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  • HER2-enriched subtype and pathological complete response in HER2-positive breast cancer: a systematic review and meta-analysis
    Cancer Treat. Rev. (IF 8.332) Pub Date : 2020-01-17
    Francesco Schettini; Tomas Pascual; Benedetta Conte; Nuria Chic; Fara Brasó-Maristany; Patricia Galván; Olga Martínez; Barbara Adamo; Maria Vidal; Montserrat Muñoz; Aranzazu Fernández-Martinez; Carla Rognoni; Gaia Griguolo; Valentina Guarneri; Pier Franco Conte; Mariavittoria Locci; Jan C. Brase; Blanca Gonzalez-Farre; Aleix Prat

    Background HER2-positive (HER2+) breast cancer (BC) comprises all the four PAM50 molecular subtypes. Among these, the HER2-E appear to be associated with higher pathological complete response (pCR) rates following anti-HER2-based regimens. Here, we present a meta-analysis to validate the association of the HER2-E subtype with pCR following anti-HER2-based neoadjuvant treatments with or without chemotherapy (CT). Methods A systematic literature search was performed in February 2019. The primary objective was to compare the association between HER2-E subtype (versus others) and pCR. Selected secondary objectives were to compare the association between 1) HER2-E subtype and pCR in CT-free studies, 2) HER2-E subtype within hormone receptor (HR)-negative and HR+ disease and 3) HR-negative disease (versus HR+) and pCR in all patients and within HER2-E subtype. A random-effect model was applied. The Higgins’ I2 was used to quantify heterogeneity. Results Sixteen studies were included, 5 of which tested CT-free regimens. HER2-E subtype was significantly associated with pCR in all patients (odds ratio [OR]=3.50, p<0.001, I2=33%), in HR+ (OR=3.61, p<0.001, I2=1%) and HR-negative tumors (OR=2.28, p=0.01, I2=47%). In CT-free studies, HER2-E subtype was associated with pCR in all patients (OR=5.52, p<0.001, I2=0%) and in HR+ disease (OR=4.08, p=0.001, I2=0%). HR-negative status was significantly associated with pCR compared to HR+ status in all patients (OR=2.41, p<0.001, I2=30%) and within the HER2-E subtype (OR=1.76, p<0.001, I2=0%). Conclusions The HER2-E biomarker identifies patients with a higher likelihood of achieving a pCR following neoadjuvant anti-HER2-based therapy beyond HR status and CT use. Future trial designs to escalate or de-escalate systemic therapy in HER2+ disease should consider this genomic biomarker.

    更新日期:2020-01-17
  • How to measure tumour response in rectal cancer? An explanation of discrepancies and suggestions for improvement
    Cancer Treat. Rev. (IF 8.332) Pub Date : 2020-01-17
    Iris D. Nagtegaal; Rob Glynne-Jones

    Various methods categorize tumour response after neoadjuvant therapy, including down-staging and tumour regression grading. Response categories allow comparison of different treatments within clinical trials and predict outcome. A reproducible response categorization could identify subgroups with high or low risk for the most appropriate subsequent treatments, like watch and wait. Lack of standardization and interpretation difficulties currently limit the usability of these approaches. In this review we describe these difficulties for the evaluation of chemoradiation in rectal cancer. An alternative approach of tumour response is based on patterns of residual disease, including fragmentation. We summarise the evidence behind this alternative method of response categorisation, which explains a number of very relevant clinical discrepancies. These issues include differences between downstaging and tumour regression, high local regrowth in advanced tumours during watchful waiting procedures, the importance of resection margins, the limited value of post-treatment biopsies and the relatively poor outcome of patients with a near complete pathological response. Recognition of these patterns of response can allow meaningful development of novel biomarkers in the future.

    更新日期:2020-01-17
  • Optimizing treatment of renal cell carcinoma with VEGFR-TKIs: a comparison of clinical pharmacology and drug-drug interactions of anti-angiogenic drugs
    Cancer Treat. Rev. (IF 8.332) Pub Date : 2020-01-17
    Stefano Fogli; Camillo Porta; Marzia Del Re; Stefania Crucitta; Giulia Gianfilippo; Romano Danesi; Brian I. Rini; Manuela Schmidinger

    Anti-angiogenic treatment is an important option that has changed the therapeutic landscape in cancer patients, particularly those affected by renal cell carcinoma (RCC). Agents that block signaling pathways governing tumor angiogenesis have raised high expectations among clinicians. Vascular endothelial growth factor receptor-tyrosine kinase inhibitors (VEGFR-TKIs) is a heterogeneous class of drugs with distinct pharmacological profiles, including potency, selectivity, pharmacokinetics and drug-drug interactions. Among them, tivozanib is one of the last TKIs introduced in the clinical practice; this drug selectively targets VEGFRs, it is characterized by a favorable pharmacokinetics and safety profile and has been approved as first-line treatment for patients with advanced RCC. In this article, we describe the clinical pharmacology of selected VEGFR-TKIs used for the treatment of RCC, highlighting the relevant differences in clinical pharmacology and we also try to define the main pharmacologic characteristics of these drugs that allow us to divide them into different generations.

    更新日期:2020-01-17
  • Breast implant-associated anaplastic large cell lymphoma: A Comprehensive Review
    Cancer Treat. Rev. (IF 8.332) Pub Date : 2020-01-13
    Antonio Marra; Giulia Viale; Stefano A. Pileri; Gabriella Pravettoni; Giuseppe Viale; Francesca De Lorenzi; Franco Nolè; Paolo Veronesi; Giuseppe Curigliano
    更新日期:2020-01-13
  • Whole exome sequencing of cell-free DNA - a systematic review and Bayesian individual patient data meta-analysis
    Cancer Treat. Rev. (IF 8.332) Pub Date : 2019-12-13
    Manouk K. Bos; Lindsay Angus; Kazem Nasserinejad; Agnes Jager; Maurice P.H.M. Jansen; John W.M. Martens; Stefan Sleijfer

    Molecular profiling of tumor derived cell free DNA (cfDNA) is gaining ground as a prognostic and predictive biomarker. However to what extent cfDNA reflects the full metastatic landscape as currently determined by tumor tissue analysis remains controversial. Though technically challenging, whole exome sequencing (WES) of cfDNA enables thorough evaluation of somatic alterations. Here, we review the feasibility of WES of cfDNA and determine the sensitivity of WES-detected single nucleotide variants (SNVs) in cfDNA on individual patient data level using paired tumor tissue as reference (sharedSNVsAlltissueSNVsx100%). The pooled sensitivity was 50% (95% credible interval (CI): 29%-72%). The tissue mutant allele frequency (MAF) of variants exclusively identified in tissue was significantly lower (12.5%, range: 0.5-18%) than the tissue MAF of variants identified in both tissue and cfDNA (23.9%, range: 17-38%), p=0.004. The overall agreement (sharedSNVsAllSNVsx100%)between SNVs in cfDNA and tumor tissue was 31% (95% CI: 15%-49%). The number of detected SNVs was positively correlated with circulating tumor DNA (ctDNA) fraction (p=0.016). A sub analysis of samples with ctDNA fractions ≥25% improved the sensitivity to 69% (95% CI: 46%-89%) and agreement to 46% (95% CI: 36%-59%), suggesting that WES is mainly feasible for patients with high ctDNA fractions. Pre- and post-analytical procedures were highly variable between studies rendering comparisons problematic. In conclusion, various aspects of WES of cfDNA are largely in its investigative phase, standardization of methodologies is highly needed to bring this promising technique to its clinical potential.

    更新日期:2019-12-17
  • The local inflammatory response in colorectal cancer – type, location or density? A systematic review and meta-analysis
    Cancer Treat. Rev. (IF 8.332) Pub Date : 2019-12-11
    Peter G. Alexander, Donald C. McMillan, James H. Park

    Introduction The host anti-tumour inflammatory response is a strong prognostic indicator, and tumour infiltrating lymphocytes (TILs) are believed to have a complimentary role alongside TNM assessment in dictating future management. However, there is wide disagreement regarding the most efficacious and cost-effective method of assessment. Methods A comprehensive literature search was performed of EMBASE, MedLine and PubMed as well as an assessment of references to identify all relevant studies relating to the assessment of the peri-tumoural inflammatory response or TILs and prognosis in colorectal cancer (CRC). A meta-analysis was performed of 67 studies meeting the REMARK criteria using RevMan software. Results Intratumoural assessment of both CD3 and CD8 in CRC were significant for disease-free survival (DFS) (combined HRs 0.46; 95%CI: 0.39-0.54 and 0.54; 95%CI: 0.45-0.65), as well as overall survival (OS) and disease-specific survival (DSS). The same was true for assessment of CD3 and CD8 at the invasive margin (DFS: combined HRs 0.45; 95%CI: 0.33-0.61 and 0.51; 95%CI: 0.41-0.62). However, similar fixed effects summaries were also observed for H&E-based methods, like Klintrup-Makinen grade (DFS: HR 0.62; 95%CI: 0.43-0.88). Furthermore, inflammatory assessments were independent of MSI status. Conclusion The evidence suggests that it is the density of a co-ordinated local inflammatory infiltrate that confers survival benefit, rather than any individual immune cell subtype. Furthermore, the location of individual cells within the tumour microenvironment does not appear to influence survival. The authors advocate a standardised assessment of the local inflammatory response, but caution against emphasizing the importance of any individual immune cell subtype.

