Postgraduate Medicine
ISSN: 0032-5481 (Print) 1941-9260 (Online) Journal homepage: http://www.tandfonline.com/loi/ipgm20
Nutritional deficiencies in patients receiving cancer chemotherapy Samuel Dreizen DDS, MD, Kenneth B. McCredie MB, ChB, Michael J. Keating MB, BS & Borje S. Andersson MD, PhD To cite this article: Samuel Dreizen DDS, MD, Kenneth B. McCredie MB, ChB, Michael J. Keating MB, BS & Borje S. Andersson MD, PhD (1990) Nutritional deficiencies in patients receiving cancer chemotherapy, Postgraduate Medicine, 87:1, 163-170, DOI: 10.1080/00325481.1990.11704531 To link to this article: http://dx.doi.org/10.1080/00325481.1990.11704531
Published online: 17 May 2016.
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Citing articles: 4 View citing articles
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Date: 30 May 2016, At: 18:32
CME credit article
Nutritional deficiencies in patients receiving cancer chemotherapy Samuel Dreizen, DDS, MD Kenneth B. McCredie, MB, ChB Michael J. Keating, MB, BS Borje S. Andersson, MD, PhD
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Preview Cancer and cancer chemotherapy often have such a profound impact on a patient's nutritional status that malnutrition becomes a major cause of morbidity and mortality. However, most nutritional deficiencies are chemically correctable. This article details the clinical presentations and treatment of various nutritional deficiencies in cancer patients who received chemotherapy at the University of Texas M. D. Anderson Hospital and Tumor Institute, Houston, during the past two decades. Maintenance of nutritional health in patients receiving treatment for widespread cancer can be difficult if not impossible. Despite the advent of sophisticated and well-tolerated methods of total parenteral alimentation. the nutritional status of most cancer patients receiving chemotherapy still ranges from subnormal to extremely precarious. The pivotal factor in each case is the vector of forces that contribute to the patient's nutritional status. These diverse forces are unique to the individual, and many patients are protected from cancer-related malnutrition while others have gross manifestations of one or more nutritional deficiencies. However, if treatment is knowledgeable and the patient's condition is still reversible, chemical correction of specific nutritional deficiency states is possible (figure l ).
Effects of advanced cancer Patients with advanced cancer have an elevated caloric expendi-
ture. increased protein catabolism. negative nitrogen balance, and a high rate of breakdown of body fat stores. 1 The degree of anorexia and weight loss parallels the extent of the cancer and is compounded by diminished or perverted senses of taste and smell. 2 Some tumors secrete potent pharmaceutical agents, including hormones. peptides, kinins. and prostaglandins, which produce systemic effects that impinge on nutritional status. 3 Other tumors create local effects that contribute to fluid and electrolyte disturbances, hypoalbuminemia. anemia, and decreased levels of vitamins and minerals in serum and tissue. 4
Effects of chemotherapy Chemotherapy is a prime contributor to inanition in cancer patients. Nearly all drugs used in cancer therapy promote anorexia. stomatitis. and alimentary tract disturbances. The effects vary. depending on type and
combination of drugs given, duration of treatment. rates of metabolism, and individual susceptibility. Any patient receiving chemotherapy who stays in the hospital for longer than 15 days and who is unable to ingest at least 1,000 calories/day is a candidate for enteral or parenteral nutritional support. 5 Reports of the debilitating effects of malnutrition in patients receiving cancer chemotherapy have focused largely on cachexia, a complex metabolic problem of uncertain etiology that affects 33% to 67% of patients with advanced cancer. lt is characterized clinically by anorexia, early satiety, weight loss, wasting. and weakness. Loss of body fat and body protein is significant. Other findings include anemia. electrolyte aberrations, hormonal dysfunction, and increased basal metabolism and energy consumption. Cachectic patients appear chronically ill and emaciated and have atrophic, shiny skin that hangs in loose folds; reduced muscle mass accentuates the underlying bony prominences (figure 2). Only complete tumor removal reverses cachexia. 6 Specific nutritional deficiencies occur in cancer patients who are treated with antimetabolites. which act as competitive inhibitors of the utilization of essential vitamins. purines, and pyrimicontinued
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Gross lesions that reflect a specific nutritional deficiency may appear when antimetabolites used to treat cancer kill rapidly dividing normal cells.
Figure 1. Patient with acute lymphocytic leukemia. a. Glossitis caused by mixed niacin-folate deficiency. b. Disappearance of glossitis after treatment.
dines. The aim is to create nutritional disruptions that prevent DNA, RNA. andjor protein synthesis, thereby impeding the replication of malignant cells. Because antimetabolites cannot distinguish between cancer cells and rapidly dividing normal cells, the number of normal cells killed is often sufficient to evoke gross lesions that reflect a specific nutritional deficiency.
Specific deficiencies Diagnosis of a specific nutritional deficiency in patients undergoing cancer chemotherapy is based almost exclusively on recognition of clinical signs and symptoms and on the patient's response to a precise, potent, and prolonged therapeutic trial. Vitamin levels in the blood are often nondiagnostic in such cases. VITAMIN B, DEFICIENCY-Vitamin B1 deficiency may be a complication of any disease or treat-
164
ment that restricts food intake andjor promotes severe and
recurrent vomiting. Clinically, vitamin B1 deficiency manifests as a type of beriberi: dry, wet, cardiac, or mixed. The major common component is peripheral neuritis. In addition, each type is distinguished by its predominant signs and symptoms. For example, edema is characteristic of wet beriberi, and the cardinal signs of cardiac failure are pathognomonic of cardiac beriberi. Figure 3 shows manifestations of wet beriberi that developed in a patient being treated for chronic myeloblastic leukemia in blastic crisis. The patient reported heaviness, weakness, and paresthesias of the legs accompanied by bilateral pedal edema, bilateral calf tenderness on pressure, and exaggerated bilateral deep tendon reflexes at the knees and ankles. All manifestations disappeared within a week after initiation
Figure 2. Cachexia in patient with metastatic carcinoma of the ovary.
