Chemotherapy-induced neutropenia and treatment efficacy in advanced non-small-cell lung cancer: a pooled analysis of three randomised trials

Maïo, Massimo Di; Gridelli, Cesare; Gallo, Ciro; Shepherd, Frances A.; Piantedosi, Franco Vito; Cigolari, S.; Manzione, Luigi; Illiano, A; Barbera, Santi; Robbiati, Sergio; Frontini, L.; Piazza, E.; Ianniello, Giovanni Pietro; Veltri, Enzo; Castiglione, F.; Rosetti, Francesco; Gebbia, Vittorio; Seymour, Lesley; Chiodini, Paolo; Perrone, Francesco

doi:10.1016/s1470-2045(05)70255-2

Cited by 202 publications

(193 citation statements)

References 25 publications

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“…Since the late 1990s, several studies have linked myelosuppression induced by adjuvant chemotherapy to a better outcome in patients with breast cancer (Saarto et al, 1997;Poikonen et al, 1999;Mayers et al, 2001;Cameron et al, 2003). Recently, Di Maio et al (2005) reported the first evidence regarding the relationship between chemotherapy-induced neutropenia and longer survival time in patients with an advanced stage of cancer. They analysed the pooled data from three randomised trials of 1265 patients with advanced NSCLC treated with one of five different regimens, and concluded that both mild (grade 1 -2) and severe (grade 3 -4) neutropenia similarly predicted longer patient survival than did the absence of such toxicity.…”

Section: Discussionmentioning

confidence: 99%

“…This can produce a false-positive association between chemotherapy-induced neutropenia and increased survival. To avoid this problem, a landmark analysis is sometimes employed, in which the study is limited to patients who survive for at least certain specific time period after the initiation of treatment, with neutropenia during that period considered as a baseline feature (Di Maio et al, 2005). However, such a landmark analysis would discard information regarding deaths occurring 'before the landmark', which could bias patient selection (Green et al, 2002).…”

Section: Methodsmentioning

confidence: 99%

“…Since the late 1990s, however, several studies have reported that neutropenia or leucopenia occurring during chemotherapy is a sign of patient's response to adjuvant chemotherapy in women with breast cancer; a significantly longer survival results in patients who have those haematological toxic effects (Saarto et al, 1997;Poikonen et al, 1999;Mayers et al, 2001;Cameron et al, 2003). A recent study by Di Maio et al (2005) confirmed the positive correlation between chemotherapy-induced neutropenia and increased survival in a pooled analysis of three randomised trials that included a total of 1265 patients with advanced non-small-cell lung cancer (NSCLC). Consideration of these findings led us to review data from a prospective survey of Japanese patients with advanced gastric cancer, and to investigate the association between neutropenia occurring during chemotherapy and patient survival.…”

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Predictive value of chemotherapy-induced neutropenia for the efficacy of oral fluoropyrimidine S-1 in advanced gastric carcinoma

et al. 2007

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Myelosuppression that occurs during chemotherapy has been reported to be a predictor of better survival in patients with breast or lung carcinomas. We evaluated the prognostic implications of chemotherapy-induced neutropenia in advanced gastric carcinoma. Data from a prospective survey of oral fluoropyrimidine S-1 for advanced gastric cancer patients in Japan were reviewed. We identified 1055 untreated patients with adequate baseline bone marrow function. During treatment with S-1, a total of 293 (28%) patients experienced grade 1 or higher neutropenia. The adjusted hazard ratio of death for the presence of neutropenia, as compared with the absence of such toxicity, from a multivariate Cox model was 0.72 (95% confidence interval, 0.54 -0.95; P ¼ 0.0189) for grade 1 neutropenia, 0.63 (0.50 -0.78; Po0.0001) for grade 2 neutropenia and 0.71 (0.51 -0.98; P ¼ 0.0388) for grade 3 -4 neutropenia. These findings suggest that the occurrence of neutropenia during chemotherapy is an independent predictor of increased survival in patients with advanced gastric cancer, whereas the absence of such toxicity indicates that the dosages of drugs are not pharmacologically adequate. Monitoring of neutropenia in patients who receive chemotherapy may contribute to improved drug efficacy and favourable survival.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Predictive value of chemotherapy-induced neutropenia for the efficacy of oral fluoropyrimidine S-1 in advanced gastric carcinoma

et al. 2007

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“…Interestingly, chemotherapy-induced neutropenia is associated with improved survival in patients with non-small cell lung, breast, gastric or colorectal cancer [182][183][184][185] . This beneficial association may be explained by two reasons, one of which is neutrophil-independent and the other neutrophil-dependent.…”