    更新日期:2019-12-11
  • Gastroesophageal Cancer: Navigating the Immune and Genetic Terrain to Improve Clinical Outcomes
    Cancer Treat. Rev. (IF 8.332) Pub Date : 2019-12-10
    James O. Jones, Elizabeth C. Smyth

    Recent advances in our understanding of the molecular biology of gastric and oesophageal cancers have shown that gastroesophageal adenocarcinoma should be considered as one disease spectrum. Clinical management of these cancers is challenging, with poor outcomes in both early and late disease settings. Certain molecular subsets of gastroesophageal adenocarcinoma demonstrate features that suggest immunotherapy could be an effective treatment. Immunogenetic markers, including mismatch repair deficiency, PD-L1 status and tumour infiltrating lymphocytes influence overall prognosis. They may also determine the response to adjuvant and neoadjuvant conventional chemotherapy. Initial results from immunotherapy trials for gastroesophageal cancer have however been mixed, with poor overall responses in the first- and second-line settings. This review aims to discuss how better understanding of these immune and genetic interactions may lead to better selection of patients for conventional and immune based therapies, and therefore improve patient outcomes. We also discuss the challenges in implementing this new understanding in routine practice, and the current limitations of immune based treatments for gastroesophageal cancer.

    更新日期:2019-12-11
  • Adjuvant chemotherapy for rectal cancer: current evidence and recommendations for clinical practice
    Cancer Treat. Rev. (IF 8.332) Pub Date : 2019-12-10
    G. Bregni, T. Akin Telli, S. Camera, A. Deleporte, L. Moretti, A.M. Bali, G. Liberale, S. Holbrechts, A. Hendlisz, F. Sclafani

    While adjuvant chemotherapy is an established treatment for pathological stage II and especially stage III colon cancer, its role in the multimodal management of rectal cancer remains controversial. As a result, there is substantial variation in the use of this treatment in clinical practice. Even among centres and physicians who consider adjuvant chemotherapy as a standard treatment, notable heterogeneity exists with regard to patient selection criteria and chemotherapy regimens. The controversy around this topic is confirmed by the lack of full consensus among national and international clinical guidelines. While most of the clinical trials do not support the contention that adjuvant chemotherapy may improve survival outcomes if pre-operative (chemo)radiotherapy is also given, these suffer from many limitations that preclude drawing definitive conclusions. Nevertheless, in the era of evidence-based medicine, physicians should be guided by the available data and refrain from extrapolating results of adjuvant colon cancer trials to inform treatment decisions for rectal cancer. Patients should be informed of the evidence gap, be given the opportunity to carefully discuss pros and cons of all the possible management options and be empowered in the decision making. In this article we review the available evidence on adjuvant chemotherapy for rectal cancer and propose a risk-adapted decisional algorithm that largely relies on informed patient preferences.

    更新日期:2019-12-11
  • Current standards and future perspectives in adjuvant treatment for biliary tract cancers
    Cancer Treat. Rev. (IF 8.332) Pub Date : 2019-12-04
    Angela Lamarca, Julien Edeline, Mairéad G McNamara, Richard A Hubner, Masato Nagino, John Bridgewater, John Primrose, Juan W Valle
    更新日期:2019-12-04
  • Contextualizing pertuzumab approval in the treatment of HER2-positive breast cancer patients
    Cancer Treat. Rev. (IF 8.332) Pub Date : 2019-11-29
    Javier Cortés, Eva Ciruelos, Jose Manuel Pérez, Joan Albanell, Laura García-Estévez, Manuel Ruiz–Borrego, Ruth Espinosa, Isabel Gallegos, Santiago González, Isabel Álvarez, Antonio Llombart
    更新日期:2019-11-30
  • Breast Cancer Vaccines: Heeding the Lessons of the Past to Guide a Path Forward
    Cancer Treat. Rev. (IF 8.332) Pub Date : 2019-11-29
    Cinzia Solinas, Marco Aiello, Edoardo Migliori, Karen Willard-Gallo, Leisha A. Emens

    The ability of cancer immunotherapy to generate lasting responses in a broad spectrum of tumors has generated great enthusiasm in medical oncology. A number of new immune-based compounds have now been approved based on the recent success of immune checkpoint blockade, either administered as monotherapy or in combination with other agents. Because clinical activity is limited only to subsets of patients, two major goals of cancer immunotherapy are (1) to reliably identify responders to these current treatments, and (2) to increase the number of patients who can respond to immunotherapy by developing new strategies. These goals are critically important since the hallmark of immune-based therapies is the induction of durable immunologic and clinical responses that result in overall survival benefit. Innovative combination strategies have great potential for bringing the benefit of immunotherapy to more patients. The use of cancer vaccines to actively induce immune effectors together with other drugs, which may include immune checkpoint blockade, chemotherapy, and/or molecularly targeted agents, is a particularly attractive strategy. Cancer vaccines have been tested both to prevent or intercept the development of cancer, and to decrease established tumor burdens. No vaccine has yet been approved for either breast cancer treatment or prevention. Here, we review the history of breast cancer vaccine development, and highlight near-term opportunities for moving forward.

    更新日期:2019-11-30
  • Survival and toxicity in neoadjuvant chemotherapy plus surgery versus definitive chemoradiotherapy for cervical cancer: a systematic review and meta-analysis
    Cancer Treat. Rev. (IF 8.332) Pub Date : 2019-11-29
    C. Marchetti, A. Fagotti, V. Tombolini, G. Scambia, F. De Felice

    Purpose Neoadjuvant chemotherapy followed by surgery (NACT+S) has been compared with definitive chemoradiothherapy (CRT) in randomized clinical trials (RCTs) in stage IB2, IIA and IIB cervical cancer (1994 Figo stage). Our aim was to evaluate efficacy and toxicity of NACT+S and CRT and identify differences in clinical outcomes and severe toxicity frequency. Methods The PRISMA statement was applied. Random-effects models were used. Results Two RCTs representing 1259 patients were identified. NACT+S was not associated with significant OS improvement compared with CRT, with HR of 1.08 (95% CI = 0.86–1.36; p = 0.51). The HR of relapse was 1.32 (95%CI = 1.07–1.62) in favor of CRT. Severe acute toxicity was lower in CRT group. Conclusion This meta-analysis showed similar OS rates between treatment and CRT superiority over NACT+S in terms of DFS and severe acute toxicity. Impact on long term toxicity and quality of life remain to be proven.

    更新日期:2019-11-30
  • Current strategies for the treatment of intermediate and advanced hepatocellular carcinoma
    Cancer Treat. Rev. (IF 8.332) Pub Date : 2019-11-29
    Arndt Vogel, Anna Saborowski

    Hepatocellular carcinoma (HCC) ranks among the most common cancers worldwide [1] and remains to be a major global health care problem. Until 2007, no effective therapies were available for patients after failure of locoregional approaches, and the approval of sorafenib as the first systemic agent with efficacy in patients suffering from advanced HCC marked a new era in the treatment of this deadly disease. However, it took nearly 10 years until the portfolio of effective drugs finally expanded and additional substances showed activity in both first and further lines of treatment. Since their recent approval, these novel substances have substantially changed the field of palliative treatment strategies in patients with advanced HCC, and their sequential application has demonstrated their potential to significantly prolong patient survival in the palliative setting. With the recently communicated data from the first positive immune-oncology (IO) trial in HCC, it appears highly likely that the implementation of IO concepts will result in a further improvement of patient prognosis. Although locoregional approaches remain an integral component of meaningful treatment concepts for patients with BCLC-B stage HCC, repetitive interventions bear the risk of a progressive deterioration of liver function. More than ever, in order to build/ implement long-term therapeutic concepts and exploit the full potential of systemic treatment strategies, it is of utmost importance to maintain a fine balance between anti-tumor activity and toxicity. With an emphasis on the systemic treatment options, this review provides a summary of the most recent results from large phase III clinical trials and discusses their clinical implications.

