Cancer-related anemia and recombinant human erythropoietin--an updated overview

For cancer patients, anemia can be a debilitating problem that negatively influences their overall quality of life and worsens their prognosis. The condition is caused either by the cancer itself or by cytotoxic treatment. Anemia is the primary indication for transfusion of red blood cells, but the development of recombinant human erythropoietins (epoetins) provides an alternative to red blood cell transfusions. Treatment with epoetins has been shown to reduce transfusion rates and increase hemoglobin response. There is some evidence that epoetins improve quality of life. It remains unclear, however, whether erythropoietin affects tumor growth and survival, and this area requires further investigation. Data from clinical trials suggest that erythropoietin increases the risk of thromboembolic complications. In the management of anemic patients, physicians should follow closely the dosing recommendations in products' package inserts or the ASCO/American Society of Hematology guidelines. Treatment of patients beyond the correction of anemia, however, has to be regarded as experimental and is potentially harmful, so should only be conducted in clinical trials.     

Update on prospective randomized trials of laparoscopic surgery for colorectal cancer.

Cosmetic improvement is perhaps the only conclusive advantage of laparoscopic colectomy for cancer. Previous retrospective studies repeatedly have demonstrated the feasibility and safety of this procedure. Although short-term prospective studies showed adequate cancer resection, comparable complication rates, and no increase in recurrence, issues of port site implantation, immune response and cost-efficiency remain unsolved. The ongoing clinical trials mentioned currently are evaluating the benefits and the potential risks of this technique as a cancer operation. Four trials will have completed accrual and three will be able to offer early analysis of the results by the year 2001. Until then, laparoscopic surgery for colorectal cancer should be considered investigational to be performed only as part of these above-mentioned trials.     

Anemia, hypoxia and transfusion in patients with cervix cancer: a review.

BACKGROUND AND PURPOSE: With the recent development of hemopoietic growth factors and alternatives to transfusion, there has been a renewed interest in the relationships between anemia, tumor hypoxia and treatment outcome in a number of human malignancies. This review is intended to provoke a reconsideration of these issues and their effect on clinical trials, aimed at improving treatment outcome in patients with cervix cancer. MATERIALS AND METHODS: Using data from the literature and from our own prospective series of tumor oxygenation in cervix cancer, we modeled the impact of anemia on tumor blood flow and hypoxia in animal models and human tumors, examined the relationship between anemia and hypoxia and treatment outcome in patients, and reviewed the impact of transfusion on tumor hypoxia and treatment outcome in cervix cancer. RESULTS: Anemia may result in a significant reduction in oxygen delivery to tumors, but compensatory mechanisms reduce the impact on tumor oxygenation. Anemia is associated with inferior treatment outcome in cervix cancer, but hemoglobin levels prior to and during treatment are strongly correlated with tumor size, and this may explain the prognostic impact of anemia in older studies. Transfusion and erythropoietin ameliorate hypoxia in only a proportion of anemic patients. Critical analysis of the published data from the Princess Margaret Hospital randomized trial of transfusion in cervix cancer reveals that, when analyzed by intention-to-treat, transfusion did not result in a benefit to patients. CONCLUSIONS: This review suggests that the relationships among anemia, hypoxia, transfusion and treatment outcome are complex. Further study of anemia as an independent prognostic factor is required and randomized studies of transfusion alternatives, such as erythropoietin, must be of sufficient size to detect small treatment effects.     

Darbepoetin alfa: potential role in managing anemia in cancer patients

Anemia in cancer patients is frequent but often under-recognized and under-treated. This may be related to misconceptions about the impact of anemia on cancer patients and ill-defined guidelines for treatment, as well as the inadequacies of current therapy. Darbepoetin alfa, a novel erythropoiesis-stimulating protein with a longer serum half-life than epoetin (α and β), is approved to treat anemia in patients with chronic kidney disease. Most recently darbepetin alfa has received approval by the FDA in USA for the treatment of anemia associated with myelosuppressive chemotherapy and approval in the EU is expected soon. Clinical trials in cancer patients indicate that darbepoetin alfa effectively and safely alleviates anemia in patients receiving chemotherapy. A Phase II trial also indicates that darbepoetin alfa is effective in patients who are not receiving chemotherapy. Thus, darbepoetin alfa has the potential to improve supportive care and thereby, cancer patients’ quality of life, and might also impact on treatment outcome.     

