 relevant toxicities were diarrhea (50%), hypokalemia (33%) and stomatitis (33%). No treatment-related deaths occurred. Of the six patients assessed four had partial response and the two others had stable disease; hence, the response rate was 66.7% (95% confidence interval 28.9–100%) and the disease control rate was 100%. Time to protocol treatment failure was 7.2 (1.4–7.3) months.

Conclusion

The FOLFOXIRI + panitumumab chemotherapy regimen was well tolerated by our patients with mCRC and showed promising anti-tumor activity. The recommended phase II dose was determined to be the same as the standard doses of this regimen used worldwide.



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Phase I study of primary treatment with 5-FU, oxaliplatin, irinotecan, levofolinate, and panitumumab combination chemotherapy in patients with advanced/recurrent colorectal cancer involving the wild-type RAS gene: the JACCRO CC-14 study

Abstract

Background

FOLFOXIRI is now regarded as the chemotherapy regimen that offers the best platform for the treatment of colorectal cancer. However, the safety and efficacy of FOLFOXIRI + panitumumab has not been demonstrated. We conducted a phase I study to determine the recommended dose of FOLFOXIRI + panitumumab as first-line treatment for RAS wild-type metastatic colorectal cancer (mCRC).

Methods

Patients received combination therapy consisting of panitumumab (6 mg/kg on day 1) + FOLFOXIRI [irinotecan (CPT-11), oxaliplatin (L-OHP) 85 mg/m2, and folinate (LV) 200 mg/m2] on day 1, followed by fluorouracil (5-FU) 3200 mg/m2 infused as a 46-h continuous infusion starting on day 1) repeated every 2 weeks as first-line treatment of RAS wild-type mCRC patients. A decrease in CPT-11 dose was planned (started at level 1: CPT-11 165 mg/m2).

Results

Seven patients were enrolled, and six were assessed for safety and efficacy. Maximum tolerated dose was not reached at level 1; all patients were treated at these levels. The common Grade 3 or 4 relevant toxicities were diarrhea (50%), hypokalemia (33%) and stomatitis (33%). No treatment-related deaths occurred. Of the six patients assessed four had partial response and the two others had stable disease; hence, the response rate was 66.7% (95% confidence interval 28.9–100%) and the disease control rate was 100%. Time to protocol treatment failure was 7.2 (1.4–7.3) months.

Conclusion

The FOLFOXIRI + panitumumab chemotherapy regimen was well tolerated by our patients with mCRC and showed promising anti-tumor activity. The recommended phase II dose was determined to be the same as the standard doses of this regimen used worldwide.



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Management of anaemia and iron deficiency in patients with cancer: ESMO Clinical Practice Guidelines†

Anaemia and iron deficiency (ID) are frequent complications in patients with solid tumours or haematological malignancies, particularly in patients treated with chemotherapeutic agents [1–3]. Frequently, anaemia is associated with fatigue, impaired physical function and reduced quality of life (QoL) [4–7]. Consequences of anaemia may include impaired response to cancer treatment and reduced overall survival (OS), even though a causal direct relationship has not yet been established [8, 9].

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Management of anaemia and iron deficiency in patients with cancer: ESMO Clinical Practice Guidelines†

Anaemia and iron deficiency (ID) are frequent complications in patients with solid tumours or haematological malignancies, particularly in patients treated with chemotherapeutic agents [1–3]. Frequently, anaemia is associated with fatigue, impaired physical function and reduced quality of life (QoL) [4–7]. Consequences of anaemia may include impaired response to cancer treatment and reduced overall survival (OS), even though a causal direct relationship has not yet been established [8, 9].

