Supportive Care in Hemato-Oncology: A Review in Light of the Latest Guidelines

Recent developments in cancer therapy have resulted in increases in treatment success rates and survival. One of thebasic goals of such therapy is improving patient quality of life. Chemotherapy protocols for solid or hematologicalmalignancies-most of which include multiple agents-negatively impact patient quality of life. Additionally, there havebeen developments in supportive care, which seeks to ameliorate or minimize the negative effects of chemotherapy.Herein we present a review and brief summarization of some of the agents used for supportive care in cancer patientsin light of the latest guidelines.


Introduction
Supportive care aims to ameliorate the adverse effects of chemotherapy, and to prevent reductions in the chemotherapy dose and delays in its schedule. These adverse effects include nausea/vomiting, diarrhea, constipation, pain, infections, cytopenia, allergic reactions, mucositis, osteoporosis, and neuropathy. Cancer patient quality of life increases with supportive care. The success of treatment increases along with the level of treatment compliance. Supportive care is critical in intolerant and elderly patients with multiple comorbidities. Chemotherapy and/ or radiotherapy target the disease, whereas patient quality of life is the target of supportive care. Physicians sometimes overlook developments in supportive care, as they primarily concentrate on disease-targeted therapy. Herein we present a review of supportive care in light of the latest guidelines, focusing only on nausea/vomiting, anemia, and myeloid growth factors, as each side effect of cancer treatment warrants individual attention.

Chemotherapy-Induced Nausea/Vomiting
Chemotherapy-induced nausea/vomiting (CInv) is a common adverse event associated with cancer treatment that occurs in 70%-80% of patients undergoing chemotherapy. CInv results in significant morbidity and negatively affects quality of life [1,2]. The risk of CInv is associated with the type of chemotherapy, and increases with age <50 years, female gender, a history of CnIv during chemotherapy, pregnancy-induced nausea/vomiting, a history of motion sickness, and anxiety [3,4]. Chemotherapeutic agents cause vomiting via activation of neurotransmitter receptors located in the chemoreceptor trigger zone, gastrointestinal tract, and vomiting center. Serotonin, substance P, and dopamine receptors are the primary neuroreceptors involved in the emetic response [5].
CInv is classified into 5 categories: acute, delayed, anticipatory, breakthrough, and refractory. Acute-onset CInv refers to nausea and/or vomiting that occurs within 24 h of chemotherapy administration [3]. nausea and/or vomiting that develop >24 h after chemotherapy administration is known as delayed emesis [2]. Anticipatory nausea and/or vomiting occur prior to the administration of next chemotherapy; because it is a conditioned response, it can occur only after a negative past experience with chemotherapy [6]. vomiting that occurs within 5 d of prophylactic antiemetic use or requires rescue antiemetic treatment is known as breakthrough emesis. vomiting in response to subsequent chemotherapy cycles that follow failed prophylactic and/or rescue antiemetic treatment during previous cycles is known as refractory emesis [7].

Dopamine Receptor Antagonists
Dopamine receptors are located in the chemoreceptor trigger zone and dopamine receptor antagonists primarily affect this area; however, high doses of dopamine receptor blockades result in extrapyramidal reactions, disorientation, and sedation, which limit the clinical use of such agents, including phenothiazines and butyrophenones (droperidol and haloperidol) [8].

Serotonin (5-HT 3 ) Receptor Antagonists
Serotonin receptors-specifically 5-HT 3 receptors-are present in the central nervous system and gastrointestinal tract. First-generation 5-HT 3 receptor antagonists (azasetron, dolasetron, granisetron, ondansetron, ramosetron, and tropisetron) are equally effective and toxic when used at the recommended doses, and differ only in terms of cost. The primary symptoms of their toxicity are mild headache, constipation, and occasional diarrhea. The second-generation 5-HT 3 receptor antagonist palonosetron might more effectively control delayed CInv than the first-generation 5-HT 3 receptor antagonists [8].