of daily intravenous administration of 15 mg of thiamine hydrochloride. VITAMIN 13, DEFICIENCY-Vitamin B2 deficiency of any origin decreases the level of flavin coenzymes in tissues and organs. Many different riboflavincontaining coenzymes have been identified, and all participate as catalysts in cellular respiration through the transfer of hydrogen by alternate oxidation and reduction. The signs of ariboflavinosis appear in the borderline between the skin and mucous membranes. The lips are a prime target site. Bilateral angular cheilosis affects the commissures in a radial fashion, and vertical striations and denudation at the line of closure characterize the remainder of the lips. Angular cheilosis starts as a pallor followed by superficial transverse fissuring, maceration, exu-
EFFECTS OF CANCER CHEMOTHERAPY • VOL 87/NO 1/JANUARY 1990/POSTGRADUATE MEDICINE
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The characteristic dermatitis of pellagra, which is caused by niacin deficiency, can be induced by the anorectic complications of chemotherapy.
dation, and superinfection. Bilateral angular cheilosis and cheilitis in a patient receiving treatment for oat cell carcinoma of the lung is shown in figure 4. These lesions cleared rapidly after oral administration of 10 mg of riboflavin in divided doses twice daily. NIACIN DEFICIENCY-Disturbances of tryptophan-niacin metabolism are conducive to the development of pellagra. Classically, pellagra has been associated with maize-eating populations. Sporadic cases have been reported in chronic alcoholics and in persons with organic diseases that Interfere with ingestion, absorption, assimilation, andjor utilization of niacin and tryptophan. Dermatitis is the characteristic manifestation of pellagra; diarrhea and dementia may or may not be present. The dermatitis is bilateral and symmetric and commonly occurs on extensor surfaces of the extremities, face, and neck. A notable feature is the sharp demarcation from aqjointng unaffected skin. The skin lesions start as erythema, which darkens and becomes scaly, dry, and hyperpigmented before desquamating to disclose a smooth, shiny, depigmented epidermis. Figure 5 shows pellagrous skin lesions on the feet and legs of a patient who was given chemo-
Samuel Drelzen, DDS, MD Kenneth a. McCredie, Ma, Cha Mlchaei.J, Keating, Ma, as aorje S. Andersson, MD, PhD Dr Dreizen (right) is professor and chairman, department of oral oncology, University of Texas Health Science Center at Houston, Dental Branch. Dr McCredie (second from right) is professor of medicine and internist, department of hematology, and chief, leukemia service; Dr Keating (left) is professor of medicine, internist, and chief of clinical studies, department of hematology; and Dr Andersson (second from left) is assistant professor and associate internist, department of hematology, University of Texas M. D. Anderson Hospital and Tumor Institute, Houston
therapy for a poorly differentiated nodular lymphoma. The dermal changes disappeared after oral administration of 50 mg of niacinamide three times a day. FOLIC ACID DEFICIENCY-Folic acid is essential to the synthesis of DNA and thus is important in cell growth and reproduction. A member of the B vitamin group, it is the nutritionally essential
precursor of a large number of compounds that act as coenzymes in one-carbon transfer reactions. 7 To become metabolically active, folic acid must be reduced to tetrahydrofolic acid by the enzyme folic acid reductase. Methotrexate, a folic acid antagonist, is an extremely potent inhibitor of the reductase reaction. continued
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Vitamin K deficiency occurs in patients with severe malnutrition, intestinal malabsorption, or obstructive jaundice and during long-term treatment with some antibiotics.
Figure 4. Bilateral angular cheilosis caused
Figure 5. Pellagrous dermatitis of legs in
by vitamin 8 2 deficiency in patient with oat cell carcinoma of the lung.
patient with poorly differentiated nodular lymphoma.
Figure 6. Cheilitis caused by folic acid deficiency in patient with acute lymphocytic leukemia.
Figure 7. Stomatitis caused by folic acid deficiency in patient with oat cell carcinoma of the lung.
Figure 8. Ecchymoses caused by vitamin K deficiency in patient with oat cell carcinoma of the lung.
Figure 9. Gingival and labial bleeding
Figure 10. Pitting edema of legs caused by
caused by vitamin K deficiency in patient with acute lymphocytic leukemia.
protein deficiency in patient with ulcerative carcinoma of the ampulla.
Figure 11. Stomatitis caused by thymine deficiency in patient with adenocarcinoma of the lung.
Figure 3. Wet beriberi in patient with chronic myelocytic leukemia in blastic crisis.
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More than 80o/o of cancer patients in one study had a reduced level of serum albumin.