Darbepoetin alfa: potential role in managing anemia in cancer patients

Anemia in cancer patients is frequent but often under-recognized and under-treated. This may be related to misconceptions about the impact of anemia on cancer patients and ill-defined guidelines for treatment, as well as the inadequacies of current therapy. Darbepoetin alfa, a novel erythropoiesis-stimulating protein with a longer serum half-life than epoetin (alpha and beta), is approved to treat anemia in patients with chronic kidney disease. Most recently darbepoetin alfa has received approval by the FDA in USA for the treatment of anemia associated with myelosuppressive chemotherapy and approval in the EU is expected soon. Clinical trials in cancer patients indicate that darbepoetin alfa effectively and safely alleviates anemia in patients receiving chemotherapy. A Phase II trial also indicates that darbepoetin alfa is effective in patients who are not receiving chemotherapy. Thus, darbepoetin alfa has the potential to improve supportive care and thereby, cancer patients' quality of life, and might also impact on treatment outcome.     

Cancer- and chemotherapy-induced anemia

Anemia is prevalent in 30% to 90% of patients with cancer. Anemia can be corrected through either treating the underlying cause or providing supportive care through transfusion with packed red blood cells or administration of erythropoiesis-stimulating agents (ESAs), with or without iron supplementation. Recent studies showing detrimental health effects of ESAs sparked a series of FDA label revisions and a sea change in the perception of these once commonly used agents. In light of this, the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Cancer- and Chemotherapy-Induced Anemia underwent substantial revisions this year. The purpose of these NCCN Guidelines is twofold: 1) to operationalize the evaluation and treatment of anemia in adult cancer patients, with an emphasis on those who are receiving concomitant chemotherapy, and 2) to enable patients and clinicians to individualize anemia treatment options based on patient condition.     

The role of recombinant erythropoietin in childhood cancer

Anemia in children with cancer is not an uncommon complication and is usually multifactorial in etiology. In numerous trials in adult cancer patients, treatment with recombinant erythropoietin has been shown to increase hemoglobin levels, reduce red blood cell transfusion requirements, and improve quality of life. Much less has been published of its use in the prevention or treatment of cancer-associated anemia (CAA) in children, in whom chemotherapy is usually more intensive and likely to result in greater myelosuppression. This review critically evaluates the published evidence of its use in childhood cancer especially; its safety and efficacy in the prevention and treatment of CAA and some indications for its use in childhood cancer are suggested.     

Cancer-related anemia

Anemia has a high prevalence in patients with cancer. Its frequency and severity depend on tumor type, tumor stage, duration of disease, and treatment status. The etiology of cancer-related anemia is multifactorial and includes myelotoxicity of treatment, bone marrow infiltration, impaired erythropoietin production, blood loss, and the anemia of chronic disease. Anemia affects health-related quality of life (QOL) and may impact on tolerance or even outcome of anticancer therapy. Despite its high prevalence and impact on QOL, anemia is often under-recognized and under-treated. Treatment should correct etiologic factors, whenever possible. Symptomatic treatments are red blood cell transfusions and administration of erythropoietic growth factors. Transfusions result in rapid improvement of anemia-related symptoms but are usually only given to patients with moderate to severe anemia. Administration of epoetins (epoetin alfa, epoetin beta) or darbepoetin alfa increases hemoglobin levels, reduces the need for blood transfusions, and improves QOL in patients with cancer-related anemia. Trials determining the exact association of anemia with both response to chemo(radio)therapy and survival are ongoing. Physicians should be aware of the clinical relevance of and treatment options for anemia in cancer patients.     

Postoperative therapy in head and neck cancer: state of the art, risk subset, prognosis and unsolved questions

Head and neck cancer may be easily controlled at early stages, but resectable locally advanced disease often relapses at T and N sites. Therefore, adequate adjuvant treatment is of crucial importance for improving local control and/or survival. Unfortunately, little data are available on the adjuvant setting. Adjuvant radiotherapy is regarded as a standard approach for patients with locally advanced radically resected head and neck cancer, while postoperative chemotherapy alone cannot be considered outside of clinical trials. However, chemoradiotherapy is widely considered superior to radiotherapy in patients at a high risk of relapse and may be considered the standard treatment in this population. In this respect, in the last few decades, there has been a growing interest due to the emerging data on both tumor biology and clinical trials. Several pathological and molecular factors, affecting behavior and head and neck cancer prognosis, could allow for a better selection of postoperative treatment. More recently, new prognostic and predictive factors were identified, including biomolecular aspects, human papillomavirus infection and lifestyle. The integration of these new factors deserves dedicated clinical studies, but the available knowledge already allows some deductive hypotheses. We performed a review of the literature to analyze the role of therapy in the postoperative setting and to discuss both the possibility of a different approach to each class of risk and the unsolved question for which randomized trials are warranted.     