    更新日期:2019-11-30
  • Biomarker-guided implementation of the old drug temozolomide as a novel treatment option for patients with metastatic colorectal cancer
    Cancer Treat. Rev. (IF 8.332) Pub Date : 2019-11-28
    Filippo Pietrantonio, Giovanni Randon, Dario Romagnoli, Samantha Di Donato, Matteo Benelli, Filippo de Braud

    Temozolomide is an oral alkylating agent used for treating several cancer types including glioblastoma and melanoma. Promising, albeit limited, activity and efficacy of temozolomide have been reported in pretreated patients with metastatic colorectal cancer bearing MGMT promoter methylation. MGMT silencing and proficiency of the mismatch repair system were considered the major predictive biomarkers of sensitivity to temozolomide. Refinement of established biomarkers and integration with novel ones including those related to alteration in specific DNA-damage response pathways such as base-excision repair are promising strategies for selecting metastatic colorectal patients to this old drug with several potential novel applications. Then, mounting preclinical and clinical observations have linked acquired resistance to temozolomide to emergence of alterations in the mismatch repair system. Whilst accounting for tumor cells capability of escaping apoptosis when exposed to temozolomide, inactivation of key mismatch-repair proteins will ultimately lead to increasing tumor mutational burden. This drug-induced mismatch deficient-like phenotype is being exploited in proof-of-concept trials combining temozolomide and immune checkpoint inhibitors in metastatic colorectal cancer.

    更新日期:2019-11-29
  • Chimeric antigen receptor T (CAR-T) cell immunotherapy for sarcomas: from mechanisms to potential clinical applications
    Cancer Treat. Rev. (IF 8.332) Pub Date : 2019-11-25
    Pichaya Thanindratarn, Dylan C. Dean, Scott D. Nelson, Francis J. Hornicek, Zhenfeng Duan

    Survival rates for sarcoma patients have plateaued in the past few decades and remain especially grim for those with recurrent or metastatic disease. This has prompted investigation into novel immunotherapies for sarcomas, especially after their recent and well-recognized successes in other cancers. One such modality, the Chimeric Antigen Receptor (CAR) T Cell therapy, has shown promising results in treating B-cell lymphoma and acute lymphoblastic leukemia. This novel therapy functions by fusing a specific antibody derived single-chain variable fragment (scFv) with a T-cell which recognizes a specific tumor-associated antigen (TAA). Several sarcoma-associated antigens (SAA) amenable to CAR-T cell treatment have recently emerged with encouraging results. These include human epidermal growth factor receptor 2 (HER2), disialoganglioside (GD2), interleukin 11 Receptor Subunit Alpha (IL-11RA), fibroblast activation protein (FAP), B7-H3, CD44v6, insulin-like growth factor 1 receptor (IGF-1R), and tyrosine kinase orphan-like receptor 1 (ROR1). Given the limitations of current medical therapies, novel treatment strategies are urgently needed. As a sarcoma treatment modality, CAR-T cell therapy is highly promising and continues to draw interest especially as new clinical trials emerge. Here we review recent breakthrough CAR-T cell studies in sarcoma, the targets which define them, and approaches to minimizing host cytotoxicity.

    更新日期:2019-11-26
  • Identification of prognostic DNA methylation biomarkers in patients with gastrointestinal adenocarcinomas: a systematic review of epigenome-wide studies
    Cancer Treat. Rev. (IF 8.332) Pub Date : 2019-11-23
    Margherita d'Errico, Elizabeth Alwers, Yan Zhang, Dominic Edelmann, Hermann Brenner, Michael Hoffmeister

    This systematic review aims to summarize epigenome-wide studies on aberrant DNA methylation and its association with survival in patients with gastrointestinal adenocarcinoma. The 15 studies identified showed a large variety of methodological approaches for the identification of prognostic epigenetic markers from genome-wide methylation analyses. None of the findings were reported by more than one study in this systematic review. Further validation studies, a better reporting of methods and results are needed, as well as a clearer definition of investigated outcomes. At present, no conclusions can be drawn on the clinical relevance of the reported epigenetic markers.

    更新日期:2019-11-26
  • Androgen receptor plasticity and its implications for prostate cancer therapy
    Cancer Treat. Rev. (IF 8.332) Pub Date : 2019-06-11
    Oliver Snow, Nada Lallous, Kriti Singh, Nathan Lack, Paul Rennie, Artem Cherkasov

    Acquired resistance to a drug treatment is a common problem across many cancers including prostate cancer (PCa) - one of the major factors for male mortality. The androgen receptor (AR) continues to be the main therapeutic PCa target and despite the success of modern targeted therapies such as enzalutamide, resistance to these drugs eventually develops. The AR has found many ways to adapt to treatments including overexpression and production of functional, constitutively active splice variants. However, of particular importance are point mutations in the ligand binding domain of the protein that convert anti-androgens into potent AR agonists. This mechanism appears to be especially prevalent with the AR in spite of some distant similarities to other hormone nuclear receptors. Despite the AR being one of the most studied and attended targets in cancer, those gain-of-function mutations in the receptor remain a significant challenge for the development of PCa therapies. This drives the need to fully characterize such mutations and to consistently screen PCa patients for their occurrence to prevent adverse reactions to anti-androgen drugs. Novel treatments should also be developed to overcome this resistance mechanism and more attention should be given to the possibility of similar occurrences in other cancers.

    更新日期:2019-11-18
  • Grey areas and evidence gaps in the management of rectal cancer as revealed by comparing recommendations from clinical guidelines
    Cancer Treat. Rev. (IF 8.332) Pub Date : 2019-11-11
    G. Bregni, T. Akin Telli, S. Camera, C. Baratelli, L. Shaza, A. Deleporte, L. Moretti, M.A. Bali, G. Liberale, A. Hendlisz, F. Sclafani

    Background While the management of nonmetastatic and oligometastatic rectal cancer has rapidly evolved over the last few decades, many grey areas and highly debated topics remain that foster significant variation in clinical practice. We aimed to identify controversial points and evidence gaps in this disease setting by systematically comparing recommendations from national and international clinical guidelines. Methods Twenty-six clinical questions reflecting practical challenges in the routine management of nonmetastatic and oligometastatic rectal cancer patients were selected. Recommendations from the ESMO, NCCN, JSCCR, Australian and Ontario guidelines were extrapolated and compared using a 4-tier classification system (i.e., identical/very similar, similar, slightly different, different). Overall agreement between guidelines (i.e., substantial/complete disagreement, partial disagreement, partial agreement, substantial/complete agreement) was assessed for each clinical question and compared against the highest level of available evidence by using the χ2 statistic test. Results Guidelines were in substantial/complete agreement, partial agreement, partial disagreement, and substantial/complete disagreement for 8 (30.8%), 2 (7.7%), 7 (26.9%), and 9 (34.6%) clinical questions, respectively. High level of evidence supported clinical recommendations in 3/10 cases (30%) where guidelines were in agreement and in 10/16 cases (62.5%) where guidelines were in disagreement (χ2=2.6, p=0.106). Agreement was frequently reached for questions regarding diagnosis, staging, and radiology/pathology pro-forma reporting, while disagreement characterised most of the treatment-related topics. Conclusions Substantial variation exists across clinical guidelines in the recommendations for the management of nonmetastatic and oligometastatic rectal cancer. This variation is only partly explained by the lack of supporting, high-level evidence.

    更新日期:2019-11-13
  • Multiple myeloma: role of autologous transplantation
    Cancer Treat. Rev. (IF 8.332) Pub Date : 2019-11-11
    Ioannis Ntanasis-Stathopoulos, Maria Gavriatopoulou, Efstathios Kastritis, Evangelos Terpos, Meletios A Dimopoulos

    Autologous stem cell transplantation (ASCT) has been the mainstay of multiple myeloma (MM) treatment for approximately 30 years. Although the continuous introduction of novel agents in the armamentarium against MM has questioned its value, ASCT remains a backbone treatment for fit MM patients. However, there is no unanimous approach for several aspects including the positioning of ASCT in the therapeutic algorithm either upfront or following the first relapse, the need for single or tandem ASCT, as well as the role of ASCT as salvage therapy. Furthermore, the anti-CD38 monoclonal antibodies along with the next generation proteasome inhibitors and immunomodulatory drugs provide a platform for optimizing the induction and consolidation/maintenance regimens. In this review, we present current data pertaining to all aspects of ASCT in MM, whereas we highlight the open issues that should be addressed in the design of future clinical trials in the field.