Folic acid deficiency results in megaloblastic dysplasia of cells in the bone marrow and the alimentary tract and culminates in macrocytic anemia, leukopenia, and a denudative, ulcerative, atrophic stomatitis. A spruelike pharyngitis, gastroenteritis, and proctitis malabsorption syndrome also develops in patients with folic acid deficiency. The devastation produced by treatment with methotrexate is shown in the lips of a patient with acute lymphocytic leukemia (figure 6) and in the mouth of a patient with oat cell carcinoma of the lungs (figure 7). Mucosal lesions are excruciatingly painful and readily superinfected. However, they are responsive to treatment with 10 mg!M2 of leucovorin calcium (Wellcovorin) given orally or intravenously every 6 hours until the methotrexate level in the serum is less than
w-sfM. VITAMIN K DEFICIENCY-The
only known biologic activity of vitamin K is in production of the so-called vitamin K-dependent coagulation factors in the liver, notably factor U (prothrombin), factor vn (proconvertin), factor IX (Christmas factor), and factor X (Stuart-Prowerfactor). 8 A normal diet provides an adequate amount of vitamin K, which is supplemented by endogenous vitamin K produced by bacteria in the distal small bowel and colon. Vitamin K deficiency
occurs in patients with severe malnutrition, intestinal malabsorption, or obstructive jaundice and in cases oflong-term treatment with antibiotics such as moxalactam disodium (Maxam) that are active against the intestinal flora andjor compete with vitamin K for intestinal absorption sites. Vitamin K deficiency leads to a pronounced bleeding tendency. Figure 8 shows skin ecchymoses in a patient with oat cell carcinoma of the lung, and figure 9 shows bleeding from the oral mucous membranes in a patient with acute lymphocytic leukemia. Both patients were given moxalactam for concomitant infections while hospitalized for chemotherapy. Other common manifestations of vitamin K deficiency include hematuria and postoperative bleeding. Muscle hematomas, intracranial hemorrhages, and submucosal intestinal hemorrhages occur less frequently. The effects of vitamin K deficiency can be reversed by intravenous administration of 20 to 50 mgofvitamin K1 oxide (phytonadione [AquaMEPHYTON]). Severe cases require fresh frozen plasma or a concentrate of vitaminK-dependent coagulation factors. HYPOPROTEINEMIA-More
than 80% of cancer patients have a reduced serum albumin concentration. 9 The decline is pro-
gressive and is caused mainly by decreased albumin synthesis. In some patients with neoplastic lesions, protein-losing enteropathy may be an important cause of the hypoalbuminemia. Proteinlosing enteropathy is suggested by the presence of a short albumin survival time and an increased fractional catabolic rate for albumin. 10 The characteristic clinical feature of hypoproteinemia, regardless of cause, is edema. Marked pitting edema in the legs of a patient with ulcerative carcinoma of the ampulla who also had anasarca is shown in figure 10. The most effective therapy for protein-losing enteropathy is (1) removal of the tumor by surgery, radiotherapy, or chemotherapy and (2) intravenous administration of albumin (Albuminar, Buminate, Plasbumin) in amounts sufficient to eliminate the deficit. THYMINE DEFICIENCY-Defi-
ciency of thymine, a pyrimidine base, often results from treatment with antimetabolites. Pyrimidine and purine bases and their nucleosides are essential for the synthesis of DNA, RNA, and certain coenzymes. Structurally related analogues of these nucleic acid precursors (eg, 5-fluorouracil [Adrucil] and 6-mercaptopurine [Purinethol), which act as antimetabolites and are incorporated in biosynthetic pathways) manufacture fraudulent intermediate continued on page 170
VOL 87/NO 1/JANUARY 1990/POSTGRADUATE MEDICINE • EFFECTS OF CANCER CHEMOTHERAPY
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AXID®
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nizatrdmecapsutes Briel Summary. ConsuH lhe package literature lor complete information. Indications and Usage: I ActiVe duodenal ulcer- for up to erght weeks ot treatment. Most patrents heat wrthm tour weeks 2. Maintenance therapy- for heated duodenal ulcer patients at areduced dosage ofl50mgh.s TheconsequencesoltherapywrthAxrdlorlongerthanoneyeararenot known Contraindication: Known hypersensrtrvrty to the drug. Use wrth cautron rn patients wrth hypersensrtrvrtyto otherHrreceptorantagonrsts Precautions: Generai- I Symptomatrc response to nrzatrdrne therapy does not precludethepresenceo!gastflcmatrgnancy 2 Dosage should be reduced in patrents wrth moderate to seYere renal tnsutftciency 3 tnpatrentswrthnormalrenatlunctronanduncomptrcatedhepatrcdystunctron, thedrspositionolnrzatrdmerssrmrlartothatrnnormalsubjects Laboratory Tests - False·posrtrve tests lor urobrlmogen wrth Mullrstrx" may occur dunng therapy Drug lnteractrons - No mteracllons have been observed w1th theophyllme, chlordiazepoxide. lorazepam. lidoca1ne, phenytom. or warfarin Axid does not mh1b1t the cytochrome P-450 enzyme system therefore. drug mteract10ns mediated by mhtbiiiOnofhepatlcmetabollsmarenotexpectedtooccurlnpatientsglvenveryhlgh doses (3,900 mg) ol asp1r1n da1ly. mcreased serum salicylate levels were seen when n1zattdme. 150 mg b1d. was admm1stered concurren!ly. Carcmogenes1s. Mutagenes1s, lmparrment of Fertr!J/y - A two-year oral carcmogeniclty study mrats w1th doses as h1gh as 500 mg/kg/day (about 80 t1mes the recommendeddallytherapeutlcdose) showednoevidenceotacarcmogen,ceftect Therewasadose-related mcreasem thedens1ty olenterochromafttn-like(ECL)cetls mthegastricoxyntrcmucosa lnatwo-yearstudylnmlce.therewasnoevidenceota carcmogemc effect 1n male m1ce. although hyperplastic nodules of the liver were mcreased mthe hrgh-dose males as compared w1lh placebo Female mrce g1ven the hrgh dose ol Axrd (2.000 mg/kg/day, aDout 330 trmes the human dose) showed margmallystatiSIIcallysiQnlficantJncreases,nhepatlccarcrnomaandhepat,cnodularhyperplaslawlthnonumeflcatlncreaseseenmanyoftheotherdosegroups The rateothepallccarcmomarntheh,gh-doseanimalswaswlthmthehiSioricatcontrol limits seen tor the stram ot m1ce used The female m1ce were g1ven adose larger than the max1mum tolerated dose. as md1cated by excess1ve (30%) we1ght decrement as comparedwlthconcurrentcontrolsandevldence ot mild liver mrury(transamrnase elevatiOns) Theoccurrerceotamargmaltmdlngathlghdoseonlylnan,malsg,ven an excessrveand somewhat hepatotoxrc dose, w1th no ev1dence of a cafCinogen1c eftect1n rats male m1ce, and female m1ce {g1ven up to 360 mg/kg/day. about 60 t1mes