Dopamine-serotonin Receptor Antagonists
metoclopramide has antiemetic properties, both at low doses as a dopamine antagonist and at high doses as a serotonin antagonist. Use of a relatively high dose (20 mg t.i.d. p.o.) may result in sedation and extrapyramidal side effects [9,10].

Corticosteroids
Corticosteroids have been shown to be effective in the prevention of CInv, although their antiemetic mechanism of action remains unknown. The control of CInv is markedly enhanced when corticosteroids are used in combination with 5-HT 3 and nK-1 receptor antagonists [12,13]. The most widely used corticosteroid antiemetic is dexamethasone [8].

Gabapentin
The anticonvulsant gabapentin has been reported to reduce delayed nausea in a small number of patients undergoing adjuvant chemotherapy for breast cancer; however, additional research is necessary to determine its efficacy more precisely [19].

Cannabinoids
Cannabinoid receptors of the CB1 type are present in the area postrema, nucleus tractus solitarius, and dorsal motor nucleus, which are key sites of emetogenic control in the brainstem. Cannabinoid CB2 receptors are present on brainstem neurons and may play a role in mediating the effects on emesis [20,21]. Dronabinol and nabilone have been approved by the US FDA for use in CInv refractory to conventional antiemetic therapy, but the role of cannabinoids in the prevention of CInv remains to be established [22].

Clinical Management of CINV
All of the following recommendations are those of the national Comprehensive Cancer network (nCCn) Practice guidelines in Oncology v.2.2010 [23].

Emesis Prevention For High Emetic Risk Intravenous Chemotherapy
Data for post-cisplatin (≥50 mg m -2 ) emesis prevention category 1; others are category 2A.

Cancer and Chemotherapy-Induced Anemia
Anemia is a frequent complication of cancer and occurs in 30%-90% of patients [24]. At the time of diagnosis 30%-40% of patients with non-Hodgkin's lymphoma or Hodgkin's lymphoma, and ≤70% of patients with multiple myeloma are anemic; rates are higher among patients with myelodysplastic syndromes. Among patients with solid cancers or lymphomas, ≤50% develop anemia following chemotherapy [25]. Anemia is a frequent cause of morbidity and might increase mortality [26].
Tumor cells activate the immune system of the host and a number of cytokines are produced. This inflammatory response affects erythropoietin production, suppresses burst-forming unit-erythroid, and colony-forming uniterythroid, and impairs iron utilization. Tumor cells may also decrease erythrocyte survival either via tumor necrosis factor or by causing erythrophagocytosis [27]. nutritional deficiency, hemolysis, bleeding, hereditary diseases, renal insufficiency, and anemia of chronic disease can also contribute to anemia in cancer patients [28,29]. The myelosuppressive effects of chemotherapy and radiation therapy are also significant factors associated with anemia [30,31]. Anemia can be corrected by treating the underlying etiology, transfusion with packed red blood cells, or erythropoiesis stimulating agents, with or without iron supplementation.
The nCCn concurs that a hemoglobin level ≤11 g dl -1 in cancer patients should be investigated. In patients with a high baseline level, a drop of ≥ 2g dl -1 should also be assessed. There are 3 general anemia categories described by the nCCn: be increased to 300 U kg -1 t.i.w. if there is no response after 4 weeks. The initial dose of epoietin beta is 30,000 IU week -1 and the dose can be increased to 60,000 IU week -1 in there is no response after 4 weeks. The initial dose of darbepoetin alfa is 2.25 µg kg -1 QWK; the dose can be increased to 4.5 µg kg -1 QWK if there is no response. The dose should be adjusted individually for each patient, so as to maintain the lowest hemoglobin level sufficient to avoid red blood cell transfusion. If the hemoglobin level is such that transfusion is unnecessary or increases >1 g dl -1 in any 2 week period the epoetin alfa or epoetin beta dose should be reduced by 25%, and the darbepoetin alfa dose should be reduced by 40%.
If ferritin is ≤800 ng ml -1 and transferrin saturation is <20%, Iv iron supplementation should be considered along with erythropoietin therapy; however, patients with active infection should not receive Iv iron therapy. Iv Iron dextran 100 mg is administered over the course of 5 min QWK for 10 doses or as a 1-g infusion administered during the course of several hours. Ferric gluconate is administered as 125 mg Iv over the course of 60 min QWK for 8 doses or as 200 mg Iv over the course of 3-4 h repeated every 3 weeks for 5 doses. Iron sucrose is given as 200 mg Iv over the course of 60 min every 2-3 weeks or as 200 mg Iv over the course of 2-5 min every 1-4 weeks [23].