    更新日期:2019-11-13
  • New therapeutic targets in pancreatic cancer
    Cancer Treat. Rev. (IF 8.332) Pub Date : 2019-11-11
    Eleonora Lai, Marco Puzzoni, Pina Ziranu, Andrea Pretta, Valentino Impera, Stefano Mariani, Nicole Liscia, Paolo Soro, Francesca Musio, Mara Persano, Clelia Donisi, Simona Tolu, Francesca Balconi, Annagrazia Pireddu, Laura Demurtas, Valeria Pusceddu, Silvia Camera, Francesco Sclafani, Mario Scartozzi

    Pancreatic ductal adenocarcinoma(PDAC) is associated with poor survival. Of all newly diagnosed patients, only about 20% can benefit from a potentially curative surgical resection, the remaining 80% presenting with unresectable locally advanced(LAPC) or metastatic(MPC) disease. Currently, there are limited therapeutic options for LAPC and MPC patients. Furthermore, despite intensive research efforts to better understand the molecular bases of PDAC and the biological relevance of its tumor microenvironment, treatments still largely consist of classical cytotoxic chemotherapy agents. Several studies of genetic and epigenetic sequencing have demonstrated the existence of 4 molecular PDAC subtypes, with heterogeneous genetic characteristics and different biological behaviour: squamous, pancreatic progenitor, immunogenic and aberrantly differentiated endocrine exocrine (ADEX). These distinct subtypes derive from alterations at multiple levels. Apart from the DNA repair pathway, however, none of these has so far been validated as a clinically relevant therapeutic target. Also, PDCA is unique from an immunological perspective and many studies have recently tried to elucidate the role of intratumoral effector T-cells, RAS oncogene, immunosuppressive leukocytes and desmoplastic reaction in maintaining the immunological homeostasis of this disease. However, there still remains much to be learned about the mechanisms whereby the pancreatic immune microenvironment promotes immune escape of cancer cells. Furthermore, while therapies targeting the stroma as well as immunotherapies hold promise for the future, these are not yet standard of care. This review aims to outline the state-of-the-art of LAPC and MPC treatment, highlighting data on the target therapies failure and current ongoing clinical trials on new promising therapeutic strategies.

    更新日期:2019-11-13
  • Hereditary prostate cancer - primetime for genetic testing?
    Cancer Treat. Rev. (IF 8.332) Pub Date : 2019-11-11
    Isabel Heidegger, Igor Tsaur, Hendrik Borgmann, Christian Surcel, Alexander Kretschmer, Romain Mathieu, Pieter De Visschere, Massimo Valerio, Roderick C.N. van den Bergh, Piet Ost, Derya Tilki, Giorgio Gandaglia, Guillaume Ploussard

    Prostate cancer (PCa) remains the most common cancer in men. The proportion of all PCa attributable to high-risk hereditary factors has been estimated to 5-15%. Recent landmark discoveries in PCa genetics led to the identification of germline mutations/alterations (eg. BRCA1, BRCA2, ATM or HOXB13), single nucleotide polymorphisms or copy number variations associated with PCa incidence and progression. However, offering germline testing to men with an assumed hereditary component is currently controversial. In the present review article, we provide an overview about the epidemiology and the genetic basis of PCa predisposition and critically discuss the significance and consequence in the clinical routine. In addition, we provide an overview about genetic tests and report latest findings from ongoing clinical studies. Lastly, we discuss the impact of genetic testing in personalized medicine and therapy in advanced stages of the disease.

    更新日期:2019-11-13
  • The evolving role of PD-L1 testing in patients with metastatic urothelial carcinoma
    Cancer Treat. Rev. (IF 8.332) Pub Date : 2019-11-11
    Thomas Powles, Jill Walker, J. Andrew Williams, Joaquim Bellmunt

    Immune checkpoint inhibitors targeting the programmed cell death 1 (PD-1)/programmed cell death ligand 1 (PD-L1) pathway improve clinical outcomes in patients with locally advanced/metastatic urothelial carcinoma (UC). PD-L1 complementary or companion diagnostic assays are now available for anti–PD-1 and anti–PD-L1 antibodies and these assays enable testing at diagnosis. The role of PD-L1 testing in UC is, however, the subject of much discussion within the medical community, particularly in light of recent restrictions on recruitment of PD-L1–low patients in clinical trials of atezolizumab and pembrolizumab as first-line therapy, and the European Medicines Agency and US Food and Drug Administration limiting use of these agents as first-line therapy in cisplatin-ineligible patients to those with high PD-L1 expression. We explore the evolving evidence for PD-L1 expression testing in UC and the role of PD-L1 expression in both tumor cells and tumor-infiltrating immune cells. We review clinical data on the prognostic and predictive value of PD-L1 expression in response to anti–PD-1/PD-L1 agents as first- and second-line therapy, considering issues such as the differences among complementary diagnostic assays in terms of the type of cells scored, antibodies used, and cutoff values. We consider how PD-L1 testing fits into decision-making and the potential of emerging biomarkers in UC. We conclude that, based on the scientific rationale for its use and evidence from clinical trials, PD-L1 testing provides enriched information on the patients most likely to benefit from immune checkpoint blockade and should be routinely offered to patients with metastatic UC.

    更新日期:2019-11-13
  • Primary and acquired resistance mechanisms to immune checkpoint inhibition in Hodgkin lymphoma
    Cancer Treat. Rev. (IF 8.332) Pub Date : 2019-11-11
    Johanna Veldman, Lydia Visser, Anke van den Berg, Arjan Diepstra

    Hodgkin lymphoma is a B cell derived malignancy characterized by a low number of tumor cells within an environment consisting of inflammatory cells. Recently, immune checkpoint blockade targeting the PD-1-PD-L1 axis has shown to be a great success in relapsed and refractory Hodgkin lymphoma patients. However, complete responses are scarce and median progression-free survival is limited to around 11-15 months. Efficiency of PD-1 blockade in HL might be dependent on CD4+ T cells, but also tumor associated macrophages (TAMs) and NK cells are implicated. The aim of this review is to highlight currently known prominent immune evasion strategies and discuss their possible contribution to primary or acquired resistance to immune checkpoint blockade in Hodgkin lymphoma. These include T cell dependent mechanisms such as shaping of the inflammatory infiltrate, lack of presentation of antigens and neoantigens and production of molecules involved in suppression of T cell functionality such as other immune checkpoints, indoleamine 2,3-dioxygenase and adenosine. Moreover, the role of NK cells and TAMs in efficient PD-1 blockade will be discussed. Targeting these mechanisms in parallel to PD-1 may potentially increase efficiency of PD-1 blockade therapy.

    更新日期:2019-11-13
  • RET Fusions in Solid Tumors
    Cancer Treat. Rev. (IF 8.332) Pub Date : 2019-10-30
    Andrew Y. Li, Michael G. McCusker, Alessandro Russo, Katherine A. Scilla, Allison Gittens, Katherine Arensmeyer, Ranee Mehra, Vincenzo Adamo, Christian Rolfo

    The RET proto-oncogene has been well-studied. RET is involved in many different physiological and developmental functions. When altered, RET mutations influence disease in a variety of organ systems from Hirschsprung’s disease and multiple endocrine neoplasia 2 (MEN2) to papillary thyroid carcinoma (PTC) and non-small cell lung cancer (NSCLC). Changes in RET expression have been discovered in 30-70% of invasive breast cancers and 50-60% of pancreatic ductal adenocarcinomas in addition to colorectal adenocarcinoma, melanoma, small cell lung cancer, neuroblastoma, and small intestine neuroendocrine tumors. RET mutations have been associated with tumor proliferation, invasion, and migration. RET fusions or rearrangements are somatic juxtapositions of 5’ sequences from other genes with 3’ RET sequences encoding tyrosine kinase. RET rearrangements occur in approximately 2.5-73% of sporadic PTC and 1-3% of NSCLC patients. The most common RET fusions are CDCC6-RET and NCOA4-RET in PTC and KIF5B-RET in NSCLC. Tyrosine kinase inhibitors are drugs that target kinases such as RET in RET-driven (RET-mutation or RET-fusion-positive) disease. Multikinase inhibitors (MKI) target various kinases and other receptors. Several MKIs are FDA-approved for cancer therapy (sunitinib, sorafenib, vandetanib, cabozantinib, regorafenib, ponatinib, lenvatinib, alectinib) and non-oncologic disease (nintedanib). Selective RET inhibitor drugs LOXO-292 (selpercatinib) and BLU-667 (pralsetinib) are also undergoing phase I/II and I clinical trials, respectively, with preliminary results demonstrating partial response and low incidence of serious adverse events. RET fusions provide a viable therapeutic target for oncologic treatment, and further study is warranted into the prevalence and pathogenesis of RET fusions as well as development of current and new tyrosine kinase inhibitors.