lhehumandose).andanegatlvemutagenrCI!ybatteryarenotconslderedevldenceof a carc1nogen1c potentral for Ax1d Ax1d was not mutage~1c 1n a battery of tests per!ormed to evaluate 1ts potent1al genetrc toxrc1ty. inctudmg bacterial mutatiOn tests, unscheduled DNA syntheSIS SISler chroma!id exchange fTlOuse ly·mphoma assay. chromosome aberratron tests, andam1cronucteustest In a two-generat1on. per1rata1 and postnatal ferlrt1ty study 1n rats. doses o' mzat1d1ne up to 650 mg/kg/day produced no adverse effects on the reproductive pertormanceofparentalammalsortheaprogeny Pregnancy~ Teratogemc Effects~ Pregnancy Category C ~Oral reproductiOn stud1eS1n ratsatdosesupto30011fTlesthehumandoseandln0utchBelted rabbitS at doses up to55!imesthehumafldoserevealednoevldenceof lmpalredfertllltyor teratogenic ettect but at a aose eqUivalent to 300 trmes the human dose. treated rabbltshadabortlons.decreasednumberofllveletuses.anddepressedletatwelghts On Intravenous admml2.000 IUtL The 1nc1dence of elevated liver enzymes overallandelevatronsotuptothreetrmestheupperlimltolnormat.however.dldnot SIQnlllcantly diller from that m placebo pat1ents All abnormalities were revrrsrble atterdlscontmuatlon oiAx1d Cardiovascular- In clrn1cal pharmacology stud1es. short ep1sodes of asymptomatlcventflculartachycardlaoccurredrntwolndJvldualsadmlnlsteredAxld andinthreeuntreatedsubtects CNS- Rare cases of reversrble mental contus1on have been reported Endocnne~ Climcat pharmacology studtes and controlled cltnicat tnals showed noevJdenceo!artllandrogenlcactlvltydueto n1zat1dlfle Impotence and decreased lib1do were reported w1th equal frequency by patients on nizatidme and those on placebo Gynecomastia has been reported rarely HematologiC - Fatal thrombocytopema was reported m a patient treated wtth n1zatldme and another Hrreceptor antagontst ThiS pat1ent had previOusly experienced thrombocytopemawhlletakmg other drugs Rare cases ot thrombocytopenic purpurahavebeenreported Integumental-Sweating and urt1cafla were reported S1gnrl1cantly more frequently m mzat1d1ne- than 111 placebo-treated pat1ents Rash and exloliat1ve dermat1t1s were also reported HypersenstttVJ/y~As wrth other Hrreceptor antagontsls. rare cases of anaphylaxIS followmg ntzatidmeadmmtstratiOn have been reported Becausecross-sens111vtty amongthlsclasshasbeenobserved.Hrreceptorantagon,stsshouldnotbeadmlnIStered to those w1tha hrstury ot hypersensitivity to these agents Rareep1sodes of hypersensitivity reacttons (eg, bronchospasm. laryngeal edema. rash and eosmophilia)havebeenreported. Other~ Hyperur1cem1a u~assoc1ated wrth gout or nephrolithiaSIS was reported tosmophllia.tever.andnausearelatedtonlzatidrnehavebeenreported Overdosage: Overdoses of Axtd have been reported rar~ly II overdosage occurs act1vated charcoal. emes1s, or lavage should be considered along w1th cl1mca1 mon1tormgand supporlivetherapy Renal dialysiS tor tour to SIX hours mcreased ptasmaclearancebyapproxlmately84% PV 2097 AMP [032389] Additional information available to the profess1on on request
products that prevent nucleic acid synthesis. 5-Fluoroura.cil blocks the methylation reaction of deoxyuridylic acid to thymidylic acid, thereby interfering with the synthesis of DNA and, to a lesser extent, with the formation of RNA. Because both DNA and RNA are essential for cell growth and division, the use of 5-fluoroura.cil creates a marked thymine deficiency in rapidly growing cells. Figure 11 shows cell death in the lips and oral cavity caused by thymine deficiency. The patient had been given 5-fluoroura.cil for treatment of adenocarcinoma of the lung. Summary
Cancer often causes malnutrition and specific vitamin and protein deficiencies. Chemotherapy also causes deficiencies by promoting anorexia, stomatitis, and alimentary
tract disturbances. Antimetabolite drugs in particular inhibit synthesis of essential vitamins, pwines, and pyrimidines. Because vitamin levels in the blood are often nondiagnostic, nutritional deficiency is identified almost exclusively on the basis of clinical signs and symptoms and the patient's response to therapy. Signs and symptoms of cachexia and hypoalbuminemia are common in patients with advanced cancer. Deficiencies of vitamins B1 , B2, and K and of niacin, folic acid, and thymine also may result from chemotherapy. Nutritional deficiencies are chemically correctable; however, the tumor must be eradicated to relieve cachexia. RJJI Address for correspondence: Samuel Dreizen, DDS, MD, Department of Oral Oncology, University of Texas Dental Branch, PO Box 20068, Houston, TX 77225.
Ref........,..
1. Falke RM. Nutrttional therapy in advanced cancer: setting reallstic goals. Postgrad Med 1985;78(1):83·90 2. Schein PS, MacdonaldJS, Walen C, et al. Nutrttional compllcatlons of cancer and Its treatment. Semln Oncoll975;2{4):337 47 3. Shl1a ME. Nutrttional problems induced by cancer. Med Clln North Am 1979;83(5):1()()9..25 4. Ohnama T, Holland JF. Nutrttional consequences of cancer chemotherapy and Immunotherapy. Cancer Res 1977:37(7 l't 2):2395-406 5. BrenDan MF. Nutrttional support of the cancer patient. In: DeVIta VT Jr. Hellman S. Rosenberg SA, eds. Cancer. prtnctples and practice of oncol~. Phlladelphla: JB Lippincott, 1982:162840 6. Theologl.des A. Cancer cachexia. Cancer 1979:43(5
Suppl):2004-12 7. Herbert V. Follc acid deficiency in man. Vitam Horm 1968;26:525-38 8. Pineo GF. Effects of nutrtent deficiencies in man: vttamtn K. in: Rechctgl M Jr, ed. Effect of nutrttlonal deficiencies in man. Vol3. Boca Raton, FL: CRC Press, 1978:133·5 (CRC handbook sertes in nutrttion and food. Section E-Nutrttional disorders) 9. Nb:on DW, Heymdeld SB, Cohen AE, et al. Protein-calorte undernutrttion in hospitaltzed cancer patients. Am J Med 1980;68{5):683·90 10. Waldmann TA, Broder S. Strober W. Protein· losing enteropathies in maltgnancy. Ann NY Acad Set 1974;230:306-17
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EFFECTS OF CANCER CHEMOTHERAPY • VOL 87/NO 1/JANUARY 1990/POSTGRADUATE MEDICINE
ISSN: 0032-5481 (Print) 1941-9260 (Online) Journal homepage: http://www.tandfonline.com/loi/ipgm20
Nutritional deficiencies in patients receiving cancer chemotherapy Samuel Dreizen DDS, MD, Kenneth B. McCredie MB, ChB, Michael J. Keating MB, BS & Borje S. Andersson MD, PhD To cite this article: Samuel Dreizen DDS, MD, Kenneth B. McCredie MB, ChB, Michael J. Keating MB, BS & Borje S. Andersson MD, PhD (1990) Nutritional deficiencies in patients receiving cancer chemotherapy, Postgraduate Medicine, 87:1, 163-170, DOI: 10.1080/00325481.1990.11704531 To link to this article: http://dx.doi.org/10.1080/00325481.1990.11704531
Published online: 17 May 2016.
