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Survival outcomes of double- and triple-sequential targeted therapy in patients with metastatic renal cell carcinoma: a retrospective comparison

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      Abstract

      Objective

      To evaluate the progression-free survival (PFS) and overall survival (OS) in patients with metastatic renal cell carcinoma (mRCC) treated with double- and triple-sequence targeted therapy (TT) using tyrosine kinase inhibitors (TKIs) and mammalian target of rapamycin inhibitors (mTORi).

      Materials and Methods

      Records of 292 patients with mRCC, treated with TT between January 2005 and July 2015, were analyzed retrospectively. Kaplan-Meier and log-rank analyses were used to calculate and compare the total PFS (tPFS) and OS when patients underwent double- or triple-TT using TKIs or mTORi.

      Results

      Eighty-one (27.7%) patients who underwent second-line TT were enrolled; 30 (10.3%) of whom underwent third-line TT. The tPFS and OS of double-TT using TKI-mTORi (5.4 and 30 months, respectively) were significantly better compared with TKI-TKI (0.3 and 2 months) or mTORi-TKI (2 and 6 months) (p <0.001). For triple-TT, the tPFS and OS of TKI-mTORi-TKI (22.8 and 25 months, respectively) were significantly superior compared with those for TKI-TKI-mTORi (4 and 9 months) (p <0.05).

      For patients with intermediate-risk according to the Heng or Memorial Sloan-Kettering Cancer Center risk models, TKI-mTORi was associated with a significantly longer tPFS and OS compared with TKI-TKI [expect for OS in the Heng group (p = 0.086)]. For the triple TT group, TKI-mTORi-TKI resulted in improved tPFS and OS compared with TKI-TKI-TKI or TKI-TKI-mTORi (p <0.05).

      Conclusion

      In patients with mRCC, sequential administration of TKI-mTORi led to a significantly superior tPFS compared with any other TT sequence. By contrast, OS did not differ significantly according to TT sequence.

      Related collections

      Most cited references 32

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      Assessment of the change in tumour burden is an important feature of the clinical evaluation of cancer therapeutics: both tumour shrinkage (objective response) and disease progression are useful endpoints in clinical trials. Since RECIST was published in 2000, many investigators, cooperative groups, industry and government authorities have adopted these criteria in the assessment of treatment outcomes. However, a number of questions and issues have arisen which have led to the development of a revised RECIST guideline (version 1.1). Evidence for changes, summarised in separate papers in this special issue, has come from assessment of a large data warehouse (>6500 patients), simulation studies and literature reviews. HIGHLIGHTS OF REVISED RECIST 1.1: Major changes include: Number of lesions to be assessed: based on evidence from numerous trial databases merged into a data warehouse for analysis purposes, the number of lesions required to assess tumour burden for response determination has been reduced from a maximum of 10 to a maximum of five total (and from five to two per organ, maximum). Assessment of pathological lymph nodes is now incorporated: nodes with a short axis of 15 mm are considered measurable and assessable as target lesions. The short axis measurement should be included in the sum of lesions in calculation of tumour response. Nodes that shrink to <10mm short axis are considered normal. Confirmation of response is required for trials with response primary endpoint but is no longer required in randomised studies since the control arm serves as appropriate means of interpretation of data. Disease progression is clarified in several aspects: in addition to the previous definition of progression in target disease of 20% increase in sum, a 5mm absolute increase is now required as well to guard against over calling PD when the total sum is very small. Furthermore, there is guidance offered on what constitutes 'unequivocal progression' of non-measurable/non-target disease, a source of confusion in the original RECIST guideline. Finally, a section on detection of new lesions, including the interpretation of FDG-PET scan assessment is included. Imaging guidance: the revised RECIST includes a new imaging appendix with updated recommendations on the optimal anatomical assessment of lesions. A key question considered by the RECIST Working Group in developing RECIST 1.1 was whether it was appropriate to move from anatomic unidimensional assessment of tumour burden to either volumetric anatomical assessment or to functional assessment with PET or MRI. It was concluded that, at present, there is not sufficient standardisation or evidence to abandon anatomical assessment of tumour burden. The only exception to this is in the use of FDG-PET imaging as an adjunct to determination of progression. As is detailed in the final paper in this special issue, the use of these promising newer approaches requires appropriate clinical validation studies.
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          Modes of resistance to anti-angiogenic therapy.

          Angiogenesis inhibitors targeting the vascular endothelial growth factor (VEGF) signalling pathways are affording demonstrable therapeutic efficacy in mouse models of cancer and in an increasing number of human cancers. However, in both preclinical and clinical settings, the benefits are at best transitory and are followed by a restoration of tumour growth and progression. Emerging data support a proposition that two modes of unconventional resistance underlie such results: evasive resistance, an adaptation to circumvent the specific angiogenic blockade; and intrinsic or pre-existing indifference. Multiple mechanisms can be invoked in different tumour contexts to manifest both evasive and intrinsic resistance, motivating assessment of their prevalence and importance and in turn the design of pharmacological strategies that confer enduring anti-angiogenic therapies.
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            Author and article information

            Affiliations
            1 Center for Prostate Cancer, Research Institute and Hospital of National Cancer Center, Goyang, Korea
            Author notes
            Correspondence to: Jinsoo Chung, cjs5225@ 123456ncc.re.kr
            Journal
            Oncotarget
            Oncotarget
            Oncotarget
            ImpactJ
            Oncotarget
            Impact Journals LLC
            1949-2553
            21 November 2017
            19 October 2017
            : 8
            : 59
            : 100056-100065
            5725002
            21926
            10.18632/oncotarget.21926
            Copyright: © 2017 Kim et al.

            This is an open-access article distributed under the terms of the Creative Commons Attribution License 3.0 (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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            Research Paper

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