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  • Corrigendum to "Gastric cancer: Translating novels concepts into clinical practice" [Cancer Treatm. Rev. 79C (2019) 101889].
    Cancer Treat. Rev. (IF 8.332) Pub Date : 2019-11-28
    Massimiliano Salati,Giulia Orsi,Elisabeth Smyth,Giuseppe Aprile,Giordano Beretta,Fernando De Vita,Maria Di Bartolomeo,Valentina Fanotto,Sara Lonardi,Federica Morano,Filippo Pietrantonio,Carmine Pinto,Lorenza Rimassa,Enrico Vasile,Caterina Vivaldi,Alberto Zaniboni,Pina Ziranu,Stefano Cascinu

    更新日期:2019-11-01
  • Corrigendum to eHealth for improving quality of life in breast cancer patients: A systematic review [Cancer Treatm. Rev. 74C (2019) 1-14].
    Cancer Treat. Rev. (IF 8.332) Pub Date : 2019-11-18
    Stefano Triberti,Lucrezia Savioni,Valeria Sebri,Gabriella Pravettoni

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  • Corrigendum to "Drug-drug interactions in breast cancer patients treated with CDK4/6 inhibitors" [Cancer Treatm. Rev. 74 (2019) 21-28].
    Cancer Treat. Rev. (IF 8.332) Pub Date : 2019-11-11
    Stefano Fogli,Marzia Del Re,Giuseppe Curigliano,Ron H van Schaik,Patrizio Lancellotti,Romano Danesi

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  • Conclusion: Bone markers in metastatic bone disease.
    Cancer Treat. Rev. (IF 8.332) Pub Date : 2006-05-09
    Robert E Coleman

    Bone metastases occur frequently in patients with multiple myeloma and breast, prostate, and lung cancer. Presence of metastatic bone disease (MBD) is correlated with abnormal bone remodelling, as high levels of biochemical markers of bone turnover can be detected in serum or urine from patients with these malignancies. The idea of using bone markers in the diagnosis and follow-up of patients with MBD is undergoing validation and gaining acceptance. In this conclusion, we summarise data from leading studies relating to the search for useful markers of bone resorption and bone formation in MBD.

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  • Markers of bone metabolism in prostate cancer.
    Cancer Treat. Rev. (IF 8.332) Pub Date : 2006-05-09
    Matthew R Smith

    Although bone metastases from prostate cancer are described as osteoblastic, markers of both osteoblastic and osteoclastic activity are strikingly elevated in men with metastatic prostate cancer. Elevated markers of osteoblastic and osteoclastic activity are associated with adverse clinical outcomes in men with prostate cancer--outcomes including shorter time to skeletal complications, disease progression, and death. Bone marker measurement appears to be a promising method for monitoring the efficacy of bone-targeted therapy. Additional studies are needed to assess the potential role of bone markers in identifying men at highest risk for development of bone metastases.

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  • Biochemical bone markers in breast cancer.
    Cancer Treat. Rev. (IF 8.332) Pub Date : 2006-05-09
    Allan Lipton

    Bone metastases, the most common metastatic manifestation of many cancers, including breast cancer and prostate cancer, contribute significantly to the pain and disability often associated with later stages of malignant disease. Although bisphosphonates have demonstrated efficacy in the treatment of metastatic bone disease (MBD), identifying patients most likely to develop bone metastases (and thus to benefit from treatment) is a challenge. In recent years, advances in understanding the pathophysiologic underpinnings of bone metastases have led to the discovery of several potential markers for dysregulation of bone coupling. Trials have been conducted to validate these biochemical markers and to explore their possible role in measuring efficacy of bisphosphonate treatment and of other metastatic bone therapies. In no area is this research more important than in the management of breast cancer. Although the value of these bone turnover markers is still unclear, and further research is necessary, results from these recent trials indicate some correlation.

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  • Biochemical markers of bone metabolism in multiple myeloma.
    Cancer Treat. Rev. (IF 8.332) Pub Date : 2006-05-09
    Evangelos Terpos

    Osteolytic bone disease is a major clinical feature of multiple myeloma (MM). Mechanisms of bone destruction are related to increased osteoclastic activity, which is not accompanied by a comparable increase in bone formation, as osteoblasts are functionally exhausted. Thus the lesions rarely heal and bone scans are often negative in myeloma patients with extensive lytic lesions, offering very little in the follow-up of bone disease. Biochemical markers of bone resorption, such as N- and C-terminal cross-linking telopeptide of type I collagen (NTX, CTX/ICTP, respectively), tartrate resistant acid phosphatase isoform-5b, bone formation (bone-specific alkaline phosphatase [BAP]), and osteocalcin provide useful information on bone dynamics. Several studies have shown that NTX, CTX, and ICTP are elevated in myeloma patients, reflect the extent of bone disease, and correlate with survival. Furthermore, they are useful in monitoring bone destruction during antimyeloma or bisphosphonate treatment. Markers of bone formation have produced conflicting results in trials. However, BAP correlates with bone pain, lytic lesions, and fractures in quite a few studies of MM. Novel markers, such as bone sialoprotein, receptor activator of nuclear factor-kappa B ligand (RANKL), osteoprotegerin, osteopontin, dickkopf-1, and soluble Frizzle-related protein-2 have been found of value in assessing bone lytic disease in MM, but their promising results must be confirmed in large trials. In conclusion, although no marker provides optimal analysis of MM or of MM treatments, combinations of markers have at times helped in assessing MM stages and lytic bone disease and in monitoring specific treatment modalities. The need for further research in this field is clear.

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  • Bone markers and current laboratory assays.
    Cancer Treat. Rev. (IF 8.332) Pub Date : 2006-05-09
    Rosemary A Hannon,Richard Eastell

    Metastasis of cancer to bone leads to significant alterations in normal bone remodelling that are reflected in changes in bone turnover markers. These markers are classically defined as markers of bone resorption or formation; markers of bone resorption are measures of osteoclastic activity, whereas markers of bone formation are measures of osteoblastic activity. Recently, there has been growing interest in the use of these markers in metastatic bone disease (MBD), and an increasing number of studies have investigated the potential use of these markers in diagnosis, monitoring of disease progression and treatment, and prediction of outcome. In this review, we briefly discuss the biology of bone metastases as well as describe the bone turnover markers and their possible role in aiding clinicians in the treatment of patients with MBD.

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  • Optimizing patient therapy: the role of bone markers?
    Cancer Treat. Rev. (IF 8.332) Pub Date : 2006-05-09
    Fred Saad

    A reduction in bone turnover activity, assayed by bone markers, appears to correlate with improved outcomes. Thus, use of bone markers to measure abnormal bone turnover may help identify patients at increased risk for bone complications or skeletal-related events (SREs). In addition, bone markers may prove useful in monitoring response to treatment and customising future treatment. Although many questions remain concerning use of bone markers in the treatment of metastatic cancer, these markers are expected to have a valuable role in managing metastatic bone disease (MBD). This review examines SREs and the burden they impose on patients, the relationship between SREs and bone turnover markers, and the potential role of bone markers in guiding treatment and improving patients' quality of life (QOL).

    更新日期:2019-11-01
  • The role of bone markers in metastatic bone disease.
    Cancer Treat. Rev. (IF 8.332) Pub Date : 2006-05-09
    Robert E Coleman

    Patients with advanced cancer often develop bone metastases that lead to significant skeletal morbidity and substantially reduced functionality and autonomy [Coleman RE, Rubens RD. Bone metastases. In: Clinical Oncology, 2nd edn. New York: Churchill Livingstone. 2004, p. 1091-128]. As current methods of diagnosing bone metastases are cumbersome and not cost-effective, there is great interest in exploring the potential of biochemical assays that measure bone turnover activity. These markers may have value in measuring metastatic bone disease (MBD) progression and identifying patients at higher risk for metastases. Bone markers are also being evaluated as a possible guide to optimize treatment of bone complications. In the reports included in this supplement, experts at the frontiers of bone marker research offer insights on their progress.