Submit your article to this journal
View related articles
Citing articles: 4 View citing articles
Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=ipgm20 Download by: [La Trobe University]
Date: 30 May 2016, At: 18:32
CME credit article
Nutritional deficiencies in patients receiving cancer chemotherapy Samuel Dreizen, DDS, MD Kenneth B. McCredie, MB, ChB Michael J. Keating, MB, BS Borje S. Andersson, MD, PhD
Downloaded by [La Trobe University] at 18:32 30 May 2016
Preview Cancer and cancer chemotherapy often have such a profound impact on a patient's nutritional status that malnutrition becomes a major cause of morbidity and mortality. However, most nutritional deficiencies are chemically correctable. This article details the clinical presentations and treatment of various nutritional deficiencies in cancer patients who received chemotherapy at the University of Texas M. D. Anderson Hospital and Tumor Institute, Houston, during the past two decades. Maintenance of nutritional health in patients receiving treatment for widespread cancer can be difficult if not impossible. Despite the advent of sophisticated and well-tolerated methods of total parenteral alimentation. the nutritional status of most cancer patients receiving chemotherapy still ranges from subnormal to extremely precarious. The pivotal factor in each case is the vector of forces that contribute to the patient's nutritional status. These diverse forces are unique to the individual, and many patients are protected from cancer-related malnutrition while others have gross manifestations of one or more nutritional deficiencies. However, if treatment is knowledgeable and the patient's condition is still reversible, chemical correction of specific nutritional deficiency states is possible (figure l ).
Effects of advanced cancer Patients with advanced cancer have an elevated caloric expendi-
ture. increased protein catabolism. negative nitrogen balance, and a high rate of breakdown of body fat stores. 1 The degree of anorexia and weight loss parallels the extent of the cancer and is compounded by diminished or perverted senses of taste and smell. 2 Some tumors secrete potent pharmaceutical agents, including hormones. peptides, kinins. and prostaglandins, which produce systemic effects that impinge on nutritional status. 3 Other tumors create local effects that contribute to fluid and electrolyte disturbances, hypoalbuminemia. anemia, and decreased levels of vitamins and minerals in serum and tissue. 4
Effects of chemotherapy Chemotherapy is a prime contributor to inanition in cancer patients. Nearly all drugs used in cancer therapy promote anorexia. stomatitis. and alimentary tract disturbances. The effects vary. depending on type and
combination of drugs given, duration of treatment. rates of metabolism, and individual susceptibility. Any patient receiving chemotherapy who stays in the hospital for longer than 15 days and who is unable to ingest at least 1,000 calories/day is a candidate for enteral or parenteral nutritional support. 5 Reports of the debilitating effects of malnutrition in patients receiving cancer chemotherapy have focused largely on cachexia, a complex metabolic problem of uncertain etiology that affects 33% to 67% of patients with advanced cancer. lt is characterized clinically by anorexia, early satiety, weight loss, wasting. and weakness. Loss of body fat and body protein is significant. Other findings include anemia. electrolyte aberrations, hormonal dysfunction, and increased basal metabolism and energy consumption. Cachectic patients appear chronically ill and emaciated and have atrophic, shiny skin that hangs in loose folds; reduced muscle mass accentuates the underlying bony prominences (figure 2). Only complete tumor removal reverses cachexia. 6 Specific nutritional deficiencies occur in cancer patients who are treated with antimetabolites. which act as competitive inhibitors of the utilization of essential vitamins. purines, and pyrimicontinued
VOL87/NO 1/JANUARY 1990/POSTGRADUATE MEDICINE • EFFECTS OF CANCER CHEMOTHERAPY
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Gross lesions that reflect a specific nutritional deficiency may appear when antimetabolites used to treat cancer kill rapidly dividing normal cells.
Figure 1. Patient with acute lymphocytic leukemia. a. Glossitis caused by mixed niacin-folate deficiency. b. Disappearance of glossitis after treatment.
dines. The aim is to create nutritional disruptions that prevent DNA, RNA. andjor protein synthesis, thereby impeding the replication of malignant cells. Because antimetabolites cannot distinguish between cancer cells and rapidly dividing normal cells, the number of normal cells killed is often sufficient to evoke gross lesions that reflect a specific nutritional deficiency.
Specific deficiencies Diagnosis of a specific nutritional deficiency in patients undergoing cancer chemotherapy is based almost exclusively on recognition of clinical signs and symptoms and on the patient's response to a precise, potent, and prolonged therapeutic trial. Vitamin levels in the blood are often nondiagnostic in such cases. VITAMIN B, DEFICIENCY-Vitamin B1 deficiency may be a complication of any disease or treat-
164
ment that restricts food intake andjor promotes severe and
recurrent vomiting. Clinically, vitamin B1 deficiency manifests as a type of beriberi: dry, wet, cardiac, or mixed. The major common component is peripheral neuritis. In addition, each type is distinguished by its predominant signs and symptoms. For example, edema is characteristic of wet beriberi, and the cardinal signs of cardiac failure are pathognomonic of cardiac beriberi. Figure 3 shows manifestations of wet beriberi that developed in a patient being treated for chronic myeloblastic leukemia in blastic crisis. The patient reported heaviness, weakness, and paresthesias of the legs accompanied by bilateral pedal edema, bilateral calf tenderness on pressure, and exaggerated bilateral deep tendon reflexes at the knees and ankles. All manifestations disappeared within a week after initiation
Figure 2. Cachexia in patient with metastatic carcinoma of the ovary.