Current and future use of hematopoietic growth factors in cancer medicine

Myelosuppression, in particular neutropenia and anemia are serious complications of malignancy and its treatment. Neutropenia can make patients vulnerable to potentially life-threatening infection. It often results in dose reductions and delay of planned chemotherapy, which can have a significant detrimental effect on tumour response and survival. Anemia can be associated with a range of debilitating effects, which can severely impair patients' QOL. In addition, there is some evidence recognizing anemia as a poor prognostic indicator, associated with reduced treatment efficacy. Reduction in the duration and severity of neutropenia and anemia is possible by initiation of appropriate growth factors during the first and subsequent cycles of chemotherapy. New and improved growth factor support with agents such as pegfilgrastim and darbepoetin alfa has the potential to improve the management of chemotherapy-induced neutropenia and anemia further. Thrombopoietin is currently in clinical trials to assess its potential role in the treatment of thrombocytopenia in patients with cancer.     

Use of epoetin in patients with cancer: evidence-based clinical practice guidelines of the American Society of Clinical Oncology and the American Society of Hematology.

Anemia resulting from cancer, or its treatment, is an important clinical problem increasingly treated with the recombinant hematopoietic growth factor erythropoietin. To address uncertainties regarding indications and efficacy, the American Society of Clinical Oncology and the American Society of Hematology developed an evidence-based clinical practice guideline for the use of epoetin in patients with cancer. The guideline panel found good evidence to recommend use of epoetin as a treatment option for patients with chemotherapy-associated anemia with a hemoglobin level less than 10 g/dL. Use of epoetin for patients with less severe anemia (hemoglobin < 12 g/dL but never below 10 g/dL) should be determined by clinical circumstances. Good evidence from clinical trials supports the use of subcutaneous epoetin thrice weekly (150 U/kg tiw) for a minimum of 4 weeks. Less strong evidence supports an alternative weekly (40,000 U/wk) dosing regimen, based on common clinical practice. With either administration schedule, dose escalation should be considered for those not responding to the initial dose. In the absence of response, continuing epoetin beyond 6 to 8 weeks does not appear to be beneficial. Epoetin should be titrated once the hemoglobin concentration reaches 12 g/dL. Evidence from one randomized controlled trial supports use of epoetin for patients with anemia associated with low-risk myelodysplasia not receiving chemotherapy; however, there are no published high-quality studies to support its use for anemia in other hematologic malignancies in the absence of chemotherapy. Therefore, for anemic patients with hematologic malignancies, it is recommended that physicians initiate conventional therapy and observe hematologic response before considering use of epoetin.     

Treatment of colorectal cancer in the elderly

Colorectal cancer has a high incidence, and approximately 60% of colorectal cancer patients are older than 70, with this incidence likely increasing in the near future. Elderly patients (> 70-75 years of age) are a very heterogeneous group, ranging from the very fit to the very frail. Traditionally, these patients have often been under-treated and recruited less frequently to clinical trials than younger patients, and thus are under-represented in publications about cancer treatment. Recent studies suggest that fit elderly patients can be treated in the same way as their younger counterparts, but the treatment of frail patients with comorbidities is still a matter of controversy. Many factors should be taken into account, including fitness for treatment, the wishes of the patient and family, and quality of life. This review will focus on the existing evidence for surgical, oncologic, and palliative treatment in patients over 70 years old with colorectal cancer. Careful patient assessment is necessary in order to individualize treatment approach, and this should rely on a multidisciplinary process. More well-designed controlled trials are needed in this patient population.     