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  • How to maximize the efficacy of taxanes in breast cancer.
    Cancer Treat. Rev. (IF 8.332) Pub Date : 2005-12-20
    M Tubiana-Hulin

    The life-expectancy of women with metastatic breast cancer (MBC) is closely linked to response to therapy. A significant increase in progression-free survival (PFS) and overall survival (OS) has been demonstrated in women who achieve a complete response. Anthracycline combinations have been proven as highly effective in MBC, and anthracycline regimens plus cyclophosphamide with or without fluorouracil were established as first-line chemotherapy for MBC in the 1990s. Clinical trials have shown that anthracycline-taxane combinations are more effective than anthracyclines or taxanes alone in terms of overall response rates (ORR), PFS and OS in women who have not received prior anthracycline chemotherapy. The use of anthracycline-based regimens is limited, however, by the widespread use of anthracycline adjuvant therapy and the development of anthracycline-resistance. Platinum-taxane combinations have similar efficacy to anthracycline-based regimens and are well-tolerated by patients. Carboplatin combined with paclitaxel or docetaxel is more effective than carboplatin or taxanes alone, with ORR of 53-62%. Taxane combinations with gemcitabine or capecitabine are also more effective than docetaxel, paclitaxel, capecitabine or gemcitabine administered alone. The efficacy of docetaxel and paclitaxel can be increased, and drug-related toxicity decreased, by adapting dose-dense schedules of drug administration. The addition of trastuzumab to taxane-based chemotherapy increases the efficacy of taxane-based regimens in women with HER2-positive MBC.

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  • Gemcitabine in patients with ovarian cancer.
    Cancer Treat. Rev. (IF 8.332) Pub Date : 2005-12-20
    Andres Poveda

    Standard first-line treatment of ovarian cancer (OC) consists of platinum-taxane combined chemotherapy. However, this regimen only cures about 25% of women with OC. Phase II studies have shown that platinum-gemcitabine doublet and platinum-taxane-gemcitabine triplet regimens are active first-line chemotherapy in advanced OC, with overall response rates (ORR) above 55%. Several phase III studies of gemcitabine-based doublet and triplet chemotherapy in OC are currently underway. Preliminary data show that these regimens are well-tolerated, with manageable haematological toxicity, and the efficacy results are eagerly awaited. Gemcitabine is also active as second-line monotherapy in women with recurrent OC, and studies combining gemcitabine with paclitaxel, docetaxel, liposomal doxorubicin or topotecan resulted in higher ORR than gemcitabine alone. Gemcitabine-cisplatin and gemcitabine-carboplatin are active in women with platinum-resistant recurrent OC suggesting in vivo synergy between these two classes of drug. These studies show that gemcitabine-based chemotherapy may have an important role as second-line treatment in women with platinum-resistant OC. Gemcitabine combinations are also highly recommended as they avoid the problems of neurotoxicity and alopecia seen with other regimens. In order to respect the quality of life of women with recurrent OC, assessment of prognostic factors is recommended so that the most appropriate chemotherapy can be administered.

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  • What is the best schedule for administration of gemcitabine-taxane?
    Cancer Treat. Rev. (IF 8.332) Pub Date : 2005-12-20
    R Colomer

    Until recently, standard adjuvant chemotherapy for metastatic breast cancer (MBC) consisted of anthracycline-based regimens, followed by a taxane. However, data suggest that taxane-based combinations can be more effective than taxanes alone for the second part of treatment. Synergy between paclitaxel and gemcitabine was demonstrated in vitro when paclitaxel was followed by gemcitabine. Dose-dense regimens administered every 2 weeks are more effective than standard 3 weekly regimens. In a phase II study, gemcitabine plus paclitaxel every 2 weeks as first-line chemotherapy of MBC was associated with an overall response rate (ORR) of 71%. Women with HER2 ECD-positive tumours have a poor ORR (40%) to first-line chemotherapy. The addition of trastuzumab to dose-dense paclitaxel-gemcitabine as first-line chemotherapy in women with HER2-positive MBC was associated with a dramatic increase in ORR to 78%, with no serious toxicity observed. Two phase III clinical trials of gemcitabine-paclitaxel as adjuvant chemotherapy in women with histologically-confirmed MBC are currently underway. Preliminary data show that this drug combination is well-tolerated, and the efficacy results are eagerly awaited.

    更新日期:2019-11-01
  • Gemcitabine plus docetaxel: a new treatment option for anthracycline pretreated metastatic breast cancer patients?
    Cancer Treat. Rev. (IF 8.332) Pub Date : 2005-12-20
    C Levy,P Fumoleau

    Antimetabolite-taxane combinations have been shown to be effective chemotherapy in patients with metastatic breast cancer (MBC). A multicentre phase III trial comparing gemcitabine-docetaxel with capecitabine-docetaxel in women with anthracycline pretreated MBC was carried out in several European countries. Its results were presented recently [1]. One-hundred and fifty-three patients were randomly assigned to receive docetaxel (75 mg/m2, day 1) plus gemcitabine (1000 mg/m2, days 1, 8) and 152 received docteaxel plus capecitabine (1250 mg/m2, bid days 1-14) every 3 weeks until disease progression. No difference in efficacy of the two treatment regimens was observed in terms of progression-free survival (35 weeks in both treatment arms), overall response rate (32% vs. 32%), time to treatment failure (19 vs. 18 weeks, respectively), or response duration (36 vs. 42 weeks). Drug-related toxicity, particularly hand-foot syndrome, mucositis and diarrhoea, was more frequent with capecitabine-docetaxel and there was a higher incidence of drug-related treatment withdrawals with this combination. Gemcitabine-docetaxel appeared to have a more favourable risk-benefit profile than capecitabine-docetaxel, and is an important new treatment option for women with anthracycline-pretreated MBC.

    更新日期:2019-11-01
  • Gemcitabine-taxane experience in the treatment of metastatic breast cancer.
    Cancer Treat. Rev. (IF 8.332) Pub Date : 2005-12-20
    A Barnadas

    Management of metastatic breast cancer (MBC) is difficult and overall response rates (ORR) resulting from anthracycline and taxane-based regimens remain modest. The antimetabolite drug gemcitabine has been shown to have high activity when used as first-line treatment of MBC, particularly when incorporated into combined therapy regimens. Gemcitabine-containing regimens have also been used successfully as salvage therapy in women with anthracycline or taxane-pretreated MBC. Phase II clinical studies have demonstrated high ORR with gemcitabine-docetaxel (ORR: 36-65.5%) and gemcitabine-paclitaxel (ORR: 40-68%) combination regimens. A highly favourable risk-benefit ratio has also been reported for gemcitabine-containing triplets such as gemcitabine-paclitaxel-epirubicin (ORR: 92%) and gemcitabine-paclitaxel-doxorubicin (ORR: 80.4%). Gemcitabine-containing regimens have a favourable toxicity profile with few serious toxic events reported. An important step forward in the evaluation of novel chemotherapeutic regimes for MBC is establishing a correlation between disease markers and response to therapy. Preliminary data suggest that there is a close relationship between HER2 extracellular domain levels (>30 ng/ml) and treatment outcome. HER2-positive patients had a lower ORR to gemcitabine-paclitaxel chemotherapy than women who were HER2-negative. Further studies to establish a link between other breast cancer markers and predicted response to treatment are warranted.

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  • Cellular pH regulators: potentially promising molecular targets for cancer chemotherapy.
    Cancer Treat. Rev. (IF 8.332) Pub Date : 2003-10-31
    Hiroto Izumi,Takayuki Torigoe,Hiroshi Ishiguchi,Hidetaka Uramoto,Yoichiro Yoshida,Mizuho Tanabe,Tomoko Ise,Tadashi Murakami,Takeshi Yoshida,Minoru Nomoto,Kimitoshi Kohno

    One of the major obstacles to the successful treatment of cancer is the complex biology of solid tumour development. Although regulation of intracellular pH has been shown to be critically important for many cellular functions, pH regulation has not been fully investigated in the field of cancer. It has, however, been shown that cellular pH is crucial for biological functions such as cell proliferation, invasion and metastasis, drug resistance and apoptosis. Hypoxic conditions are often observed during the development of solid tumours and lead to intracellular and extracellular acidosis. Cellular acidosis has been shown to be a trigger in the early phase of apoptosis and leads to activation of endonucleases inducing DNA fragmentation. To avoid intracellular acidification under such conditions, pH regulators are thought to be up-regulated in tumour cells. Four major types of pH regulator have been identified: the proton pump, the sodium-proton exchanger family (NHE), the bicarbonate transporter family (BCT) and the monocarboxylate transporter family (MCT). Here, we describe the structure and function of pH regulators expressed in tumour tissue. Understanding pH regulation in tumour cells may provide new ways of inducing tumour-specific apoptosis, thus aiding cancer chemotherapy.