Myeloid Growth Factors
myelosuppression is the major dose-limiting toxicity associated with many chemotherapy regimens and can also result in chemotherapy schedule delay, compromising the effectiveness of chemotherapy [49][50][51][52]. Infections associated with neutropenia may be accompanied by sepsis and occasionally death. Severe myelosuppression is accompanied by impaired quality of life, even in the absence of fever [53]. myeloid growth factors stimulate proliferation of neutrophil progenitors and enhance neutrophil function. The use of myeloid growth factors is designed to reduce the duration of myelosuppression and the depth of neutropenia, and decrease the likelihood of infection [54].
A meta-analysis of myeloid growth factors trials reported that there were significant reductions in severe neutropenia, neutropenic fever, and infections in patients treated for non-Hodgkin's lymphoma and Hodgkin's lymphoma [55]. Trials of myeloid growth factors in patients treated for acute leukemia indicate they can reduce the duration of both neutropenia and hospitalization during induction therapy; however, their benefit is modest, and remission and survival rates associated with their use are inconsistent. The concern that using myeloid growth fac-1. Asymptomatic anemia without significant comorbidity, for which observation and periodic reevaluation are appropriate; 2. Asymptomatic anemia with comorbidity or high risk, for which transfusion should be a consideration; 3. Symptomatic anemia, for which transfusion should be performed.
If the hemoglobin level decreases following chemotherapy, transfusion may be appropriate even in the absence of symptoms or significant comorbidity [23]. Packed red blood cell (PrBC) transfusion is the only treatment option in patients that require immediate correction of anemia. risks associated with PrBC transfusion include transfusion-related reactions, congestive heart failure, bacterial contamination, viral infections, iron overload, and an increase in thrombotic events [32].
Administration of erythropoiesis-stimulating agents (ESAs) decrease the need for PrBC transfusion in cancer patients undergoing chemotherapy [33][34][35]; however, there are risks associated with ESA therapy, including an increase in mortality, and an increase in tumor progression of breast cancer [36], head and neck cancer [37], cervical cancer [38], non-small cell lung cancer [39], nonmyeloid cancer [40], and lymphoid malignancy [41]. Elevated thromboembolic risk has also been associated with ESA treatment [42][43][44]. Hypertension/seizures and pure red cell aplasia 90% of occured with epoetin alfa have also been reported in chronic renal failure [23]. In addition to safety concerns, ESAs also have considerable impact on healthcare financial resources [45].
Historically, ESA treatment strategies were designed to achieve and maintain hemoglobin levels >12 g dl -1 , decrease the need for transfusion, and improve patient quality of life [46]. In 2008 the US FDA prohibited use of ESAs in cancer patients seeking cure. reimbursement is limited to patients with hemoglobin levels <10 g dl -1 [25]. The University of Texas mD Anderson Cancer Center mandates that following initial administration of ESAs, subsequent doses be given only to those with a hemoglobin level <11 g dl -1 , leading to intermittent treatment versus the once standard continuous treatment pattern [47]. myelodysplastic syndrome patients with low intermediate-1 IPSS risk, hemoglobin <10 g dl -1 , and serum erythropoietin <500 mIU ml -1 should be considered for ESA treatment [48].
According to the package insert dosing schedule, the initial dose of epoetin alfa is 150 U kg -1 t.i.w; the dose can porting the therapeutic use of pegfilgrastim; therefore, only filgrastim or sargramostim should be administered in the therapeutic setting. In patients that have not received prophylactic g-CSF the nCCn recommends evaluating the risk factors for infection-related complications or poor clinical outcome, including advanced age (>65 years), sepsis syndrome, severe (absolute neutrophil count <100 µl) or anticipated prolonged (>10 d) neutropenia, pneumonia, invasive fungal infection or other clinically documented infections, hospitalization, and a history of febrile neutropenia. If risk factors are present g-CSF should be considered. myeloid growth factors currently used for the prophylaxis of febrile neutropenia and maintenance of scheduled dose delivery include filgrastim, pegfilgrastim (category 1), and sargramostim (category 2B). Filgrastim treatment is initiated within 1-3 d after the completion of chemotherapy at a dose of 5 µg·kg -1 ·d -1 until post nadir absolute neutrophil count (AnC) recovery is normal or near normal, according to laboratory standards. The dose may be rounded to the nearest vial site by intitution defined weight limits. moreover, evidence exists that supports the initiation of pegfilgrastim 24 h after completion of chemotherapy, administered every 3 weeks at a dose of 6 mg for each chemotherapy cycle. Same-day administration of filgrastim or pegfilgrastim (within 24 h of the completion of chemotherapy) is not recommended [67,68] Conclusion By means of all summarized supportive care interventions we are able to better treat our patients, prolong their survival and decrease complications of cancer chemotherapy. new therapies may add new complications but supportive care is also improving. If we know the complications of our therapy we can be able to choose the suitable supportive care intervention to increase the quality of life. Supportive care must be a more essential part of main therapy in the future.