Issues surrounding the participation of adolescents with cancer in clinical trials in the UK

Cancer in adolescents is rare with approximately 600 adolescents being diagnosed with cancer in the UK each year. With such small numbers, clinical trials are imperative if improvements in treatment and prognosis are to be achieved. However, the availability of such trials and the issues surrounding clinical trials in adolescents with cancer has rarely been reviewed. There are a number of issues regarding clinical trials that are particularly pertinent to this group. Primarily, despite evidence that adolescents with cancer fare better when treated on clinical trials, it would appear that adolescents do not have equal access to trials because of the fragmentation of adolescent cancer care between adult and paediatric oncology. For those who are treated within clinical trials, issues of informed consent need to be addressed, such as who should give consent and the provision of age-appropriate information. Finally, it has been suggested that adolescents are less compliant with treatment than both their adult and paediatric counterparts. As many adolescents with cancer can now been cured, this should be an area of great concern and more research is needed to ascertain the full extent of the problem and ways of overcoming it. The availability of clinical trials, along with the issues surrounding clinical trials in adolescents, need to be addressed if continued improvements in the outcome of this group of patients are to be seen.     

The size of clinical trials in cancer research--what are the current needs? Medical Research Council Cancer Therapy Committee.

Most randomised clinical trials of cancer treatment include a few hundred patients or less. Recent statistical papers advocate that sometimes thousands of patients should be entered. In this paper I show that for certain types of cancer trials the 'thousands policy' is not required while for others it is desirable but not feasible. In the latter case other strategies should be considered, such as two-stage phase III studies or parallel studies leading to overviews. There is, however, an important subset of trials for which application of the thousands policy is both necessary and feasible. The key to progress lies partly in the achievement of greater recruitment rates in trails of common cancers and partly in greater inter-group collaboration.     

Anemia in lung cancer: clinical impact and management

Anemia has a high prevalence in patients with lung cancer. Its frequency and severity depend on tumor stage, duration of disease, and previous and current treatment. Anemia affects the health-related quality of life and impacts prognosis and outcome of therapy. Despite this clinical relevance, anemia is often underrecognized and undertreated. Treatment options include the administration of hematopoietic growth factors and red blood cell transfusions. Blood transfusions result in rapid but often transient improvement of anemia. Administration of epoetin or darbepoetin alfa increases hemoglobin levels, decreases blood transfusions, and improves quality of life in patients with lung cancer. Trials determining the exact association of anemia with response to chemotherapy/radiation therapy and survival are ongoing. Oncologists must be aware of the clinical relevance of anemia and offer adequate treatment options to their patients.     

September 2007 update on EORTC guidelines and anemia management with erythropoiesis-stimulating agents

Anemia is frequently experienced by cancer patients receiving chemotherapy and can negatively impact the patient's prognosis. Blood transfusions, iron supplementation (in absolute or functionally iron-deficient anemias), and erythropoiesis-stimulating agents (ESAs) are among the treatment options for anemia. Treatment options for anemia management should be selected based on the best benefit-to-risk ratio for each individual patient. In September 2007, the working party of the European Organization for Research and Treatment of Cancer (EORTC) updated their guidelines on the use of ESAs, which are summarized in this paper. ESAs reduce the number of transfusions required and significantly improve quality of life in patients with chemotherapy-induced anemia. A sustained hemoglobin level of about 12 g/dl should be the target for treatment with ESAs. ESAs should be used according to the EORTC guidelines and within label with carefully considered exceptions.     

Standards of care for anemia management in oncology: focus on lung carcinoma

BACKGROUND: Anemia is common in patients with lung carcinoma, particularly among those undergoing platinum-based cytotoxic chemotherapy. Evidence is growing that anemia can have a profound impact on the patient's quality of life, often manifested as the patient's inability to function normally. METHODS: A literature review was conducted to provide a current picture of the incidence and impact of anemia in patients with lung carcinoma and the usage and limitations of current treatment. RESULTS: The incidence of anemia (a hemoglobin [Hb] level < 11g/dL) in lung carcinoma patients is approximately 50-60%, varying according to treatment regimen. However, despite evidence supporting the treatment of anemia, many clinicians only intervene when Hb levels fall below 8 g/dL. This may be because of a lack of awareness of the incidence and impact of anemia on cancer patients, but most likely is because of limitations of current treatment options (blood transfusion and recombinant human erythropoietin [epoetin-alpha]). Darbepoetin-alpha represents a new generation of erythropoiesis-stimulating proteins. Biochemically distinct from epoetin-alpha, darbepoetin-alpha has a greater sialic acid content and biologic half-life than epoetin-alpha, but stimulates erythropoiesis in the same manner. Clinical trials involving patients with cancer-related anemia have shown that darbepoetin-alpha has a threefold longer half-life than epoetin-alpha, which may allow less frequent dosing. The results from an ongoing clinical trial dedicated to testing the clinical benefits of darbepoetin-alpha in treating anemia in lung carcinoma patients will provide a valuable insight into its full potential in this setting. CONCLUSIONS: Anemia is common but is reported to be undertreated in patients with lung carcinoma. The introduction of darbepoetin-alpha into clinical practice may overcome some of the limitations of current treatments and facilitate improvement in the management of cancer-related anemia.     