of daily intravenous administration of 15 mg of thiamine hydrochloride. VITAMIN 13, DEFICIENCY-Vitamin B2 deficiency of any origin decreases the level of flavin coenzymes in tissues and organs. Many different riboflavincontaining coenzymes have been identified, and all participate as catalysts in cellular respiration through the transfer of hydrogen by alternate oxidation and reduction. The signs of ariboflavinosis appear in the borderline between the skin and mucous membranes. The lips are a prime target site. Bilateral angular cheilosis affects the commissures in a radial fashion, and vertical striations and denudation at the line of closure characterize the remainder of the lips. Angular cheilosis starts as a pallor followed by superficial transverse fissuring, maceration, exu-
EFFECTS OF CANCER CHEMOTHERAPY • VOL 87/NO 1/JANUARY 1990/POSTGRADUATE MEDICINE
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The characteristic dermatitis of pellagra, which is caused by niacin deficiency, can be induced by the anorectic complications of chemotherapy.
dation, and superinfection. Bilateral angular cheilosis and cheilitis in a patient receiving treatment for oat cell carcinoma of the lung is shown in figure 4. These lesions cleared rapidly after oral administration of 10 mg of riboflavin in divided doses twice daily. NIACIN DEFICIENCY-Disturbances of tryptophan-niacin metabolism are conducive to the development of pellagra. Classically, pellagra has been associated with maize-eating populations. Sporadic cases have been reported in chronic alcoholics and in persons with organic diseases that Interfere with ingestion, absorption, assimilation, andjor utilization of niacin and tryptophan. Dermatitis is the characteristic manifestation of pellagra; diarrhea and dementia may or may not be present. The dermatitis is bilateral and symmetric and commonly occurs on extensor surfaces of the extremities, face, and neck. A notable feature is the sharp demarcation from aqjointng unaffected skin. The skin lesions start as erythema, which darkens and becomes scaly, dry, and hyperpigmented before desquamating to disclose a smooth, shiny, depigmented epidermis. Figure 5 shows pellagrous skin lesions on the feet and legs of a patient who was given chemo-
Samuel Drelzen, DDS, MD Kenneth a. McCredie, Ma, Cha Mlchaei.J, Keating, Ma, as aorje S. Andersson, MD, PhD Dr Dreizen (right) is professor and chairman, department of oral oncology, University of Texas Health Science Center at Houston, Dental Branch. Dr McCredie (second from right) is professor of medicine and internist, department of hematology, and chief, leukemia service; Dr Keating (left) is professor of medicine, internist, and chief of clinical studies, department of hematology; and Dr Andersson (second from left) is assistant professor and associate internist, department of hematology, University of Texas M. D. Anderson Hospital and Tumor Institute, Houston
therapy for a poorly differentiated nodular lymphoma. The dermal changes disappeared after oral administration of 50 mg of niacinamide three times a day. FOLIC ACID DEFICIENCY-Folic acid is essential to the synthesis of DNA and thus is important in cell growth and reproduction. A member of the B vitamin group, it is the nutritionally essential
precursor of a large number of compounds that act as coenzymes in one-carbon transfer reactions. 7 To become metabolically active, folic acid must be reduced to tetrahydrofolic acid by the enzyme folic acid reductase. Methotrexate, a folic acid antagonist, is an extremely potent inhibitor of the reductase reaction. continued
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Vitamin K deficiency occurs in patients with severe malnutrition, intestinal malabsorption, or obstructive jaundice and during long-term treatment with some antibiotics.
Figure 4. Bilateral angular cheilosis caused
Figure 5. Pellagrous dermatitis of legs in
by vitamin 8 2 deficiency in patient with oat cell carcinoma of the lung.
patient with poorly differentiated nodular lymphoma.
Figure 6. Cheilitis caused by folic acid deficiency in patient with acute lymphocytic leukemia.
Figure 7. Stomatitis caused by folic acid deficiency in patient with oat cell carcinoma of the lung.
Figure 8. Ecchymoses caused by vitamin K deficiency in patient with oat cell carcinoma of the lung.
Figure 9. Gingival and labial bleeding
Figure 10. Pitting edema of legs caused by
caused by vitamin K deficiency in patient with acute lymphocytic leukemia.
protein deficiency in patient with ulcerative carcinoma of the ampulla.
Figure 11. Stomatitis caused by thymine deficiency in patient with adenocarcinoma of the lung.
Figure 3. Wet beriberi in patient with chronic myelocytic leukemia in blastic crisis.
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More than 80o/o of cancer patients in one study had a reduced level of serum albumin.
