Cele mai importante toxicităţi ale chimioterapicelor folosite în tratamentul tumorilor solide

 Main toxicity of chemotherapy for solid tumors

First published: 24 octombrie 2015

Editorial Group: MEDICHUB MEDIA

DOI: 10.26416/OnHe.32.3.2015.4317


The main toxicities induced by chemotherapy of solid tumors are haematological toxicity (anemia, leukopenia, thrombopenia) and non hematologic (cardiotoxicity, neurotoxicity, gastrointestinal toxicity). These toxicities may damage the quality of life of patients. Another undesirable effect of toxic phenomena is the need for chemotherapy dose reduction and dose intensity also decreased. We intend to briefly describe these important manifestations of the toxicity of chemotherapy and supportive care for these toxic events.

toxicities, toxicity of chemotherapy


Principalele toxicităţi induse de chimioterapia tumorilor solide sunt: toxicitatea hematologică (anemia, leucopenia, trombopenia) şi cea nonhematologică (cardiotoxicitatea, neurotoxicitatea, toxicitatea digestivă). Aceste toxicităţi pot duce la deteriorarea calităţii vieţii pacienţilor. Un alt efect nedorit al apariţiei fenomenelor toxice este reprezentat de necesitatea scăderii dozelor de citostatice şi scăderea, de asemenea, a intensităţii dozei. Ne propunem să descriem succint aceste manifestări importante ale toxicităţii chimioterapiei şi terapia suportivă necesară.

The toxic effects of chemotherapy, such as neutropenia, anemia, mucositis, cardiomyopathy, and neuropathy, are frequent in patients treated with chemotherapy but more common in elderly patients than in younger patients. This susceptibility to the toxicity of chemotherapy for elderly patients may be due to age-related physiologic different from young patients,  and the higher prevalence of comorbidities in older patients . Chemotherapy can be more safer by correcting comorbidities and nutritional deficits, but supportive care to ameliorate the side effects of chemotherapy in older patients is also important(3).


Anemia in cancer patients is similar to anemia in chronic disease. This means that the marrow progenitor response to erythropoietin and iron utilization is impaired. The endogenous erythropoietin level could be decreased. Tumor infiltration of the bone morrow could be another factor of anemia. Other causes are nutritional deficiencies, chronic renal dysfunction, myelodysplastic syndrome but also chemotherapy. We will discuss about the chemotherapy-induced anemia and its treatment. In current practice the chemotherapy is safety to be done when hemoglobin is more than 10 g/dl. The most used treatment for this anemia is blood transfusion and  erythropoietin. Blood transfusion has a lot of complication: hemolytic anemia and allergic reactions.

Post transfusion hemolytic anemia

The value of Hgb and Ht decrease quickly (several days). There are no evidence of hemorrhage. Laboratory tests reveal elevated lactate dehydrogenase, unconjugated bilirubin, positive direct Coombs test. This patients need only follow-up until the hemolysis resolve.

Allergic reaction to transfusion

These reaction could be treated by irradiated blood, but this treatment is unlikely to prevent this reactions. Plasmapheresis is not an adequate option for these reactions too. Corticosteroids prior to transfusion may help suppress these reactions, but in patients with repeated or severe reactions their usefulness is limited. Because the cause of this reaction is doe to plasma components, patients with repeated or severe allergic reactions may benefit of washed red blood cells in which residual donor plasma has been removed and replace by saline.


Darbepoetin-alpha is similar to endogenous human erythropoietin. After initiation of erythropoietins treatment is a delayed with two weeks until can be appreciated a rise in hemoglobin level. Erythropoietins could be considered for treatment of any patients with hemoglobin less than 10 mg per dL with symptoms of anemia. Alpha Epoetin: patient has responded to Epoetin alpha therapy with more than 1 g Hgb by 4 weeks, until the value of Hgb becomes 9.8 g/dL. The treatment must be continued until the value of Hgb will be stabilized at 12g/dL. Epoetin Beta 30,000 IU once weekly is equally effective as the conventional 10,000 IU three-times weekly regimen in alleviating cancer-related anemia(4).

Chemotherapy-induced neutropenia (CIN)

Definition and cflasification of CIN: The most commonly used scale for grading the severity of CIN is derived from the Common Toxicity Criteria of the National Cancer Institute. It delineates neutropenia into four grades following the absolute neutrophil count (ANC): grade 1, ANC ≥1.5 to <2 × 109/l; grade 2, ≥1 to <1.5 × 109/l; grade 3, ≥0.5 to <1 × 109/l; grade 4, <0.5 × 109/l. During a neutropenic episode, all patients treated with chemotherapy have a risk of developing febrile neutropenia. Febrile neutropenia (FN) is defined as an oral temperature >38.5°C or two consecutive readings of >38°C for 2 hours and an absolute neutrophil count <0.5 × 109/l, or expected to fall below 0.5 × 109/l(5).