    更新日期:2019-11-01
  • The management of brain metastases.
    Cancer Treat. Rev. (IF 8.332) Pub Date : 2003-10-31
    Roy A Patchell

    Brain metastases are neoplasms that originate in tissues outside the brain and then spread secondarily to the brain. Metastases to the brain are the most common intracranial tumours in adults. Substantial progress has been made in the treatment of these tumours, and radiotherapy, surgery, and stereotactic radiosurgery are now established treatments. With aggressive treatment, most patients experience meaningful symptom reduction and extension of life.

    更新日期:2019-11-01
  • Oesophageal cancer: new developments in systemic therapy.
    Cancer Treat. Rev. (IF 8.332) Pub Date : 2003-10-31
    David H Ilson

    Oesophageal cancer is a rare but highly virulent malignancy in the United States and Western countries, and adenocarcinoma of the oesophagus has had the most rapid rate of increase of any solid tumour malignancy. Systemic metastatic disease is present in 50% of patients at diagnosis, and in the remaining 50% of patients presenting initially with loco-regional disease, systemic metastatic disease will develop in the vast majority of these patients. Combined chemotherapy and radiotherapy is the standard of care in the nonsurgical management of oesophageal cancer. Preoperative chemoradiotherapy followed by surgery continues to be actively studied in the surgical management of locally advanced oesophageal cancer. Pathologic complete responses are seen in 20-40% of patients, with five-year survival achieved in 25-35% of patients. The limited efficacy and substantial toxicity of conventional 5-FU-cisplatin-based chemotherapy combined with radiation, or used to treat advanced disease, has prompted the evaluation of newer agents, including the taxanes and irinotecan. These trials have indicated promising antitumour activity and therapy tolerance in both advanced disease and in combined modality therapy trials, depending on the dose and schedule of therapy administered. The advent of newer, targeted therapies, including agents directed against growth factor receptor pathways, tumour angiogenesis, and tumour invasion and metastasis, is leading to a new generation of clinical trials combining these agents with conventional cytotoxic chemotherapy and radiation.

    更新日期:2019-11-01
  • Classification of anticancer drugs--a new system based on therapeutic targets.
    Cancer Treat. Rev. (IF 8.332) Pub Date : 2003-10-31
    Enrique Espinosa,Pilar Zamora,Jaime Feliu,Manuel González Barón

    The arrival of a great number of new antineoplastic agents has made it necessary to reclassify all of them. Anticancer drugs may act at different levels: cancer cells, endothelium, extracellular matrix, the immune system or host cells. The tumour cell can be targeted at the DNA, RNA or protein level. Most classical chemotherapeutic agents interact with tumour DNA, whereas monoclonal antibodies and small molecules are directed against proteins. The endothelium and extracellular matrix may be affected also by specific antibodies and small molecules.

    更新日期:2019-11-01
  • Prevention of chemotherapy and radiation toxicity with glutamine.
    Cancer Treat. Rev. (IF 8.332) Pub Date : 2003-10-31
    Diane M F Savarese,Gayle Savy,Linda Vahdat,Paul E Wischmeyer,Barbara Corey

    GOALS OF THE WORK Malignancy produces a state of physiologic stress that is characterized by a relative deficiency of glutamine, a condition that is further exacerbated by the effects of cancer treatment. Glutamine deficiency may impact on normal tissue tolerance to antitumor treatment, and may lead to dose reductions and compromised treatment outcome. Providing supplemental glutamine during cancer treatment has the potential to abrogate treatment-related toxicity. We reviewed the available data on the use of glutamine to decrease the incidence and severity of adverse effects due to chemotherapy and/or radiation in cancer patients. METHODS We performed a search of the MEDLINE database during the time period 1980-2003, and reviewed the English language literature of both human and animal studies pertaining to the use of glutamine in subjects with cancer. We also manually searched the bibliographies of published articles for relevant references. MAIN RESULTS The available evidence suggests that glutamine supplementation may decrease the incidence and/or severity of chemotherapy-associated mucositis, irinotecan-associated diarrhea, paclitaxel-induced neuropathy, hepatic veno-occlusive disease in the setting of high dose chemotherapy and stem cell transplantation, and the cardiotoxicity that accompanies anthracycline use. Oral glutamine supplementation may enhance the therapeutic index by protecting normal tissues from, and sensitizing tumor cells to chemotherapy and radiation-related injury. CONCLUSIONS The role of glutamine in the prevention of chemotherapy and radiation-induced toxicity is evolving. Glutamine supplementation is inexpensive and it may reduce the incidence of gastrointestinal, neurologic, and possibly cardiac complications of cancer therapy. Further studies, particularly placebo-controlled phase III trials, are needed to define its role in chemotherapy-induced toxicity.

    更新日期:2019-11-01
  • Methionine dependency and cancer treatment.
    Cancer Treat. Rev. (IF 8.332) Pub Date : 2003-10-31
    E Cellarier,X Durando,M P Vasson,M C Farges,A Demiden,J C Maurizis,J C Madelmont,P Chollet

    Conventional chemotherapies have showed their limits, notably for patients with advanced cancer. New therapeutic strategies must be identified, and the metabolic abnormalities of cancer cells offer such opportunities. Many human cancer cell lines and primary tumors have absolute requirements for methionine, an essential amino acid. In contrast, normal cells are relatively resistant to exogenous methionine restriction. The biochemical mechanism for methionine dependency has been studied extensively, but the fundamental mechanism remains unclear. A number of investigators have attempted to exploit the methionine dependence of tumors for therapeutic effects in vivo. To reduce in vivo methionine in plasma and tumours, dietary and pharmacological treatments have been used. Methionine-free diet or methionine-deprived total parenteral nutrition causes regression of a variety of animal tumours. Alternatively, methionine depletion was achieved by the use of methioninase. This enzyme specifically degrades methionine and inhibits tumour growth in preclinical models. Because of potential toxicity and quality of life problems, prolonged methionine restriction with diet or with methioninase is not suitable for clinical use. Methionine restriction may find greater application in association with various chemotherapeutic agents. Several preclinical studies have demonstrated synergy between methionine restriction and various cytotoxic chemotherapy drugs. The experimental results accumulated during the last three decades suggest that methionine restriction can become an additional cancer therapeutic strategy, notably in association with chemotherapy.

    更新日期:2019-11-01
  • Acute and long-term toxicity following radiotherapy alone or in combination with chemotherapy for locally advanced cervical cancer.
    Cancer Treat. Rev. (IF 8.332) Pub Date : 2003-10-31
    J H Maduro,E Pras,P H B Willemse,E G E de Vries

    Randomised studies in locally advanced cervical cancer patients showed that cisplatin should be given concurrently with radiotherapy, because of a better long-term survival compared to radiotherapy alone. This increases the relevance of treatment related toxicity. This review summarises the acute and long-term toxicity of radiotherapy given with or without chemotherapy for cervical cancer. Acute toxicity (all grades) of radiotherapy is reported in 61% of the patients in the rectosigmoid, in 27% as urological, in 27% as skin and in 20% as gynaecological toxicity. Moderate and severe morbidity consists of 5% to 7% gastrointestinal and 1% to 4% genitourinary toxicity. Adding chemotherapy to radiotherapy increases acute haematological toxicity to 5% to 37% of the patients and nausea and vomiting in 12% to 14%. Late effects of radiotherapy include gastrointestinal, urological, female reproductive tract, skeletal and vascular toxicity, secondary malignancies and quality of life issues. For at least 20 years after treatment, new side effects may develop. Gastrointestinal toxicity usually occurs in the first 2 years after treatment in about 10% of the patients. The incidence of moderate and severe urological toxicity can increase up to 10% and rises over time. Gynaecological toxicity usually occurs shortly after treatment while skeletal and vascular toxicity can occur years to decades later. Thus far, no increase in late toxicity has been observed after the addition of cisplatin to radiotherapy. Finally, methods to prevent or decrease late toxicity and therapeutical options are discussed. However, most randomised studies still have a limited follow-up period.