Folic acid deficiency results in megaloblastic dysplasia of cells in the bone marrow and the alimentary tract and culminates in macrocytic anemia, leukopenia, and a denudative, ulcerative, atrophic stomatitis. A spruelike pharyngitis, gastroenteritis, and proctitis malabsorption syndrome also develops in patients with folic acid deficiency. The devastation produced by treatment with methotrexate is shown in the lips of a patient with acute lymphocytic leukemia (figure 6) and in the mouth of a patient with oat cell carcinoma of the lungs (figure 7). Mucosal lesions are excruciatingly painful and readily superinfected. However, they are responsive to treatment with 10 mg!M2 of leucovorin calcium (Wellcovorin) given orally or intravenously every 6 hours until the methotrexate level in the serum is less than
w-sfM. VITAMIN K DEFICIENCY-The
only known biologic activity of vitamin K is in production of the so-called vitamin K-dependent coagulation factors in the liver, notably factor U (prothrombin), factor vn (proconvertin), factor IX (Christmas factor), and factor X (Stuart-Prowerfactor). 8 A normal diet provides an adequate amount of vitamin K, which is supplemented by endogenous vitamin K produced by bacteria in the distal small bowel and colon. Vitamin K deficiency
occurs in patients with severe malnutrition, intestinal malabsorption, or obstructive jaundice and in cases oflong-term treatment with antibiotics such as moxalactam disodium (Maxam) that are active against the intestinal flora andjor compete with vitamin K for intestinal absorption sites. Vitamin K deficiency leads to a pronounced bleeding tendency. Figure 8 shows skin ecchymoses in a patient with oat cell carcinoma of the lung, and figure 9 shows bleeding from the oral mucous membranes in a patient with acute lymphocytic leukemia. Both patients were given moxalactam for concomitant infections while hospitalized for chemotherapy. Other common manifestations of vitamin K deficiency include hematuria and postoperative bleeding. Muscle hematomas, intracranial hemorrhages, and submucosal intestinal hemorrhages occur less frequently. The effects of vitamin K deficiency can be reversed by intravenous administration of 20 to 50 mgofvitamin K1 oxide (phytonadione [AquaMEPHYTON]). Severe cases require fresh frozen plasma or a concentrate of vitaminK-dependent coagulation factors. HYPOPROTEINEMIA-More
than 80% of cancer patients have a reduced serum albumin concentration. 9 The decline is pro-
gressive and is caused mainly by decreased albumin synthesis. In some patients with neoplastic lesions, protein-losing enteropathy may be an important cause of the hypoalbuminemia. Proteinlosing enteropathy is suggested by the presence of a short albumin survival time and an increased fractional catabolic rate for albumin. 10 The characteristic clinical feature of hypoproteinemia, regardless of cause, is edema. Marked pitting edema in the legs of a patient with ulcerative carcinoma of the ampulla who also had anasarca is shown in figure 10. The most effective therapy for protein-losing enteropathy is (1) removal of the tumor by surgery, radiotherapy, or chemotherapy and (2) intravenous administration of albumin (Albuminar, Buminate, Plasbumin) in amounts sufficient to eliminate the deficit. THYMINE DEFICIENCY-Defi-
ciency of thymine, a pyrimidine base, often results from treatment with antimetabolites. Pyrimidine and purine bases and their nucleosides are essential for the synthesis of DNA, RNA, and certain coenzymes. Structurally related analogues of these nucleic acid precursors (eg, 5-fluorouracil [Adrucil] and 6-mercaptopurine [Purinethol), which act as antimetabolites and are incorporated in biosynthetic pathways) manufacture fraudulent intermediate continued on page 170
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AXID®
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nizatrdmecapsutes Briel Summary. ConsuH lhe package literature lor complete information. Indications and Usage: I ActiVe duodenal ulcer- for up to erght weeks ot treatment. Most patrents heat wrthm tour weeks 2. Maintenance therapy- for heated duodenal ulcer patients at areduced dosage ofl50mgh.s TheconsequencesoltherapywrthAxrdlorlongerthanoneyeararenot known Contraindication: Known hypersensrtrvrty to the drug. Use wrth cautron rn patients wrth hypersensrtrvrtyto otherHrreceptorantagonrsts Precautions: Generai- I Symptomatrc response to nrzatrdrne therapy does not precludethepresenceo!gastflcmatrgnancy 2 Dosage should be reduced in patrents wrth moderate to seYere renal tnsutftciency 3 tnpatrentswrthnormalrenatlunctronanduncomptrcatedhepatrcdystunctron, thedrspositionolnrzatrdmerssrmrlartothatrnnormalsubjects Laboratory Tests - False·posrtrve tests lor urobrlmogen wrth Mullrstrx" may occur dunng therapy Drug lnteractrons - No mteracllons have been observed w1th theophyllme, chlordiazepoxide. lorazepam. lidoca1ne, phenytom. or warfarin Axid does not mh1b1t the cytochrome P-450 enzyme system therefore. drug mteract10ns mediated by mhtbiiiOnofhepatlcmetabollsmarenotexpectedtooccurlnpatientsglvenveryhlgh doses (3,900 mg) ol asp1r1n da1ly. mcreased serum salicylate levels were seen when n1zattdme. 150 mg b1d. was admm1stered concurren!ly. Carcmogenes1s. Mutagenes1s, lmparrment of Fertr!J/y - A two-year oral carcmogeniclty study mrats w1th doses as h1gh as 500 mg/kg/day (about 80 t1mes the recommendeddallytherapeutlcdose) showednoevidenceotacarcmogen,ceftect Therewasadose-related mcreasem thedens1ty olenterochromafttn-like(ECL)cetls mthegastricoxyntrcmucosa lnatwo-yearstudylnmlce.therewasnoevidenceota carcmogemc effect 1n male m1ce. although hyperplastic nodules of the liver were mcreased mthe hrgh-dose males as compared w1lh placebo Female mrce g1ven the hrgh dose ol Axrd (2.000 mg/kg/day, aDout 330 trmes the human dose) showed margmallystatiSIIcallysiQnlficantJncreases,nhepatlccarcrnomaandhepat,cnodularhyperplaslawlthnonumeflcatlncreaseseenmanyoftheotherdosegroups The rateothepallccarcmomarntheh,gh-doseanimalswaswlthmthehiSioricatcontrol limits seen tor the stram ot m1ce used The female m1ce were g1ven adose larger than the max1mum tolerated dose. as md1cated by excess1ve (30%) we1ght decrement as