Prophylaxis of CIN by using Granulocyte-colony Stimulating Factor (G-CSF)

A recombinant human G-CSF, filgrastim (Neupogen), registration trials of filgrastim in patients with small-cell lung cancer (SCLC) receiving cyclophosphamide, doxorubicin and etoposide demonstrated a reduction in the incidence, duration and severity of febrile neutropenia (FN) with G-CSF use. A pegylated form of G-CSF (pegfilgrastim [Neulasta®]) was also approved by FDA for the treatment of CIN. In recent years, three biosimilar filgrastim molecules have been introduced and approved in the EU. Haematopoietic  growth factors could help to manage febrile neutropenia (FN) post chemotherapy(6). The more conservative management for the treatment of febrile neutropenia approach consists of aggressive fluid resuscitation, restoring the electrolyte balance, bowel rest, alimentary decompression, parenteral nutrition, supplementing blood products (platelets, fresh frozen plasma, and cryoprecipitate), and broad spectrum antibiotics to cover gram positive cocci, gram negative bacilli, and anaerobes. A frequent CT scan to assess the progress is suggested. Many management guidelines also advocate the potential advantage of using G-CSF in neutropenic patients with septicaemia, abscess or shock. The empirical anti fungal therapy is also recommended as there is substantial difference in mortality for those receiving it, especially if neutropenic fever has more than 5-day duration. Laparotomy is often indicated in cases of peritonitis, persistent gastrointestinal bleeding despite improvement of neutropenia, thrombocytopenia and coagulopathy and if the patient deteriorates despite aggressive conservative medical management. The use of anticholinergics, antidiarrheals, and narcotic analgesics should be avoided as they may mask or confuse the clinical picture. The effective antibiotics are metronidazole, 3rd or 4th generation cephalosporins, meropenem, imipinem, pencillins, and aminoglycosides in varying(7,8). Low-risk FN patients can be safely treated on an outpatient basis, so retail pharmacists are likely to see them. Still, controversy surrounds the best treatment approaches in this setting. Some oncologists routinely use colony-stimulating factor in combination with antibiotics for CIN, but its effect on infection-related mortality has not been documented. A recent review has concluded that inpatient oral antibacterial therapy can be safely substituted for conventional intravenous (i.v.) treatment in some low-risk FN patients, namely those who are haemodynamically stable, who do not have acute leukaemia or evidence of organ failure, who do not have pneumonia, an indwelling venous catheter or severe soft tissue infection. Patients with FN who are at high risk as assessed by the MASCC criteria, or have high-risk features as judged by the admitting doctor, should be admitted and commenced on broad-spectrum i.v. antibiotics(9). Local epidemiological bacterial isolate and resistance patterns are crucially important in determining first-choice empirical therapy. A meta-analysis comparing monotherapy (ceftazidime or a carbopenem) with combination therapy found equivalent efficacy. This was less clear in the subsets at high risk of prolonged neutropenia and those with bacteraemia, where the bactericidal activity and synergistic effect of a b-lactam antibiotic in combination with an aminoglycoside is preferable(10)


Thrombocytopenia remains a significant clinical problem with an unmet medical need. Although platelet transfusions can provide a temporary solution, they do not address the underlying cause of thrombocytopenia. Platelet transfusions are often necessary to reduce bleeding complications once platelet counts reach 10,000 cells/mL to 20,000 cells/ mL. Management of chemotherapy-associated thrombocytopenia often involves dose reductions or treatment delays.

Despite the extensive efforts in the clinical development of thrombopoietic agents in the past decade, recombinant interleukin-11 (IL-11-Nerumega) is the only agent currently approved by the US Food and Drug Administration for thrombocytopenia induced by chemotherapy. The use of this agent is limited due to its narrow therapeutic index. Invasive approaches aiming to reduce the sequestration of the platelets by the spleen have been explored in the management of chemotherapy-induced thrombocytopenia. Splenectomy is a rarely used alternative for management of thrombocytopenia due to high incidence of significant morbidities and complications, especially in immunocompromised patients(11,12).