    更新日期:2019-11-01
  • Hereditary nonpolyposis colorectal cancer: preventive management.
    Cancer Treat. Rev. (IF 8.332) Pub Date : 2003-10-31
    Hwei-Ju Annie Yu,Kevin M Lin,David M Ota,Henry T Lynch

    Hereditary nonpolyposis colorectal cancer (HNPCC) is the most common form of hereditary colorectal cancer. Inherited mutations in the mismatch repair genes associated with this syndrome have an approximate 80% lifetime risk of colorectal cancer. Since there are no premonitory signs of susceptibility to HNPCC, family history is the initial method for identifying those at increased risk. At risk individuals should undergo genetic counseling and testing. Although an algorithmic indication for genetic testing in at risk HNPCC patients is yet to be determined, many advocate initial screening for microsatellite instability (MSI) of the cancer specimen in individuals suspected of carrying HNPCC mutations. Those who test positive for MSI can then undergo further testing for mutations in the associated germline mismatch repair genes. Techniques for detecting these mutations currently include in vitro synthesized-protein assay, single-strand conformational polymorphism, and DNA sequencing. Given the aggressive nature of HNPCC adenomas, individuals who test positive for HNPCC mutations are recommended to undergo yearly colonoscopic surveillance starting at the age of 25. A reasonable alternative to lifetime colonoscopic surveillance for the prevention of colorectal cancer in these individuals is prophylactic colectomy. The prevention of colorectal cancer through pharmacological means is under investigation as another option in the management of HNPCC patients. Specifically, chemoprevention trials are currently ongoing to evaluate the efficacy of COX-2 inhibitors in the prevention of colorectal cancer in HNPCC and familial adenomatous polyposis patients.

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  • Role of quinupristin/dalfopristin in the treatment of Gram-positive nosocomial infections in haematological or oncological patients.
    Cancer Treat. Rev. (IF 8.332) Pub Date : 2003-09-16
    J Klastersky

    Gram-positive pathogens, primarily Staphylococcus aureus, coagulase-negative staphylococci, viridans group streptococci, and enterococci, are now the predominant causes of infection in neutropenic haematology/oncology patients, but are often resistant to multiple antibiotics. Glycopeptides have been the only alternative antibiotic treatments for multidrug-resistant Gram-positive infections to date. However, glycopeptides are not always effective or well tolerated, and can produce nephrotoxic or ototoxic effects. Quinupristin/dalfopristin is a recently introduced streptogramin antibiotic that is active in vitro against most of the major Gram-positive pathogens causing infection in neutropenic patients. Recent studies of the in vitro susceptibility of clinical isolates of Gram-positive pathogens to quinupristin/dalfopristin are summarized. Pre-clinical and clinical studies of the efficacy and safety of quinupristin/dalfopristin in the treatment of Gram-positive infections are reviewed. Quinupristin/dalfopristin is active in vitro against the vast majority of recent isolates of relevant Gram-positive pathogens, including methicillin-resistant staphylococci, viridans group streptococci, and vancomycin-resistant Enterococcus faecium, but excluding Enterococcus faecalis. Pre-clinical and clinical data indicate the efficacy of quinupristin/dalfopristin in infections caused by these organisms, including bacteraemia and catheter-related infections. Quinupristin/dalfopristin is not associated with nephrotoxicity or ototoxicity. Quinupristin/dalfopristin is a potential alternative to glycopeptides in haematology or oncology patients with multidrug-resistant Gram-positive infections, especially those who are unresponsive to, or intolerant of, glycopeptides.

    更新日期:2019-11-01
  • Radiotherapy-induced ear toxicity.
    Cancer Treat. Rev. (IF 8.332) Pub Date : 2003-09-16
    Barbara A Jereczek-Fossa,Andrzej Zarowski,Franco Milani,Roberto Orecchia

    Despite their particular functional consequences, radiotherapy-induced ear injuries remain under-evaluated and under-reported. These reactions may have acute or late character, may affect all structures of the hearing organ, and result in conductive, sensorineural or mixed hearing loss. Up to 40% of patients have acute middle ear side effects during radical irradiation including acoustic structures and about one-third of patients develop late sensorineural hearing loss (SNHL). Total radiotherapy dose and tumour site seem to be among the most important factors associated with the risk of hearing impairment. Thus, reduction in radiation dose to the auditory structures should be attempted whenever possible. New radiotherapy techniques (3-dimensional conformal irradiation, intensity modulated radiotherapy, proton therapy) allow better dose distribution with lower dose to the non-target organs. Treatment of acute and late external otitis is mainly conservative and includes the anti-inflammatory agents (applied topically and systematically). Post-radiation chronic otitis media and the eustachian tube pathology may be managed with tympanic membrane incision with insertion of a tympanostomy tube (grommet), although the benefit of such approach is controversial and some authors advocate a more conservative approach. In these patients the functional deficit can be alleviated by application of bone conduction hearing aids such as, e.g., the bone anchored hearing aid (BAHA). There is no standard therapy for post-irradiation sudden or progressive SNHL yet corticosteroid therapy, rheologic medications, hyperbaric oxygen or carbogen therapy are usually employed (as for idiopathic SNHL), although controversial data on the efficacy of these treatment modalities have been published. In selected cases with bilateral profound hearing loss or total deafness, cochlear implants may prove effective. Further improvements in radiotherapy techniques and progress in otologic diagnostics and therapy may allow better prevention and management of radiation-related acoustic injury.

    更新日期:2019-11-01
  • Mode of action of docetaxel - a basis for combination with novel anticancer agents.
    Cancer Treat. Rev. (IF 8.332) Pub Date : 2003-09-16
    Roy S Herbst,Fadlo R Khuri

    Different tumors have different aberrations in signaling and growth stimulation pathways that drive cancer growth. An understanding of these processes is key to the development of new anticancer agents and to identifying optimal treatment strategies and patient populations suitable for specific therapies. It is becoming clear that certain chemotherapeutic drugs such as docetaxel are not simply inhibitors of mitosis and may interact with these tumorigenic mechanisms at a number of levels. This review describes docetaxel's mechanism of action, and provides a basis for understanding how its antitumor activity can integrate with that of different novel agents. Against this background, key docetaxel-novel agent combinations that are currently under clinical investigation are reviewed. How these strategies can be targeted towards specific patient populations (e.g., HER-2 overexpressing metastatic breast cancer patients) to provide optimal therapy is highlighted.

    更新日期:2019-11-01
  • Treatment of stage IB2 (bulky) cervical carcinoma.
    Cancer Treat. Rev. (IF 8.332) Pub Date : 2003-09-16
    David H Moore

    Tumour size is an important prognostic factor in patients with stage IB cervical cancer. The patient with stage IB2 (bulky) cervical cancer represents a therapeutic challenge. Neither radical hysterectomy nor primary radiation therapy are sufficiently effective and are associated with significant treatment-related complications including ovarian failure and psychosexual deficits. A number of phase III studies have explored alternative management approaches in this patient population. It appears that extrafascial hysterectomy following radiation therapy does not improve overall survival relative to radiation therapy alone. Consistent with results seen in locally advanced cervical carcinoma, chemoradiation therapy is superior to radiation therapy alone as primary treatment for stage IB2 cervical cancer and as adjuvant therapy for surgically treated patients with high-risk factors for recurrence. Neoadjuvant chemotherapy has resulted in high clinical response rates and operability rates. There are two phase III trials suggesting an improvement in survival with neoadjuvant chemotherapy followed by radical hysterectomy versus either surgery (and selected postoperative radiation) or radiation therapy alone. These emerging treatments should be scrutinized in prospective controlled trials.

    更新日期:2019-11-01
  • Modern management of locally advanced cervical carcinoma.
    Cancer Treat. Rev. (IF 8.332) Pub Date : 2003-09-16
    Alfonso Dueñas-Gonzalez,Lucely Cetina,Ignacio Mariscal,Jaime de la Garza

    Radiation was until recently the key and only modality for the routine treatment of locally advanced cervical carcinoma. However after years of studying multi-modality treatments as an alternative to radiation alone in randomized phase III trials, the standard treatment has changed to chemo-radiation based on cisplatin. Three recent meta-analyses have confirmed that cisplatin-based chemo-radiation adds an absolute 12% benefit in five-year survival over radiation therapy alone. Neoadjuvant chemotherapy followed by radiation has not been of proven benefit, but when neoadjuvant chemotherapy is followed by surgery, an absolute increase of 15% in five-year survival over radiation alone is seen. This benefit in survival is comparable to that obtained with the current chemo-radiation schedules based on cisplatin. Despite these encouraging results there remains room for improvement as the five-year survival of patients treated with chemo-radiation ranges from nearly 80% in bulky IB tumours to only 25% in stage IVA disease. Other therapeutic approaches need to be fully evaluated including the use of chemo-radiation after neoadjuvant chemotherapy; the use of new drug combinations and the multi-modality combination of neoadjuvant chemotherapy followed by radical surgery plus adjuvant chemo-radiation. Likewise, the addition of radiosensitizers to cisplatin, preoperative chemo-radiation and/or adjuvant chemotherapy may eventually improve the currents results of cisplatin-based chemo-radiation. Nevertheless, it is hard to foresee a dramatic increase in cure rate, even with the most optimal combination of cytotoxic drugs, surgery and radiation, and thus the testing of molecular targeted therapies against cervical cancer is a logical step to follow.

    更新日期:2019-11-01
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