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Centralization errors in comparative genomic hybridization array analysis of pituitary tumor samples

Abstract

Reliable interpretation of comparative genomic hybridization array (aCGH) results requires centralization and normalization of the data. We evaluated the reliability of aCGH centralization by comparing aCGH results (with classical centralization-normalization steps) to fluorescence in situ hybridization (FISH) results. In addition, we propose a method to correct centralization bias. Sixty-six pituitary tumors were analyzed (Agilent aCGH+SNP 4 × 180K microarray). For each tumor, the FISH-based log2(ratios) of a subset of chromosomes were compared with the corresponding aCGH raw log2(ratios). With our new normalization-centralization process, this difference was added to all log2(ratios), before performing loess regression on non-altered probes only. Finally, the mean log2(ratio) and the percentage of normal probes were compared between CGHnormaliter and our new FISH-based method. For 11 tumors, FISH results and raw CGH log2(ratios) differed significantly. In addition, nine tumors showed discrepancies between results generated by CGHnormaliter and our new-method. Such discrepancies seemed to occur with tumours with many abnormalities (0 to 40% normal probes), rather than in those tumours with fewer abnormalities (31 to 100% normal probes). Five tumors had too few normal probes to allow normalization. In these tumors, which can exhibit many changes in DNA copy number, we found that centralization bias was frequent and uncorrected by current normalization methods. Therefore, an external control for centralization, such as FISH analysis, is required to insure reliable interpretation of aCGH data. This article is protected by copyright. All rights reserved.



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A hedgehog pathway-dependent gene signature is associated with poor clinical outcomes in Luminal A breast cancer

Abstract

Purpose

High expression of glioma-associated oncogene homolog-1 (GLI1) is associated with poor prognosis in estrogen receptor (ER) positive breast cancers. We sought to define a GLI1-dependent gene signature in ER-positive tumors that could further stratify patients at higher risk for disease recurrence and potentially lead to novel combination therapies.

Methods

We identified an inverse correlation between GLI1 expression and distant disease-free survival (DFS) using a dataset developed at MD Anderson Cancer Center (Hatzis dataset) containing clinical data from 508 breast cancer patients. Using a qPCR-based microarray platform, we identified genes differentially regulated by GLI1 in MCF7 cells and then determined if expression of these genes correlated with GLI1 expression in patient tumor samples. Statistical comparison between the groups was performed by ANOVA. Direct comparison of two groups was done by a two-tailed t test. Correlations between variables were done by Pearson's method.

Results

Expression of GLI1 and its target genes correlated significantly with worse distant DFS in breast cancer patients with Luminal A molecular subtype. Particularly, co-expression of GLI1 with EGFR and/or SNAI1, two of the identified GLI1 targets, was predictive of worse distant DFS in this subtype. Furthermore, patients with Luminal A tumors with a high GLI1 signature had a shorter distant DFS compared to the Luminal B subtype and the outcome for this group was comparable to patients with HER2-positive or basal-like tumors.

Conclusion

We have identified a novel GLI1 gene signature that is associated with worse clinical outcomes among the patients with Luminal A subtype of breast cancer.



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Centralization errors in comparative genomic hybridization array analysis of pituitary tumor samples

Abstract

Reliable interpretation of comparative genomic hybridization array (aCGH) results requires centralization and normalization of the data. We evaluated the reliability of aCGH centralization by comparing aCGH results (with classical centralization-normalization steps) to fluorescence in situ hybridization (FISH) results. In addition, we propose a method to correct centralization bias. Sixty-six pituitary tumors were analyzed (Agilent aCGH+SNP 4 × 180K microarray). For each tumor, the FISH-based log2(ratios) of a subset of chromosomes were compared with the corresponding aCGH raw log2(ratios). With our new normalization-centralization process, this difference was added to all log2(ratios), before performing loess regression on non-altered probes only. Finally, the mean log2(ratio) and the percentage of normal probes were compared between CGHnormaliter and our new FISH-based method. For 11 tumors, FISH results and raw CGH log2(ratios) differed significantly. In addition, nine tumors showed discrepancies between results generated by CGHnormaliter and our new-method. Such discrepancies seemed to occur with tumours with many abnormalities (0 to 40% normal probes), rather than in those tumours with fewer abnormalities (31 to 100% normal probes). Five tumors had too few normal probes to allow normalization. In these tumors, which can exhibit many changes in DNA copy number, we found that centralization bias was frequent and uncorrected by current normalization methods. Therefore, an external control for centralization, such as FISH analysis, is required to insure reliable interpretation of aCGH data. This article is protected by copyright. All rights reserved.



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