Stomatitis is a term generally used for inflammatory, erosive and ulcerative oral mucosa. Drugs that may cause these side effects are: chemotherapeutical agents, corticosteroids, antibiotics, anticholinergic. The treatment consists in medication change: stopping or reducing the dose of anticholinergic. Treatment consists in: use of a gel with choline salicylate, gargling with Benzydamine, a nonsteroidal anti-inflammatory with mild local anesthetic, which is absorbed through the skin and oral mucosa, administration of carbenoxolone sodium gels four times per day. 2% lidocaine gel can be applied to the mouth before meals and when needed. Changes in taste could be another side effect after chemotherapy. Drugs that cause alterations of taste: 5-fluorouracil (alters sensitivity to bitter and acid gustatory), Doxorubicin, Flurazepamul. Treatment consists in a series of general measures: improving oral and dental hygiene, the treatment of oral candidiasis when this exists. Changes in diet: consumption of foods with strong taste, change the taste of sugar content of food. Reduce the amount of urea in the diet by eating white meat, eggs, dairy products. Maske the bitter taste of foods that contain urea by adding wine or beer to soups or sauces, salted meat consumption, use of spices, food consumption at room temperature or lower, consumption of liquid regrown(13,14).


Neuropathy is a common symptom associated with chemotherapy - would be considered a peripheral nervous system (PNS) disorder. Neurotoxicity is more pronounced when chemotherapy is associated with radiotherapy. Many patients experience peripheral neuropathy from drugs such as vinca alkaloids, taxanes, and platinum-based therapies. Patients typically complain of a numbness and tingling sensation in the extremities, specifically in the fingers, toes, and feet. Currently, there are no established agents available to prevent neuropathic toxicity, but there are pharmacological and non-pharmacological treatment options available: Duloxetine, anticonvulsant drugs (gabapentin, pregabalin), tricyclic antidepressant drugs (nortriptyline, amitriptyline). Compounded topical gel containing baclofen, amitriptyline, HCL, and ketamine can be used, occupational medicine, cognitive and behavioral modifications such as guided imagery for pain control(15).


Mucositis is defined as inflammatory and/or ulcerative lesions of the oral and/or gastrointestinal tract. Infectious diseases, immune deficiency and medications can be the cause. One of the major causes of mucositis is high-dose cancer therapy.

Oral mucositis

There is a multidisciplinary development and evaluation of oral care protocols that include frequent use of non-medicated oral rinses (e.g. saline mouth rinses 4-6 times/day), recommended for the reduction of severity of oral mucositis from chemotherapy and/or radiation therapy. Alcohol-based mouth rinses should be avoided. A soft toothbrush that is replaced on a regular basis is also suggested. Because of the high risk of malnutrition following a high-dose chemo-radiotherapy regimen, all treated patients should be screened for nutritional risk and early enteral nutrition started in the case of swallowing problems. Topical anesthetics can provide short-term pain relief for oral mucositis on an empiric basis. Acyclovir and its analogs intravenously (i.v.) are not recommended to prevent mucositis caused by standard-dose chemotherapy. However, antivirals may be indicated to treat a newly emergent or recurrent oral viral infection that may co-exist with mucositis. Topically administered agents: Gelclair, Caphasol and Biotene lack research evidence base and practices is limited. However, these agents appear to have an effective safety profile and may be of benefit for some patients(14).

Gastrointestinal mucositis guidelines

In addition to the evidence-based guidelines below, basic bowel care should include maintenance of adequate hydration. In addition, consideration should be given to the potential for transient lactose intolerance and the presence of bacterial pathogens. These suggestions are consistent with good clinical practice. Either ranitidine or omeprazole orally is recommended for prevention of epigastric pain following treatment with standard-dose cyclophosphamide. Octreotide is recommended at a dose of at least 100 mg subcutaneously (s.c.) twice daily when loperamide fails to control diarrhea induced by standard-dose or high-dose chemotherapy(16).

Nausea, vomiting

Prevention of acute nausea and vomiting induced by highly emetogenic chemotherapy before the introduction of aprepitant. Combination of a 5-HT3 receptor antagonist plus dexamethasone is in many services of oncology the standard of care because in many countries aprepitant is not available. The best combination for highly emetogenic cytostatic like cisplatin is outdated as effectiveness by combination of 5-HT3 receptor antagonist plus dexamethasone plus aprepitant. The mechanism of action of aprepitant is the antagonism of the neurokin (NK) neurotransmitter receptor. The recommended dose is ondansetron 32 mg plus dexamethasone 20 mg on day 1, followed by dexamethasone 8 mg twice a day on days 2-4. When is possible to add aprepitant the follow schedule is recomanded: ondansetron 32 mg, dexamethasone 12 mg and aprepitant 125 mg on day 1, followed by dexamethasone 8 mg daily on days 2-4 and aprepitant 80 mg on days 2 and 3. Intravenous and oral formulations are equally effective and safe. No differences between the 5-HT3 receptor antagonists, dolasetron, granisetron, ondansetron, tropisetron exist in terms of efficacy. Aprepitant provides protection against delayed vomiting regardless of response in the acute phase. Aprepitant should be used as a single 80-mg oral dose on days 2 and 3 after cisplatin administration. Prevention of acute nausea and vomiting induced by moderately emetogenic chemotherapy use the some drugs. Palonosetrom seems to be preferred by some clinicians for this condition. The dose and period of treatment is shorter than that used for nausea and vomiting induced by highly emetogenic chemotherapy.