Never too old? Age should not be a barrier to enrollment in cancer clinical trials

Throughout Europe and the U.S., over 60% of the total incidence of cancer occurs in the elderly (> or =65 years) population, a patient group that requires particular consideration when making treatment decisions due to a number of factors. Despite this, elderly patients are generally under-represented in clinical trials such that study data should be interpreted with caution because results in younger cancer patients may not always extrapolate to the typical elderly cancer patient. Reports suggest that elderly cancer patients represent around 22% of patients enrolled in phase II clinical studies. Barriers to the accrual of elderly patients to clinical trials include lack of appropriate trials, high burden of comorbidity, study-imposed restrictions, and attitudes of physicians. There is a belief that elderly patients may be unable to tolerate various cancer therapies, which may result in this patient population being excluded from prospective trials. However, clinical data demonstrate that age alone is not a sufficient reason to withhold treatment. Lack of clinical trial data and the associated lack of evidence-based guidelines for elderly patients mean physicians have little to guide them, with the result that patients may not receive the optimal therapy. As clinical trials are the primary method of evaluating the efficacy and safety of adjuvant and palliative cancer therapies, trials that specifically target the elderly cancer patient are required to adequately assess the risks and benefits of treatment in this vulnerable population. This review aims to assess the clinical reality and clinical trial age mismatch to evaluate implications for elderly cancer patients and to identify how this situation may be addressed. Possible reasons for the disparity, and the resulting clinical consequences, are also considered.     

Evolving Role of Risk Tailored Therapy in Early Stage HER2-Positive Breast Cancer: A Canadian Perspective

The advent of HER2-targeted therapies has led to an important shift in the management of HER2-positive early breast cancer. However, initial treatment approaches apply uniform treatment regimens to all patients, with significant treatment-related and financial toxicities for both the patient and the health care system. Recent data demonstrates that for many patients, the chemotherapy backbone, duration and nature (mono- versus dual-targeted therapy) of the HER2 blockade can be better targeted to an individual patient’s risk of recurrence. We will provide a review of current data supporting risk tailored therapy in early stage HER2-positive breast cancer along with key completed and ongoing Canadian and international risk tailored trials. Neoadjuvant systemic therapy should now be considered for patients with clinical stage 2 disease, with greater use of non-anthracycline based chemotherapy regimens. Patients with residual disease following neoadjuvant therapy should be considered for escalated treatment with adjuvant T-DM1. Patients with stage I disease can often be managed with upfront surgery and evidence-based de-escalated adjuvant chemotherapy regimens. The modest benefit of 12- versus 6 months of adjuvant HER2 therapy and/or dual adjuvant HER2 therapy should be carefully weighed against the toxicities. All patients with HER2-positive breast cancer should be enrolled in ongoing risk tailored treatment trials whenever possible. Increasing data supports risk tailored therapy in early stage HER2-positive breast cancer in place of the routine application of aggressive and toxic systemic therapy regimens to all patients. While much progress has been made towards treatment de-escalation in appropriate patients, more is needed, as we highlight in this review. Indeed, Canadian-led clinical trials are helping to lead these efforts.     

Current status of chemotherapy in metastatic pancreatic cancer

The role of chemotherapy, and especially the experience of the EORTC Gastrointestinal Group with this treatment, in advanced pancreatic cancer is discussed. Combination chemotherapy is not superior to single agents and to date chemotherapy in this disease must be considered as experimental. There is no standard treatment available and patients should only be treated in clinical trials.