Conflict of Interest Statement
The authors of this paper have no conflicts of interest, including specific financial interests, relationships, and/ or affiliations relevant to the subject matter or materials included.
tors may interfere with the evaluation of remission may be dealt with delaying the start of growth factors until after the day 14 bone marrow and stopping at neutrophil recovery several days prior to performing the bone marrow biopsy to assess remission. Stimulation of leukemic cell proliferation has not been observed in clinical trials. Recruitment leukemia into cycling, making the leukemia cells more sensitive to chemotherapy, has also not demonstrated convincing evidence of clinical benefit. Thus, use of granulocyte colony-stimulating factor (g-CSF) in patients with acute leukemia should be based only on preventing neutropenic complications. During post-remission consolidation therapy the benefits may be more substantial [54,56].
The most common toxicity associated with g-CSF therapy is mild-to-moderate bone pain, which is usually effectively controlled with non-narcotic analgesics. There have also been reports of splenic rupture in patients treated with g-CSF [54]. A retrospective review reported that a high rate of bleomycin toxicity has been linked to g-CSF use in Hodgkin's lymphoma patients receiving bleomycincontaining therapy [57]. Some patients develop allergic skin, respiratory system, and cardiovascular system reactions [58].
Primary prophylaxis is achieved via administration of myeloid growth factors during the initial chemotherapy cycle, in anticipation of the risk of neutropenic complications. The use of prophylactic myeloid growth factors is recommended for solid tumor/lymphoma patients that have ≥20% likelihood of developing fever; in patients with a 10%-20% risk of fever g-CSF should be considered if there are additional risk factors (advanced age, history of chemotherapy or radiotherapy, and pre-existing neutropenia, or tumor involvement in the bone marrow, poor performance status, and comorbidity, including renal and liver dysfunction). g-CSF should not be routinely used in patients with a <10% risk of fever. According to American Society of Clinical Oncology (ASCO) guidelines, secondary prophylaxis with g-CSF should be considered if maintaining the dose intensity is considered to be important [59][60][61][62].
Compared to its prophylactic use, there is less evidence supporting the therapeutic use of g-CSF for febrile neutropenia as an adjunct to antibiotics [63][64][65]. Patients with febrile neutropenia given prophylactic filgrastim or sargramostim should continue with g-CSF therapy; however, as pegfilgrastim is long acting patients given prophylactic pegfilgrastim should not be treated with additional g-CSF [66]. Currently, there is a lack of evidence sup-