Prevention of anticipatory nausea and vomiting

Benzodiazepines are the only drugs that reduced the occurrence of anticipatory nausea and vomiting but their efficacy tended to decrease as chemotherapy treatment continued. Ondansetron was used too for prevention of anticipatory nausea and vomiting and was shown to be superior to metoclopramide and droperidol,  granisetron showed similar efficacy to standard antiemetic therapy and a continuous infusion of chlorpromazine was comparable to, but more toxic than a continuous infusion of ondansetron(17).

Cardiovascular toxicity

One of the most common manifestations of cardiotoxicity associated with exposure to anticancer therapies is the development of LVD (left ventricular dysfunction) and overt heart failure (HF). ESMO practice guideline defines LVD as the common manifestation of cardiotoxicity associated with exposure to anticancer therapy. Recent definitions have varied and include a greater change in LVEF below the lower limit of normal (LLN) or LVEF <50%. As a consequence, at present, a consensus definition for cardiotoxicity is still lacking. Anthracyclines are a class of chemotherapeutics widely used in the management of multiple malignancies. Acute cardiotoxicity occurs in <1% of patients immediately after infusion of the anthracycline and manifests as an acute, transient decline in myocardial contractility, which is usually reversible. The early-onset chronic progressive form occurs in 1.6-2.1% of patients, during therapy or within the first year after treatment. Lateonset chronic progressive anthracycline-induced cardiotoxicity occurs at least at 1 year after completion of therapy in 1.6-5% of patients clinically evident until 10-20 years after the first dose of cancer treatment. Administration: higher single doses; history of prior irradiation; the use of other concomitant agents known to have cardiotoxicity including cyclophosphamide, trastuzumab and paclitaxel; female gender; underlying CV disease; age (young and elderly); increased length of time since completion of chemotherapy; increase in cardiac biomarkers, as troponins and natriuretic peptides, during and after administration. The risk of clinical cardiotoxicity increases with a cumulative dose. Studies evaluating cumulative probability of doxorubicin-induced HF have found rates in the range of 3-5% with 400 mg/m2, 7-26% at 550 mg/m2 and 18-48% at 700 mg/m2. The recommended maximum lifetime cumulative dose for doxorubicin is 400-550 mg/m2. Treatment of anthracycline-induced cardiac dysfunction warrants aggressive intervention with standard modalities consistent with treatments for other forms of HF. No clear consensus regarding the duration of the follow-up for asymptomatic patients exists(18).

LVD has been associated with cyclophosphamide therapy in 7-28% of patients.

Inhibitors of microtubule polymerization

Paclitaxel and docetaxel are widely used in the treatment of multiple malignancies. The incidence of HF associated with taxanes according to retrospective analysis is relatively low. Bevacizumab, a humanized monoclonal antibody directed against vascular endothelial growth factor (VEGF), has demonstrated substantial antitumor activity when combined with chemotherapy, leading to regulatory approval for several advanced solid tumors, including breast, lung, colorectal and renal carcinomas. With greater use of bevacizumab, data are emerging regarding potential cardiac toxicity. To date, the rates of cardiac toxicity associated with bevacizumab therapy appear to be relatively low.

Treatment of anticancer drug-induced LVD

All patients with cancer who are treated with potentially cardiotoxic therapy represent a high-risk group for the development of HF. Recent findings reported in a large population of anthracycline-induced CMP patients demonstrated that the time elapsed from the end of chemotherapy to the start of HF therapy (time-to-treatment), with ACE-I (angiotensin-converting enzyme inhibitors) and, when tolerated, with BB, is a crucial variable for recovery of cardiac dysfunction. Indeed, the likelihood of obtaining a complete LVEF recovery is higher in patients in whom treatment is initiated within 2 months from the end of chemotherapy.

Prevention of anticancer drug-induced LVD

Carvedilol may prevent cardiac damage induced by doxorubicin due to its antioxidant activity. The effect of carvedilol was confirmed in a randomized study in which prophylactic use of carvedilol in a small population of patients treated with anthracycline prevented LVD and reduced mortality.

Dexrazoxane, an iron-chelating agent, significantly reduces anthracycline-related cardiotoxicity in adults with different solid tumors and in children with acute lymphoblastic leukemia and Ewing’s sarcoma. Dexrazoxane is not routinely used in clinical practice and is recommended as a cardioprotector by the American Society of Clinical Oncology only for patients with metastatic breast cancer who have already received more than 300 mg/m2 of doxorubicin(19,20).  


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