comparedwlthconcurrentcontrolsandevldence ot mild liver mrury(transamrnase elevatiOns) Theoccurrerceotamargmaltmdlngathlghdoseonlylnan,malsg,ven an excessrveand somewhat hepatotoxrc dose, w1th no ev1dence of a cafCinogen1c eftect1n rats male m1ce, and female m1ce {g1ven up to 360 mg/kg/day. about 60 t1mes lhehumandose).andanegatlvemutagenrCI!ybatteryarenotconslderedevldenceof a carc1nogen1c potentral for Ax1d Ax1d was not mutage~1c 1n a battery of tests per!ormed to evaluate 1ts potent1al genetrc toxrc1ty. inctudmg bacterial mutatiOn tests, unscheduled DNA syntheSIS SISler chroma!id exchange fTlOuse ly·mphoma assay. chromosome aberratron tests, andam1cronucteustest In a two-generat1on. per1rata1 and postnatal ferlrt1ty study 1n rats. doses o' mzat1d1ne up to 650 mg/kg/day produced no adverse effects on the reproductive pertormanceofparentalammalsortheaprogeny Pregnancy~ Teratogemc Effects~ Pregnancy Category C ~Oral reproductiOn stud1eS1n ratsatdosesupto30011fTlesthehumandoseandln0utchBelted rabbitS at doses up to55!imesthehumafldoserevealednoevldenceof lmpalredfertllltyor teratogenic ettect but at a aose eqUivalent to 300 trmes the human dose. treated rabbltshadabortlons.decreasednumberofllveletuses.anddepressedletatwelghts On Intravenous admml2.000 IUtL The 1nc1dence of elevated liver enzymes overallandelevatronsotuptothreetrmestheupperlimltolnormat.however.dldnot SIQnlllcantly diller from that m placebo pat1ents All abnormalities were revrrsrble atterdlscontmuatlon oiAx1d Cardiovascular- In clrn1cal pharmacology stud1es. short ep1sodes of asymptomatlcventflculartachycardlaoccurredrntwolndJvldualsadmlnlsteredAxld andinthreeuntreatedsubtects CNS- Rare cases of reversrble mental contus1on have been reported Endocnne~ Climcat pharmacology studtes and controlled cltnicat tnals showed noevJdenceo!artllandrogenlcactlvltydueto n1zat1dlfle Impotence and decreased lib1do were reported w1th equal frequency by patients on nizatidme and those on placebo Gynecomastia has been reported rarely HematologiC - Fatal thrombocytopema was reported m a patient treated wtth n1zatldme and another Hrreceptor antagontst ThiS pat1ent had previOusly experienced thrombocytopemawhlletakmg other drugs Rare cases ot thrombocytopenic purpurahavebeenreported Integumental-Sweating and urt1cafla were reported S1gnrl1cantly more frequently m mzat1d1ne- than 111 placebo-treated pat1ents Rash and exloliat1ve dermat1t1s were also reported HypersenstttVJ/y~As wrth other Hrreceptor antagontsls. rare cases of anaphylaxIS followmg ntzatidmeadmmtstratiOn have been reported Becausecross-sens111vtty amongthlsclasshasbeenobserved.Hrreceptorantagon,stsshouldnotbeadmlnIStered to those w1tha hrstury ot hypersensitivity to these agents Rareep1sodes of hypersensitivity reacttons (eg, bronchospasm. laryngeal edema. rash and eosmophilia)havebeenreported. Other~ Hyperur1cem1a u~assoc1ated wrth gout or nephrolithiaSIS was reported tosmophllia.tever.andnausearelatedtonlzatidrnehavebeenreported Overdosage: Overdoses of Axtd have been reported rar~ly II overdosage occurs act1vated charcoal. emes1s, or lavage should be considered along w1th cl1mca1 mon1tormgand supporlivetherapy Renal dialysiS tor tour to SIX hours mcreased ptasmaclearancebyapproxlmately84% PV 2097 AMP [032389] Additional information available to the profess1on on request
products that prevent nucleic acid synthesis. 5-Fluoroura.cil blocks the methylation reaction of deoxyuridylic acid to thymidylic acid, thereby interfering with the synthesis of DNA and, to a lesser extent, with the formation of RNA. Because both DNA and RNA are essential for cell growth and division, the use of 5-fluoroura.cil creates a marked thymine deficiency in rapidly growing cells. Figure 11 shows cell death in the lips and oral cavity caused by thymine deficiency. The patient had been given 5-fluoroura.cil for treatment of adenocarcinoma of the lung. Summary
Cancer often causes malnutrition and specific vitamin and protein deficiencies. Chemotherapy also causes deficiencies by promoting anorexia, stomatitis, and alimentary
tract disturbances. Antimetabolite drugs in particular inhibit synthesis of essential vitamins, pwines, and pyrimidines. Because vitamin levels in the blood are often nondiagnostic, nutritional deficiency is identified almost exclusively on the basis of clinical signs and symptoms and the patient's response to therapy. Signs and symptoms of cachexia and hypoalbuminemia are common in patients with advanced cancer. Deficiencies of vitamins B1 , B2, and K and of niacin, folic acid, and thymine also may result from chemotherapy. Nutritional deficiencies are chemically correctable; however, the tumor must be eradicated to relieve cachexia. RJJI Address for correspondence: Samuel Dreizen, DDS, MD, Department of Oral Oncology, University of Texas Dental Branch, PO Box 20068, Houston, TX 77225.
Ref........,..
1. Falke RM. Nutrttional therapy in advanced cancer: setting reallstic goals. Postgrad Med 1985;78(1):83·90 2. Schein PS, MacdonaldJS, Walen C, et al. Nutrttional compllcatlons of cancer and Its treatment. Semln Oncoll975;2{4):337 47 3. Shl1a ME. Nutrttional problems induced by cancer. Med Clln North Am 1979;83(5):1()()9..25 4. Ohnama T, Holland JF. Nutrttional consequences of cancer chemotherapy and Immunotherapy. Cancer Res 1977:37(7 l't 2):2395-406 5. BrenDan MF. Nutrttional support of the cancer patient. In: DeVIta VT Jr. Hellman S. Rosenberg SA, eds. Cancer. prtnctples and practice of oncol~. Phlladelphla: JB Lippincott, 1982:162840 6. Theologl.des A. Cancer cachexia. Cancer 1979:43(5
Suppl):2004-12 7. Herbert V. Follc acid deficiency in man. Vitam Horm 1968;26:525-38 8. Pineo GF. Effects of nutrtent deficiencies in man: vttamtn K. in: Rechctgl M Jr, ed. Effect of nutrttlonal deficiencies in man. Vol3. Boca Raton, FL: CRC Press, 1978:133·5 (CRC handbook sertes in nutrttion and food. Section E-Nutrttional disorders) 9. Nb:on DW, Heymdeld SB, Cohen AE, et al. Protein-calorte undernutrttion in hospitaltzed cancer patients. Am J Med 1980;68{5):683·90 10. Waldmann TA, Broder S. Strober W. Protein· losing enteropathies in maltgnancy. Ann NY Acad Set 1974;230:306-17
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