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confidence: 99%

Neutrophils in cancer: neutral no more

2016

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SummaryNeutrophils are indispensable antagonists of microbial infection and facilitators of wound healing. In the cancer setting, a newfound appreciation for neutrophils has come into view.The traditionally held belief that neutrophils are inert bystanders is being challenged by recent literature. Emerging evidence indicates that tumors manipulate neutrophils, sometimes early in their differentiation process, to create diverse phenotypic and functional polarization states able to alter tumor behavior. In this Review, we discuss the involvement of neutrophils in cancer initiation and progression, and their potential as clinical biomarkers and therapeutic targets. 2The name neutrophil -given to polymorphonuclear, granulocytic cells by Paul Ehrlich in the late 19th century -is based on the inability of these cells to retain acidic or basic dyes and for their preferential uptake of pH neutral dyes 1 . Although their neutral staining led to the identification of these cells, neutrophils in the cancer setting are anything but neutral.Neutrophils in tumor-bearing hosts can oppose or potentiate cancer progression. These two types of behavior are controlled by signals emanating from cancer cells or stromal cells within the tumor microenvironment, which educate neutrophils to execute the demise of the tumor or facilitate support networks that lead to its expansive spread. These functions can occur locally in or around the tumor microenvironment, as well as systemically in distant organs.Until the past few years, other immune cells such as macrophages have overshadowed the role of neutrophils in cancer. But recent studies and the development of new genetic tools have provided the cancer community with new insights into the profound influence of these dynamic cells by uncovering distinct capabilities for neutrophils throughout each step of carcinogenesis: from tumor initiation to primary tumor growth to metastasis.During these processes, neutrophils take on different phenotypes and sometimes opposing functions. Emerging evidence also indicates that these cells are highly influential, and are able to change the behavior of other tumor-associated cell types -primarily other immune cells. In this Review, we focus on how tumors manipulate the generation and release of neutrophils from the bone marrow. We discuss the mechanisms identified in animal models by which neutrophils participate in tumor initiation, growth and metastasis. Finally, we highlight the potential of these cells as clinical biomarkers and therapeutic targets. In humans, neutrophils are the most abundant immune cell population, representing 50-70% of all leukocytes. Over 10 11 neutrophils may be produced per day 2 , and tumors can increase this number by even more. Indeed, patients with various cancer types, including but not limited to breast, lung and colorectal cancer, often exhibit increased numbers of circulating neutrophils 3,4 . Recent studies have identified key pathways that tumors exploit to disrupt normal neutrophil homeostasis and these are discuss...

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“…In these prostate tumors, infiltrating neutrophils secrete IL1RA to counteract cancer cell senescence and activate proliferation. Clinical support for a role of neutrophils in chemotherapy response comes from observations in a variety of cancer patients, such as breast and non-small cell lung cancer patients, where chemotherapyinduced neutropenia is associated with better patient prognosis [46,47]. We and others have established a metastasis-promoting role for neutrophils in breast and melanoma models [48][49][50].…”

Section: Innate Immune Cellsmentioning

confidence: 94%

Immune-mediated mechanisms influencing the efficacy of anticancer therapies

Coffelt

Visser

2015

Trends in Immunology

125

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SummaryConventional anti-cancer therapies, such as chemotherapy, radiotherapy and targeted therapy, are designed to kill cancer cells. Yet, the efficacy of anti-cancer therapies is not only determined by their direct effects on cancer cells, but also by off-target effects within the host immune system. Cytotoxic treatment regimens elicit a number of changes in immune-related parameters including the composition, phenotype and function of immune cells. In this review, we discuss the impact of innate and adaptive immune cells on the success of anti-cancer therapy, we examine the opportunities to exploit host immune responses to boost tumor clearing and we highlight the challenges facing the treatment of advanced metastatic disease. Then and now: The link between the immune system and anti-cancer therapiesThe relationship between anti-cancer therapies and the immune system is as old as the invention of anti-cancer therapies themselves. After the use of mustard gas in the trenches of World War I, a seminal observation was made that some exposed soldiers displayed severe loss of bone marrow and lymph node cells [1]. This observation then spurred the idea that the anti-proliferative capacity of mustard gas may also slow the growth of cancer cells.Experiments carried out in mice transplanted with lymphoid tumors were convincing enough to treat a lymphoma patient [2], and these events initiated the standardized treatment of cancer patients with chemotherapy [3,4].Fast forward 100 years later. The influence of immune cells on tumor progression and metastasis is well established [5], and an appreciation for the immune system's impact during conventional anti-cancer therapy treatment is growing. Recent seminal advances indicate that immune cells can shape the outcome of various anti-cancer therapies. As such, 2 immune cells and their molecular mediators have evolved into bona vide targets of therapeutic manipulation in cancer patients. The recent breakthrough of immunotherapeutics that inhibit negative immune regulatory pathways, such as anti-CTLA4 and anti-PD1, has initiated a new era in the treatment of cancer [6]. In parallel, immunomodulatory strategies aimed at dampening pro-tumor functions of immune cells are currently being tested in cancer patients [7]. Immune cells also function as reliable biomarkers, since their abundance or activation status often predicts how well patients respond to a particular treatment regimen.Here, we review these novel experimental and clinical insights, highlighting potential implications for the development of synergistic therapies designed to combat primary tumors and, more importantly, metastatic disease. The pros and cons of experimental mouse modelsResearch questions aimed at understanding the role of immune cells during anti-cancer therapy require models that mirror the complex interactions between the immune system and diverse forms of human cancers. Transplantable cancer cell line models and carcinogeninduced cancer models are the most frequently used for these purposes. However...

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Chemotherapy-induced neutropenia and treatment efficacy in advanced non-small-cell lung cancer: a pooled analysis of three randomised trials

Cited by 202 publications

References 25 publications

Predictive value of chemotherapy-induced neutropenia for the efficacy of oral fluoropyrimidine S-1 in advanced gastric carcinoma

Predictive value of chemotherapy-induced neutropenia for the efficacy of oral fluoropyrimidine S-1 in advanced gastric carcinoma

Neutrophils in cancer: neutral no more

Immune-mediated mechanisms influencing the efficacy of anticancer therapies

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